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/Title (Cascade Screening for Familial Hypercholesterolemia \(FH\) � PLOS Currents Evidence on Genomic Tests)
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15.000 709.302 577.500 28.698 re W n
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BT 15.000 718.042 Td /F2 21.0 Tf  [(Cascade Screening for Familial Hypercholesterolemia \(FH\))] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 700.036 Td /F3 9.8 Tf  [(July 1, 2011)] TJ ET
BT 26.250 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 688.195 Td /F1 9.8 Tf  [(Ren�e M. Ned)] TJ ET
0.271 0.267 0.267 rg
BT 99.950 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 105.371 688.195 Td /F1 9.8 Tf  [(Eric Sijbrands)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 676.290 Td /F1 9.8 Tf  [(Ned RM, Sijbrands E. Cascade Screening for Familial Hypercholesterolemia \(FH\). PLOS Currents Evidence on Genomic )] TJ ET
BT 549.659 676.290 Td /F1 9.8 Tf  [(Tests. )] TJ ET
BT 26.250 664.386 Td /F1 9.8 Tf  [(2011 Jul 1 . Edition 1. doi: 10.1371/currents.RRN1238.)] TJ ET
q
15.000 30.448 577.500 631.556 re W n
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BT 26.250 635.283 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 615.329 Td /F1 9.8 Tf  [(Familial hypercholesterolemia \(FH\) is an autosomal dominant disorder characterized by abnormally high concentrations of low-)] TJ ET
BT 26.250 603.424 Td /F1 9.8 Tf  [(density lipoprotein \(LDL\) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease )] TJ ET
BT 26.250 591.519 Td /F1 9.8 Tf  [(\(CHD\) and death. FH is one of the most common inherited disorders and the most common one known to cause premature )] TJ ET
BT 26.250 579.615 Td /F1 9.8 Tf  [(CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in )] TJ ET
BT 26.250 567.710 Td /F1 9.8 Tf  [(either the LDL receptor \(LDLR\), apolipoprotein B \(APOB\), or proprotein convertase subtilisin/kexin type 9 \(PCSK9\) genes. )] TJ ET
BT 26.250 555.805 Td /F1 9.8 Tf  [(Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or )] TJ ET
BT 26.250 543.900 Td /F1 9.8 Tf  [(inadequately treated.)] TJ ET
BT 26.250 524.496 Td /F1 9.8 Tf  [(Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family )] TJ ET
BT 26.250 512.591 Td /F1 9.8 Tf  [(tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of )] TJ ET
BT 26.250 500.686 Td /F1 9.8 Tf  [(close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The )] TJ ET
BT 26.250 488.781 Td /F1 9.8 Tf  [(ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis )] TJ ET
BT 26.250 476.877 Td /F1 9.8 Tf  [(and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of )] TJ ET
BT 26.250 464.972 Td /F1 9.8 Tf  [(cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing \(if the )] TJ ET
BT 26.250 453.067 Td /F1 9.8 Tf  [(disease-causing mutation has been identified\).)] TJ ET
BT 26.250 433.662 Td /F4 9.8 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 414.258 Td /F1 9.8 Tf  [(A patient has been diagnosed with familial hypercholesterolemia \(FH\). Use cascade screening to identify biological relatives of )] TJ ET
BT 26.250 402.353 Td /F1 9.8 Tf  [(the patient who are also affected with the disorder.)] TJ ET
BT 26.250 382.948 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 363.543 Td /F1 9.8 Tf  [(Identifying and contacting biological relatives of a person diagnosed with FH \(the index case\) and then systematically testing )] TJ ET
BT 26.250 351.639 Td /F1 9.8 Tf  [(these relatives \(first-, second-, third-, etc. degree\) using a combination of serum LDL cholesterol concentration measurements )] TJ ET
BT 26.250 339.734 Td /F1 9.8 Tf  [(and a variety of mutation detection or screening assays for mutations in the )] TJ ET
BT 353.031 339.734 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 377.952 339.734 Td /F1 9.8 Tf  [( , )] TJ ET
BT 386.084 339.734 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 413.179 339.734 Td /F1 9.8 Tf  [( , or )] TJ ET
BT 432.689 339.734 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 464.659 339.734 Td /F1 9.8 Tf  [( genes.)] TJ ET
BT 26.250 320.329 Td /F4 9.8 Tf  [(Public Health Importance)] TJ ET
BT 26.250 300.924 Td /F1 9.8 Tf  [(FH is one of the most common inherited disorders, with an estimated worldwide prevalence of 1 in 500 \(0.2%\), though the )] TJ ET
BT 26.250 289.020 Td /F1 9.8 Tf  [(frequency is considerably higher in some populations because of a founder effect )] TJ ET
0.267 0.267 0.267 rg
BT 379.054 289.020 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 389.896 289.020 Td /F1 9.8 Tf  [( . This estimate corresponds to )] TJ ET
BT 26.250 277.115 Td /F1 9.8 Tf  [(approximately 13 million people worldwide and ~600,000 in the United States who have FH. The overwhelming majority of )] TJ ET
BT 26.250 265.210 Td /F1 9.8 Tf  [(affected persons are heterozygotes \(those who have inherited one disease-causing mutation\). A smaller number of patients \(~1 )] TJ ET
BT 26.250 253.305 Td /F1 9.8 Tf  [(in 200,000\) are compound heterozygotes \(who have inherited one copy each of two different mutations\), while persons with )] TJ ET
BT 26.250 241.401 Td /F1 9.8 Tf  [(homozygous FH \(who have inherited two identical disease-causing mutations\) are extremely rare \(~1 in 1 million\).)] TJ ET
BT 26.250 221.996 Td /F1 9.8 Tf  [(The elevated serum cholesterol levels associated with FH lead to a greatly elevated risk for coronary heart disease \(CHD\) and )] TJ ET
BT 26.250 210.091 Td /F1 9.8 Tf  [(death )] TJ ET
0.267 0.267 0.267 rg
BT 53.355 210.091 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 64.197 210.091 Td /F1 9.8 Tf  [( . In fact, for those with heterozygous FH, the cumulative risk for CHD is greater than 50% in men by the age of 50 and )] TJ ET
BT 26.250 198.186 Td /F1 9.8 Tf  [(at least 30% in women by the age of 60 )] TJ ET
0.267 0.267 0.267 rg
BT 199.683 198.186 Td /F1 9.8 Tf  [([3])] TJ ET
BT 210.525 198.186 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 221.367 198.186 Td /F1 9.8 Tf  [( . Persons with homozygous FH manifest an even more severe form of the )] TJ ET
BT 26.250 186.282 Td /F1 9.8 Tf  [(disorder. There is variation in the onset and severity of atherosclerotic disease in persons with FH, since environmental, )] TJ ET
BT 26.250 174.377 Td /F1 9.8 Tf  [(metabolic, and genetic factors influence the clinical phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 296.676 174.377 Td /F1 9.8 Tf  [([2])] TJ ET
BT 307.518 174.377 Td /F1 9.8 Tf  [([5])] TJ ET
BT 318.360 174.377 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 329.202 174.377 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 154.972 Td /F1 9.8 Tf  [(Overall, estimates are that fewer than 25% of persons with FH are diagnosed; and the majority remain untreated or improperly )] TJ ET
BT 26.250 143.067 Td /F1 9.8 Tf  [(treated )] TJ ET
0.267 0.267 0.267 rg
BT 59.312 143.067 Td /F1 9.8 Tf  [([7])] TJ ET
BT 70.154 143.067 Td /F1 9.8 Tf  [([8])] TJ ET
BT 80.996 143.067 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 91.838 143.067 Td /F1 9.8 Tf  [( , though there are no recent estimates available for the United States )] TJ ET
0.267 0.267 0.267 rg
BT 394.790 143.067 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 411.053 143.067 Td /F1 9.8 Tf  [( . \(Persons may be treated for high )] TJ ET
BT 26.250 131.163 Td /F1 9.8 Tf  [(cholesterol without knowledge that they have FH. False-negative diagnoses can result in inadequate treatment, while false-)] TJ ET
BT 26.250 119.258 Td /F1 9.8 Tf  [(positive diagnoses may result in overtreatment.\))] TJ ET
BT 26.250 99.853 Td /F1 9.8 Tf  [(Because of the high prevalence of FH among family members \(50% of first-degree relatives of heterozygotes are affected\), )] TJ ET
BT 26.250 87.948 Td /F1 9.8 Tf  [(cascade screening has been shown to be a cost-effective method of identifying people with FH )] TJ ET
0.267 0.267 0.267 rg
BT 437.037 87.948 Td /F1 9.8 Tf  [([3])] TJ ET
BT 447.879 87.948 Td /F1 9.8 Tf  [([11])] TJ ET
BT 464.142 87.948 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 480.405 87.948 Td /F1 9.8 Tf  [( . Early detection and )] TJ ET
BT 26.250 76.044 Td /F1 9.8 Tf  [(treatment with statins have been shown to reduce morbidity and mortality among those with heterozygous FH )] TJ ET
0.267 0.267 0.267 rg
BT 500.412 76.044 Td /F1 9.8 Tf  [([3])] TJ ET
BT 511.254 76.044 Td /F1 9.8 Tf  [([4])] TJ ET
BT 522.096 76.044 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 538.359 76.044 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 56.639 Td /F1 9.8 Tf  [(Despite an international effort to improve the identification and management of patients with FH )] TJ ET
0.267 0.267 0.267 rg
BT 439.738 56.639 Td /F1 9.8 Tf  [([7])] TJ ET
BT 450.580 56.639 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 461.422 56.639 Td /F1 9.8 Tf  [( , few countries have )] TJ ET
BT 26.250 44.734 Td /F1 9.8 Tf  [(established large-scale programs to systematically determine the FH status of relatives of these patients )] TJ ET
0.267 0.267 0.267 rg
BT 477.636 44.734 Td /F1 9.8 Tf  [([13])] TJ ET
BT 493.899 44.734 Td /F1 9.8 Tf  [([14])] TJ ET
BT 510.162 44.734 Td /F1 9.8 Tf  [([15])] TJ ET
BT 526.425 44.734 Td /F1 9.8 Tf  [([16])] TJ ET
BT 542.688 44.734 Td /F1 9.8 Tf  [([17])] TJ ET
BT 558.951 44.734 Td /F1 9.8 Tf  [([18])] TJ ET
BT 26.250 32.829 Td /F1 9.8 Tf  [([19])] TJ ET
BT 42.513 32.829 Td /F1 9.8 Tf  [([20])] TJ ET
BT 58.776 32.829 Td /F1 9.8 Tf  [([21])] TJ ET
Q
q
15.000 709.302 577.500 28.698 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Cascade Screening for Familial Hypercholesterolemia \(FH\))] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 700.036 Td /F3 9.8 Tf  [(July 1, 2011)] TJ ET
BT 26.250 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 688.195 Td /F1 9.8 Tf  [(Ren�e M. Ned)] TJ ET
0.271 0.267 0.267 rg
BT 99.950 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 105.371 688.195 Td /F1 9.8 Tf  [(Eric Sijbrands)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 676.290 Td /F1 9.8 Tf  [(Ned RM, Sijbrands E. Cascade Screening for Familial Hypercholesterolemia \(FH\). PLOS Currents Evidence on Genomic )] TJ ET
BT 549.659 676.290 Td /F1 9.8 Tf  [(Tests. )] TJ ET
BT 26.250 664.386 Td /F1 9.8 Tf  [(2011 Jul 1 . Edition 1. doi: 10.1371/currents.RRN1238.)] TJ ET
q
15.000 30.448 577.500 631.556 re W n
0.271 0.267 0.267 rg
BT 26.250 635.283 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 615.329 Td /F1 9.8 Tf  [(Familial hypercholesterolemia \(FH\) is an autosomal dominant disorder characterized by abnormally high concentrations of low-)] TJ ET
BT 26.250 603.424 Td /F1 9.8 Tf  [(density lipoprotein \(LDL\) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease )] TJ ET
BT 26.250 591.519 Td /F1 9.8 Tf  [(\(CHD\) and death. FH is one of the most common inherited disorders and the most common one known to cause premature )] TJ ET
BT 26.250 579.615 Td /F1 9.8 Tf  [(CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in )] TJ ET
BT 26.250 567.710 Td /F1 9.8 Tf  [(either the LDL receptor \(LDLR\), apolipoprotein B \(APOB\), or proprotein convertase subtilisin/kexin type 9 \(PCSK9\) genes. )] TJ ET
BT 26.250 555.805 Td /F1 9.8 Tf  [(Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or )] TJ ET
BT 26.250 543.900 Td /F1 9.8 Tf  [(inadequately treated.)] TJ ET
BT 26.250 524.496 Td /F1 9.8 Tf  [(Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family )] TJ ET
BT 26.250 512.591 Td /F1 9.8 Tf  [(tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of )] TJ ET
BT 26.250 500.686 Td /F1 9.8 Tf  [(close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The )] TJ ET
BT 26.250 488.781 Td /F1 9.8 Tf  [(ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis )] TJ ET
BT 26.250 476.877 Td /F1 9.8 Tf  [(and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of )] TJ ET
BT 26.250 464.972 Td /F1 9.8 Tf  [(cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing \(if the )] TJ ET
BT 26.250 453.067 Td /F1 9.8 Tf  [(disease-causing mutation has been identified\).)] TJ ET
BT 26.250 433.662 Td /F4 9.8 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 414.258 Td /F1 9.8 Tf  [(A patient has been diagnosed with familial hypercholesterolemia \(FH\). Use cascade screening to identify biological relatives of )] TJ ET
BT 26.250 402.353 Td /F1 9.8 Tf  [(the patient who are also affected with the disorder.)] TJ ET
BT 26.250 382.948 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 363.543 Td /F1 9.8 Tf  [(Identifying and contacting biological relatives of a person diagnosed with FH \(the index case\) and then systematically testing )] TJ ET
BT 26.250 351.639 Td /F1 9.8 Tf  [(these relatives \(first-, second-, third-, etc. degree\) using a combination of serum LDL cholesterol concentration measurements )] TJ ET
BT 26.250 339.734 Td /F1 9.8 Tf  [(and a variety of mutation detection or screening assays for mutations in the )] TJ ET
BT 353.031 339.734 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 377.952 339.734 Td /F1 9.8 Tf  [( , )] TJ ET
BT 386.084 339.734 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 413.179 339.734 Td /F1 9.8 Tf  [( , or )] TJ ET
BT 432.689 339.734 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 464.659 339.734 Td /F1 9.8 Tf  [( genes.)] TJ ET
BT 26.250 320.329 Td /F4 9.8 Tf  [(Public Health Importance)] TJ ET
BT 26.250 300.924 Td /F1 9.8 Tf  [(FH is one of the most common inherited disorders, with an estimated worldwide prevalence of 1 in 500 \(0.2%\), though the )] TJ ET
BT 26.250 289.020 Td /F1 9.8 Tf  [(frequency is considerably higher in some populations because of a founder effect )] TJ ET
0.267 0.267 0.267 rg
BT 379.054 289.020 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 389.896 289.020 Td /F1 9.8 Tf  [( . This estimate corresponds to )] TJ ET
BT 26.250 277.115 Td /F1 9.8 Tf  [(approximately 13 million people worldwide and ~600,000 in the United States who have FH. The overwhelming majority of )] TJ ET
BT 26.250 265.210 Td /F1 9.8 Tf  [(affected persons are heterozygotes \(those who have inherited one disease-causing mutation\). A smaller number of patients \(~1 )] TJ ET
BT 26.250 253.305 Td /F1 9.8 Tf  [(in 200,000\) are compound heterozygotes \(who have inherited one copy each of two different mutations\), while persons with )] TJ ET
BT 26.250 241.401 Td /F1 9.8 Tf  [(homozygous FH \(who have inherited two identical disease-causing mutations\) are extremely rare \(~1 in 1 million\).)] TJ ET
BT 26.250 221.996 Td /F1 9.8 Tf  [(The elevated serum cholesterol levels associated with FH lead to a greatly elevated risk for coronary heart disease \(CHD\) and )] TJ ET
BT 26.250 210.091 Td /F1 9.8 Tf  [(death )] TJ ET
0.267 0.267 0.267 rg
BT 53.355 210.091 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 64.197 210.091 Td /F1 9.8 Tf  [( . In fact, for those with heterozygous FH, the cumulative risk for CHD is greater than 50% in men by the age of 50 and )] TJ ET
BT 26.250 198.186 Td /F1 9.8 Tf  [(at least 30% in women by the age of 60 )] TJ ET
0.267 0.267 0.267 rg
BT 199.683 198.186 Td /F1 9.8 Tf  [([3])] TJ ET
BT 210.525 198.186 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 221.367 198.186 Td /F1 9.8 Tf  [( . Persons with homozygous FH manifest an even more severe form of the )] TJ ET
BT 26.250 186.282 Td /F1 9.8 Tf  [(disorder. There is variation in the onset and severity of atherosclerotic disease in persons with FH, since environmental, )] TJ ET
BT 26.250 174.377 Td /F1 9.8 Tf  [(metabolic, and genetic factors influence the clinical phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 296.676 174.377 Td /F1 9.8 Tf  [([2])] TJ ET
BT 307.518 174.377 Td /F1 9.8 Tf  [([5])] TJ ET
BT 318.360 174.377 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 329.202 174.377 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 154.972 Td /F1 9.8 Tf  [(Overall, estimates are that fewer than 25% of persons with FH are diagnosed; and the majority remain untreated or improperly )] TJ ET
BT 26.250 143.067 Td /F1 9.8 Tf  [(treated )] TJ ET
0.267 0.267 0.267 rg
BT 59.312 143.067 Td /F1 9.8 Tf  [([7])] TJ ET
BT 70.154 143.067 Td /F1 9.8 Tf  [([8])] TJ ET
BT 80.996 143.067 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 91.838 143.067 Td /F1 9.8 Tf  [( , though there are no recent estimates available for the United States )] TJ ET
0.267 0.267 0.267 rg
BT 394.790 143.067 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 411.053 143.067 Td /F1 9.8 Tf  [( . \(Persons may be treated for high )] TJ ET
BT 26.250 131.163 Td /F1 9.8 Tf  [(cholesterol without knowledge that they have FH. False-negative diagnoses can result in inadequate treatment, while false-)] TJ ET
BT 26.250 119.258 Td /F1 9.8 Tf  [(positive diagnoses may result in overtreatment.\))] TJ ET
BT 26.250 99.853 Td /F1 9.8 Tf  [(Because of the high prevalence of FH among family members \(50% of first-degree relatives of heterozygotes are affected\), )] TJ ET
BT 26.250 87.948 Td /F1 9.8 Tf  [(cascade screening has been shown to be a cost-effective method of identifying people with FH )] TJ ET
0.267 0.267 0.267 rg
BT 437.037 87.948 Td /F1 9.8 Tf  [([3])] TJ ET
BT 447.879 87.948 Td /F1 9.8 Tf  [([11])] TJ ET
BT 464.142 87.948 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 480.405 87.948 Td /F1 9.8 Tf  [( . Early detection and )] TJ ET
BT 26.250 76.044 Td /F1 9.8 Tf  [(treatment with statins have been shown to reduce morbidity and mortality among those with heterozygous FH )] TJ ET
0.267 0.267 0.267 rg
BT 500.412 76.044 Td /F1 9.8 Tf  [([3])] TJ ET
BT 511.254 76.044 Td /F1 9.8 Tf  [([4])] TJ ET
BT 522.096 76.044 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 538.359 76.044 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 56.639 Td /F1 9.8 Tf  [(Despite an international effort to improve the identification and management of patients with FH )] TJ ET
0.267 0.267 0.267 rg
BT 439.738 56.639 Td /F1 9.8 Tf  [([7])] TJ ET
BT 450.580 56.639 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 461.422 56.639 Td /F1 9.8 Tf  [( , few countries have )] TJ ET
BT 26.250 44.734 Td /F1 9.8 Tf  [(established large-scale programs to systematically determine the FH status of relatives of these patients )] TJ ET
0.267 0.267 0.267 rg
BT 477.636 44.734 Td /F1 9.8 Tf  [([13])] TJ ET
BT 493.899 44.734 Td /F1 9.8 Tf  [([14])] TJ ET
BT 510.162 44.734 Td /F1 9.8 Tf  [([15])] TJ ET
BT 526.425 44.734 Td /F1 9.8 Tf  [([16])] TJ ET
BT 542.688 44.734 Td /F1 9.8 Tf  [([17])] TJ ET
BT 558.951 44.734 Td /F1 9.8 Tf  [([18])] TJ ET
BT 26.250 32.829 Td /F1 9.8 Tf  [([19])] TJ ET
BT 42.513 32.829 Td /F1 9.8 Tf  [([20])] TJ ET
BT 58.776 32.829 Td /F1 9.8 Tf  [([21])] TJ ET
Q
q
15.000 709.302 577.500 28.698 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Cascade Screening for Familial Hypercholesterolemia \(FH\))] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 700.036 Td /F3 9.8 Tf  [(July 1, 2011)] TJ ET
BT 26.250 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 688.195 Td /F1 9.8 Tf  [(Ren�e M. Ned)] TJ ET
0.271 0.267 0.267 rg
BT 99.950 688.195 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 105.371 688.195 Td /F1 9.8 Tf  [(Eric Sijbrands)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 676.290 Td /F1 9.8 Tf  [(Ned RM, Sijbrands E. Cascade Screening for Familial Hypercholesterolemia \(FH\). PLOS Currents Evidence on Genomic )] TJ ET
BT 549.659 676.290 Td /F1 9.8 Tf  [(Tests. )] TJ ET
BT 26.250 664.386 Td /F1 9.8 Tf  [(2011 Jul 1 . Edition 1. doi: 10.1371/currents.RRN1238.)] TJ ET
q
15.000 30.448 577.500 631.556 re W n
0.271 0.267 0.267 rg
BT 26.250 635.283 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 615.329 Td /F1 9.8 Tf  [(Familial hypercholesterolemia \(FH\) is an autosomal dominant disorder characterized by abnormally high concentrations of low-)] TJ ET
BT 26.250 603.424 Td /F1 9.8 Tf  [(density lipoprotein \(LDL\) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease )] TJ ET
BT 26.250 591.519 Td /F1 9.8 Tf  [(\(CHD\) and death. FH is one of the most common inherited disorders and the most common one known to cause premature )] TJ ET
BT 26.250 579.615 Td /F1 9.8 Tf  [(CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in )] TJ ET
BT 26.250 567.710 Td /F1 9.8 Tf  [(either the LDL receptor \(LDLR\), apolipoprotein B \(APOB\), or proprotein convertase subtilisin/kexin type 9 \(PCSK9\) genes. )] TJ ET
BT 26.250 555.805 Td /F1 9.8 Tf  [(Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or )] TJ ET
BT 26.250 543.900 Td /F1 9.8 Tf  [(inadequately treated.)] TJ ET
BT 26.250 524.496 Td /F1 9.8 Tf  [(Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family )] TJ ET
BT 26.250 512.591 Td /F1 9.8 Tf  [(tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of )] TJ ET
BT 26.250 500.686 Td /F1 9.8 Tf  [(close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The )] TJ ET
BT 26.250 488.781 Td /F1 9.8 Tf  [(ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis )] TJ ET
BT 26.250 476.877 Td /F1 9.8 Tf  [(and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of )] TJ ET
BT 26.250 464.972 Td /F1 9.8 Tf  [(cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing \(if the )] TJ ET
BT 26.250 453.067 Td /F1 9.8 Tf  [(disease-causing mutation has been identified\).)] TJ ET
BT 26.250 433.662 Td /F4 9.8 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 414.258 Td /F1 9.8 Tf  [(A patient has been diagnosed with familial hypercholesterolemia \(FH\). Use cascade screening to identify biological relatives of )] TJ ET
BT 26.250 402.353 Td /F1 9.8 Tf  [(the patient who are also affected with the disorder.)] TJ ET
BT 26.250 382.948 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 363.543 Td /F1 9.8 Tf  [(Identifying and contacting biological relatives of a person diagnosed with FH \(the index case\) and then systematically testing )] TJ ET
BT 26.250 351.639 Td /F1 9.8 Tf  [(these relatives \(first-, second-, third-, etc. degree\) using a combination of serum LDL cholesterol concentration measurements )] TJ ET
BT 26.250 339.734 Td /F1 9.8 Tf  [(and a variety of mutation detection or screening assays for mutations in the )] TJ ET
BT 353.031 339.734 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 377.952 339.734 Td /F1 9.8 Tf  [( , )] TJ ET
BT 386.084 339.734 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 413.179 339.734 Td /F1 9.8 Tf  [( , or )] TJ ET
BT 432.689 339.734 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 464.659 339.734 Td /F1 9.8 Tf  [( genes.)] TJ ET
BT 26.250 320.329 Td /F4 9.8 Tf  [(Public Health Importance)] TJ ET
BT 26.250 300.924 Td /F1 9.8 Tf  [(FH is one of the most common inherited disorders, with an estimated worldwide prevalence of 1 in 500 \(0.2%\), though the )] TJ ET
BT 26.250 289.020 Td /F1 9.8 Tf  [(frequency is considerably higher in some populations because of a founder effect )] TJ ET
0.267 0.267 0.267 rg
BT 379.054 289.020 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 389.896 289.020 Td /F1 9.8 Tf  [( . This estimate corresponds to )] TJ ET
BT 26.250 277.115 Td /F1 9.8 Tf  [(approximately 13 million people worldwide and ~600,000 in the United States who have FH. The overwhelming majority of )] TJ ET
BT 26.250 265.210 Td /F1 9.8 Tf  [(affected persons are heterozygotes \(those who have inherited one disease-causing mutation\). A smaller number of patients \(~1 )] TJ ET
BT 26.250 253.305 Td /F1 9.8 Tf  [(in 200,000\) are compound heterozygotes \(who have inherited one copy each of two different mutations\), while persons with )] TJ ET
BT 26.250 241.401 Td /F1 9.8 Tf  [(homozygous FH \(who have inherited two identical disease-causing mutations\) are extremely rare \(~1 in 1 million\).)] TJ ET
BT 26.250 221.996 Td /F1 9.8 Tf  [(The elevated serum cholesterol levels associated with FH lead to a greatly elevated risk for coronary heart disease \(CHD\) and )] TJ ET
BT 26.250 210.091 Td /F1 9.8 Tf  [(death )] TJ ET
0.267 0.267 0.267 rg
BT 53.355 210.091 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 64.197 210.091 Td /F1 9.8 Tf  [( . In fact, for those with heterozygous FH, the cumulative risk for CHD is greater than 50% in men by the age of 50 and )] TJ ET
BT 26.250 198.186 Td /F1 9.8 Tf  [(at least 30% in women by the age of 60 )] TJ ET
0.267 0.267 0.267 rg
BT 199.683 198.186 Td /F1 9.8 Tf  [([3])] TJ ET
BT 210.525 198.186 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 221.367 198.186 Td /F1 9.8 Tf  [( . Persons with homozygous FH manifest an even more severe form of the )] TJ ET
BT 26.250 186.282 Td /F1 9.8 Tf  [(disorder. There is variation in the onset and severity of atherosclerotic disease in persons with FH, since environmental, )] TJ ET
BT 26.250 174.377 Td /F1 9.8 Tf  [(metabolic, and genetic factors influence the clinical phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 296.676 174.377 Td /F1 9.8 Tf  [([2])] TJ ET
BT 307.518 174.377 Td /F1 9.8 Tf  [([5])] TJ ET
BT 318.360 174.377 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 329.202 174.377 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 154.972 Td /F1 9.8 Tf  [(Overall, estimates are that fewer than 25% of persons with FH are diagnosed; and the majority remain untreated or improperly )] TJ ET
BT 26.250 143.067 Td /F1 9.8 Tf  [(treated )] TJ ET
0.267 0.267 0.267 rg
BT 59.312 143.067 Td /F1 9.8 Tf  [([7])] TJ ET
BT 70.154 143.067 Td /F1 9.8 Tf  [([8])] TJ ET
BT 80.996 143.067 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 91.838 143.067 Td /F1 9.8 Tf  [( , though there are no recent estimates available for the United States )] TJ ET
0.267 0.267 0.267 rg
BT 394.790 143.067 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 411.053 143.067 Td /F1 9.8 Tf  [( . \(Persons may be treated for high )] TJ ET
BT 26.250 131.163 Td /F1 9.8 Tf  [(cholesterol without knowledge that they have FH. False-negative diagnoses can result in inadequate treatment, while false-)] TJ ET
BT 26.250 119.258 Td /F1 9.8 Tf  [(positive diagnoses may result in overtreatment.\))] TJ ET
BT 26.250 99.853 Td /F1 9.8 Tf  [(Because of the high prevalence of FH among family members \(50% of first-degree relatives of heterozygotes are affected\), )] TJ ET
BT 26.250 87.948 Td /F1 9.8 Tf  [(cascade screening has been shown to be a cost-effective method of identifying people with FH )] TJ ET
0.267 0.267 0.267 rg
BT 437.037 87.948 Td /F1 9.8 Tf  [([3])] TJ ET
BT 447.879 87.948 Td /F1 9.8 Tf  [([11])] TJ ET
BT 464.142 87.948 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 480.405 87.948 Td /F1 9.8 Tf  [( . Early detection and )] TJ ET
BT 26.250 76.044 Td /F1 9.8 Tf  [(treatment with statins have been shown to reduce morbidity and mortality among those with heterozygous FH )] TJ ET
0.267 0.267 0.267 rg
BT 500.412 76.044 Td /F1 9.8 Tf  [([3])] TJ ET
BT 511.254 76.044 Td /F1 9.8 Tf  [([4])] TJ ET
BT 522.096 76.044 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 538.359 76.044 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 56.639 Td /F1 9.8 Tf  [(Despite an international effort to improve the identification and management of patients with FH )] TJ ET
0.267 0.267 0.267 rg
BT 439.738 56.639 Td /F1 9.8 Tf  [([7])] TJ ET
BT 450.580 56.639 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 461.422 56.639 Td /F1 9.8 Tf  [( , few countries have )] TJ ET
BT 26.250 44.734 Td /F1 9.8 Tf  [(established large-scale programs to systematically determine the FH status of relatives of these patients )] TJ ET
0.267 0.267 0.267 rg
BT 477.636 44.734 Td /F1 9.8 Tf  [([13])] TJ ET
BT 493.899 44.734 Td /F1 9.8 Tf  [([14])] TJ ET
BT 510.162 44.734 Td /F1 9.8 Tf  [([15])] TJ ET
BT 526.425 44.734 Td /F1 9.8 Tf  [([16])] TJ ET
BT 542.688 44.734 Td /F1 9.8 Tf  [([17])] TJ ET
BT 558.951 44.734 Td /F1 9.8 Tf  [([18])] TJ ET
BT 26.250 32.829 Td /F1 9.8 Tf  [([19])] TJ ET
BT 42.513 32.829 Td /F1 9.8 Tf  [([20])] TJ ET
BT 58.776 32.829 Td /F1 9.8 Tf  [([21])] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(1)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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q
15.000 32.417 577.500 744.583 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 748.071 Td /F4 9.8 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 728.667 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 709.262 Td /F1 9.8 Tf  [(A systematic evidence review )] TJ ET
0.267 0.267 0.267 rg
BT 156.832 709.262 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 167.674 709.262 Td /F1 9.8 Tf  [( was conducted during the formulation of guidelines from the National Institute for Health and )] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(Clinical Excellence \(NICE\) in the United Kingdom \(see next subsection\).)] TJ ET
BT 26.250 677.952 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 658.548 Td /F1 9.8 Tf  [(The NICE guidelines on the identification and management of FH recommend cascade screening using a combination of )] TJ ET
BT 26.250 646.643 Td /F1 9.8 Tf  [(genetic testing and LDL cholesterol concentration measurement �is recommended to identify affected relatives of those index )] TJ ET
BT 26.250 634.738 Td /F1 9.8 Tf  [(individuals with a clinical diagnosis of FH. This should include at least the first- and second- and, when possible, third-degree )] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(biological relatives� )] TJ ET
0.267 0.267 0.267 rg
BT 111.855 622.833 Td /F1 9.8 Tf  [([3])] TJ ET
BT 122.697 622.833 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 138.960 622.833 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 603.429 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 584.024 Td /F1 9.8 Tf  [(Until recently, there were no formal clinical guidelines or recommendations in the United States regarding cascade screening for )] TJ ET
BT 26.250 572.119 Td /F1 9.8 Tf  [(FH. However, in June 2011, the National Lipid Association issued guidelines strongly encouraging the use of cascade screening )] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(to identify persons with FH )] TJ ET
0.267 0.267 0.267 rg
BT 143.835 560.214 Td /F1 9.8 Tf  [([23])] TJ ET
BT 160.098 560.214 Td /F1 9.8 Tf  [([24])] TJ ET
0.271 0.267 0.267 rg
BT 176.361 560.214 Td /F1 9.8 Tf  [( . Also in June 2011, the European Society of Cardiology and the European Atherosclerosis )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(Society jointly issued guidelines recommending family screening \(and cascade screening, if resources are available\) for the )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(detection of FH )] TJ ET
0.267 0.267 0.267 rg
BT 95.075 536.405 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 111.338 536.405 Td /F1 9.8 Tf  [( . In both of these guidelines, cascade screening does not necessarily incorporate genetic testing, though )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(DNA analysis is noted as being useful in some cases )] TJ ET
0.267 0.267 0.267 rg
BT 257.637 524.500 Td /F1 9.8 Tf  [([23])] TJ ET
BT 273.900 524.500 Td /F1 9.8 Tf  [([24])] TJ ET
0.271 0.267 0.267 rg
BT 290.163 524.500 Td /F1 9.8 Tf  [( or is recommended whenever resources are available )] TJ ET
0.267 0.267 0.267 rg
BT 527.497 524.500 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 543.760 524.500 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 505.095 Td /F4 9.8 Tf  [(Evidence Overview)] TJ ET
BT 26.250 485.691 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 485.691 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 485.691 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the genomic markers of interest� mutations in the )] TJ ET
BT 515.008 485.691 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 539.929 485.691 Td /F1 9.8 Tf  [( , )] TJ ET
BT 548.060 485.691 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(, or )] TJ ET
BT 43.049 473.786 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 75.019 473.786 Td /F1 9.8 Tf  [(genes \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 457.349 m 
40.337 457.795 40.154 458.239 39.838 458.555 c
39.522 458.871 39.078 459.055 38.631 459.055 c
38.185 459.055 37.741 458.871 37.425 458.555 c
37.109 458.239 36.925 457.795 36.925 457.349 c
36.925 456.902 37.109 456.458 37.425 456.142 c
37.741 455.826 38.185 455.642 38.631 455.642 c
39.078 455.642 39.522 455.826 39.838 456.142 c
40.154 456.458 40.337 456.902 40.337 457.349 c f
BT 45.750 454.381 Td /F1 9.8 Tf  [(Mutations known to cause FH have been found in the LDL receptor )] TJ ET
BT 337.860 454.381 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 362.781 454.381 Td /F1 9.8 Tf  [(\), apolipoprotein B \()] TJ ET
BT 447.860 454.381 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 474.955 454.381 Td /F1 9.8 Tf  [(\), and proprotein )] TJ ET
BT 45.750 442.476 Td /F1 9.8 Tf  [(convertase subtilisin/kexin type 9 \()] TJ ET
BT 194.223 442.476 Td /F5 9.8 Tf  [(PCSK9\))] TJ ET
BT 229.440 442.476 Td /F1 9.8 Tf  [(genes. Several methods are currently used to identify sequence changes in )] TJ ET
BT 45.750 430.572 Td /F1 9.8 Tf  [(these genes )] TJ ET
0.267 0.267 0.267 rg
BT 101.578 430.572 Td /F1 9.8 Tf  [([3])] TJ ET
BT 112.421 430.572 Td /F1 9.8 Tf  [([26])] TJ ET
BT 128.684 430.572 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 144.947 430.572 Td /F1 9.8 Tf  [( ; and additional technologies are under development.)] TJ ET
40.337 410.385 m 
40.337 410.831 40.154 411.275 39.838 411.591 c
39.522 411.907 39.078 412.091 38.631 412.091 c
38.185 412.091 37.741 411.907 37.425 411.591 c
37.109 411.275 36.925 410.831 36.925 410.385 c
36.925 409.938 37.109 409.494 37.425 409.178 c
37.741 408.862 38.185 408.678 38.631 408.678 c
39.078 408.678 39.522 408.862 39.838 409.178 c
40.154 409.494 40.337 409.938 40.337 410.385 c f
BT 45.750 407.417 Td /F1 9.8 Tf  [(The analytic sensitivity and specificity of each DNA test for FH will depend on the particular mutations being assayed and )] TJ ET
BT 45.750 395.512 Td /F1 9.8 Tf  [(on the population\(s\) tested. \(Often, labs will initially test only for those mutations that are most prevalent in a particular )] TJ ET
BT 45.750 383.607 Td /F1 9.8 Tf  [(population.\))] TJ ET
40.337 363.420 m 
40.337 363.867 40.154 364.311 39.838 364.627 c
39.522 364.943 39.078 365.127 38.631 365.127 c
38.185 365.127 37.741 364.943 37.425 364.627 c
37.109 364.311 36.925 363.867 36.925 363.420 c
36.925 362.974 37.109 362.530 37.425 362.214 c
37.741 361.898 38.185 361.714 38.631 361.714 c
39.078 361.714 39.522 361.898 39.838 362.214 c
40.154 362.530 40.337 362.974 40.337 363.420 c f
BT 45.750 360.453 Td /F1 9.8 Tf  [(Because of the number of common polymorphisms that exist and because some scanning methods are not very efficient in )] TJ ET
BT 45.750 348.548 Td /F1 9.8 Tf  [(detecting large-scale genetic rearrangements, many diagnostic labs are switching to direct sequencing strategies to )] TJ ET
BT 45.750 336.643 Td /F1 9.8 Tf  [(improve the sensitivity of their mutation detection efforts )] TJ ET
0.267 0.267 0.267 rg
BT 289.061 336.643 Td /F1 9.8 Tf  [([26])] TJ ET
0.271 0.267 0.267 rg
BT 305.324 336.643 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 313.488 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 313.488 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 313.488 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying relatives of patients with FH \(predictive value\).)] TJ ET
40.337 297.051 m 
40.337 297.498 40.154 297.942 39.838 298.258 c
39.522 298.574 39.078 298.758 38.631 298.758 c
38.185 298.758 37.741 298.574 37.425 298.258 c
37.109 297.942 36.925 297.498 36.925 297.051 c
36.925 296.605 37.109 296.161 37.425 295.845 c
37.741 295.529 38.185 295.345 38.631 295.345 c
39.078 295.345 39.522 295.529 39.838 295.845 c
40.154 296.161 40.337 296.605 40.337 297.051 c f
BT 45.750 294.084 Td /F1 9.8 Tf  [(More than 1,000 mutations in the )] TJ ET
BT 190.996 294.084 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 215.917 294.084 Td /F1 9.8 Tf  [( gene have been identified in patients with FH )] TJ ET
0.267 0.267 0.267 rg
BT 415.899 294.084 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 432.162 294.084 Td /F1 9.8 Tf  [( ; and DNA testing on this gene )] TJ ET
BT 45.750 282.179 Td /F1 9.8 Tf  [(alone has been found to identify 70-80% of people with a definitive clinical diagnosis of FH and 20-30% of those whose )] TJ ET
BT 45.750 270.274 Td /F1 9.8 Tf  [(diagnosis is less certain )] TJ ET
0.267 0.267 0.267 rg
BT 151.411 270.274 Td /F1 9.8 Tf  [([3])] TJ ET
BT 162.253 270.274 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 178.516 270.274 Td /F1 9.8 Tf  [( . Researchers have estimated that mutations in the )] TJ ET
BT 403.955 270.274 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 431.050 270.274 Td /F1 9.8 Tf  [( and )] TJ ET
BT 452.735 270.274 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 484.705 270.274 Td /F1 9.8 Tf  [( genes account for )] TJ ET
BT 45.750 258.369 Td /F1 9.8 Tf  [(only about 5.5% and 1.5% of FH cases, respectively )] TJ ET
0.267 0.267 0.267 rg
BT 273.900 258.369 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 290.163 258.369 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 238.182 m 
40.337 238.629 40.154 239.073 39.838 239.389 c
39.522 239.705 39.078 239.889 38.631 239.889 c
38.185 239.889 37.741 239.705 37.425 239.389 c
37.109 239.073 36.925 238.629 36.925 238.182 c
36.925 237.736 37.109 237.292 37.425 236.976 c
37.741 236.660 38.185 236.476 38.631 236.476 c
39.078 236.476 39.522 236.660 39.838 236.976 c
40.154 237.292 40.337 237.736 40.337 238.182 c f
BT 45.750 235.215 Td /F1 9.8 Tf  [(Current DNA testing for FH is not 100% sensitive because the disorder may be caused by a mutation that is not assessed. )] TJ ET
BT 45.750 223.310 Td /F1 9.8 Tf  [(Therefore, )] TJ ET
BT 93.437 223.310 Td /F5 9.8 Tf  [(not)] TJ ET
BT 106.990 223.310 Td /F1 9.8 Tf  [( finding a mutation does not necessarily exclude a diagnosis of FH )] TJ ET
0.267 0.267 0.267 rg
BT 395.834 223.310 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 406.675 223.310 Td /F1 9.8 Tf  [( . Research has shown that ~15% of )] TJ ET
BT 45.750 211.405 Td /F1 9.8 Tf  [(people with FH do not have a mutation in their )] TJ ET
BT 247.351 211.405 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 272.272 211.405 Td /F1 9.8 Tf  [(, )] TJ ET
BT 277.693 211.405 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 304.788 211.405 Td /F1 9.8 Tf  [(, or )] TJ ET
BT 321.587 211.405 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 353.558 211.405 Td /F1 9.8 Tf  [(genes \(though reliable estimates range from 12% to )] TJ ET
BT 45.750 199.500 Td /F1 9.8 Tf  [(48%\) )] TJ ET
0.267 0.267 0.267 rg
BT 71.217 199.500 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 87.480 199.500 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 179.313 m 
40.337 179.760 40.154 180.204 39.838 180.520 c
39.522 180.836 39.078 181.020 38.631 181.020 c
38.185 181.020 37.741 180.836 37.425 180.520 c
37.109 180.204 36.925 179.760 36.925 179.313 c
36.925 178.867 37.109 178.423 37.425 178.107 c
37.741 177.791 38.185 177.607 38.631 177.607 c
39.078 177.607 39.522 177.791 39.838 178.107 c
40.154 178.423 40.337 178.867 40.337 179.313 c f
BT 45.750 176.346 Td /F1 9.8 Tf  [(Conversely, though mutation screening for FH is highly specific, it may produce false positives because some sequence )] TJ ET
BT 45.750 164.441 Td /F1 9.8 Tf  [(changes that are detected can be non-pathogenic )] TJ ET
0.267 0.267 0.267 rg
BT 263.097 164.441 Td /F1 9.8 Tf  [([26])] TJ ET
BT 279.360 164.441 Td /F1 9.8 Tf  [([27])] TJ ET
BT 295.623 164.441 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 311.886 164.441 Td /F1 9.8 Tf  [( . However, a false positive mutation will likely become )] TJ ET
BT 45.750 152.536 Td /F1 9.8 Tf  [(evident during cascade screening, since it should fail to consistently associate with the FH phenotype.)] TJ ET
40.337 132.349 m 
40.337 132.796 40.154 133.240 39.838 133.556 c
39.522 133.871 39.078 134.055 38.631 134.055 c
38.185 134.055 37.741 133.871 37.425 133.556 c
37.109 133.240 36.925 132.796 36.925 132.349 c
36.925 131.902 37.109 131.458 37.425 131.142 c
37.741 130.827 38.185 130.643 38.631 130.643 c
39.078 130.643 39.522 130.827 39.838 131.142 c
40.154 131.458 40.337 131.902 40.337 132.349 c f
BT 45.750 129.381 Td /F1 9.8 Tf  [(Since FH is a disease inherited in an autosomal dominant fashion, the identification of the true mutation responsible for the )] TJ ET
BT 45.750 117.477 Td /F1 9.8 Tf  [(disease in a family allows for the definitive diagnosis of biological relatives who have the mutation )] TJ ET
0.267 0.267 0.267 rg
BT 467.886 117.477 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 478.728 117.477 Td /F1 9.8 Tf  [( \(i.e., 100% positive )] TJ ET
BT 45.750 105.572 Td /F1 9.8 Tf  [(predictive value\).)] TJ ET
40.337 85.385 m 
40.337 85.831 40.154 86.275 39.838 86.591 c
39.522 86.907 39.078 87.091 38.631 87.091 c
38.185 87.091 37.741 86.907 37.425 86.591 c
37.109 86.275 36.925 85.831 36.925 85.385 c
36.925 84.938 37.109 84.494 37.425 84.178 c
37.741 83.862 38.185 83.679 38.631 83.679 c
39.078 83.679 39.522 83.862 39.838 84.178 c
40.154 84.494 40.337 84.938 40.337 85.385 c f
BT 45.750 82.417 Td /F1 9.8 Tf  [(If a familial FH mutation is not identified or if genetic testing is not available, relatives of an FH patient can be diagnosed )] TJ ET
BT 45.750 70.512 Td /F1 9.8 Tf  [(with the disorder on the basis of sex- and age-specific LDL cholesterol thresholds \(as recommended by NICE\) )] TJ ET
0.267 0.267 0.267 rg
BT 522.603 70.512 Td /F1 9.8 Tf  [([3])] TJ ET
BT 533.445 70.512 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 549.708 70.512 Td /F1 9.8 Tf  [( . )] TJ ET
BT 45.750 58.608 Td /F1 9.8 Tf  [(However, because of an overlap in LDL cholesterol levels between people with FH and those without, there is still )] TJ ET
BT 45.750 46.703 Td /F1 9.8 Tf  [(diagnostic uncertainty in over 15% of individuals )] TJ ET
0.267 0.267 0.267 rg
BT 256.009 46.703 Td /F1 9.8 Tf  [([3])] TJ ET
BT 266.851 46.703 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 283.114 46.703 Td /F1 9.8 Tf  [( . Relatives can also be diagnosed on the basis of specific clinical )] TJ ET
Q
q
15.000 32.417 577.500 744.583 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 748.071 Td /F4 9.8 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 728.667 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 709.262 Td /F1 9.8 Tf  [(A systematic evidence review )] TJ ET
0.267 0.267 0.267 rg
BT 156.832 709.262 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 167.674 709.262 Td /F1 9.8 Tf  [( was conducted during the formulation of guidelines from the National Institute for Health and )] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(Clinical Excellence \(NICE\) in the United Kingdom \(see next subsection\).)] TJ ET
BT 26.250 677.952 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 658.548 Td /F1 9.8 Tf  [(The NICE guidelines on the identification and management of FH recommend cascade screening using a combination of )] TJ ET
BT 26.250 646.643 Td /F1 9.8 Tf  [(genetic testing and LDL cholesterol concentration measurement �is recommended to identify affected relatives of those index )] TJ ET
BT 26.250 634.738 Td /F1 9.8 Tf  [(individuals with a clinical diagnosis of FH. This should include at least the first- and second- and, when possible, third-degree )] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(biological relatives� )] TJ ET
0.267 0.267 0.267 rg
BT 111.855 622.833 Td /F1 9.8 Tf  [([3])] TJ ET
BT 122.697 622.833 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 138.960 622.833 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 603.429 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 584.024 Td /F1 9.8 Tf  [(Until recently, there were no formal clinical guidelines or recommendations in the United States regarding cascade screening for )] TJ ET
BT 26.250 572.119 Td /F1 9.8 Tf  [(FH. However, in June 2011, the National Lipid Association issued guidelines strongly encouraging the use of cascade screening )] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(to identify persons with FH )] TJ ET
0.267 0.267 0.267 rg
BT 143.835 560.214 Td /F1 9.8 Tf  [([23])] TJ ET
BT 160.098 560.214 Td /F1 9.8 Tf  [([24])] TJ ET
0.271 0.267 0.267 rg
BT 176.361 560.214 Td /F1 9.8 Tf  [( . Also in June 2011, the European Society of Cardiology and the European Atherosclerosis )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(Society jointly issued guidelines recommending family screening \(and cascade screening, if resources are available\) for the )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(detection of FH )] TJ ET
0.267 0.267 0.267 rg
BT 95.075 536.405 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 111.338 536.405 Td /F1 9.8 Tf  [( . In both of these guidelines, cascade screening does not necessarily incorporate genetic testing, though )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(DNA analysis is noted as being useful in some cases )] TJ ET
0.267 0.267 0.267 rg
BT 257.637 524.500 Td /F1 9.8 Tf  [([23])] TJ ET
BT 273.900 524.500 Td /F1 9.8 Tf  [([24])] TJ ET
0.271 0.267 0.267 rg
BT 290.163 524.500 Td /F1 9.8 Tf  [( or is recommended whenever resources are available )] TJ ET
0.267 0.267 0.267 rg
BT 527.497 524.500 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 543.760 524.500 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 505.095 Td /F4 9.8 Tf  [(Evidence Overview)] TJ ET
BT 26.250 485.691 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 485.691 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 485.691 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the genomic markers of interest� mutations in the )] TJ ET
BT 515.008 485.691 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 539.929 485.691 Td /F1 9.8 Tf  [( , )] TJ ET
BT 548.060 485.691 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(, or )] TJ ET
BT 43.049 473.786 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 75.019 473.786 Td /F1 9.8 Tf  [(genes \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 457.349 m 
40.337 457.795 40.154 458.239 39.838 458.555 c
39.522 458.871 39.078 459.055 38.631 459.055 c
38.185 459.055 37.741 458.871 37.425 458.555 c
37.109 458.239 36.925 457.795 36.925 457.349 c
36.925 456.902 37.109 456.458 37.425 456.142 c
37.741 455.826 38.185 455.642 38.631 455.642 c
39.078 455.642 39.522 455.826 39.838 456.142 c
40.154 456.458 40.337 456.902 40.337 457.349 c f
BT 45.750 454.381 Td /F1 9.8 Tf  [(Mutations known to cause FH have been found in the LDL receptor )] TJ ET
BT 337.860 454.381 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 362.781 454.381 Td /F1 9.8 Tf  [(\), apolipoprotein B \()] TJ ET
BT 447.860 454.381 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 474.955 454.381 Td /F1 9.8 Tf  [(\), and proprotein )] TJ ET
BT 45.750 442.476 Td /F1 9.8 Tf  [(convertase subtilisin/kexin type 9 \()] TJ ET
BT 194.223 442.476 Td /F5 9.8 Tf  [(PCSK9\))] TJ ET
BT 229.440 442.476 Td /F1 9.8 Tf  [(genes. Several methods are currently used to identify sequence changes in )] TJ ET
BT 45.750 430.572 Td /F1 9.8 Tf  [(these genes )] TJ ET
0.267 0.267 0.267 rg
BT 101.578 430.572 Td /F1 9.8 Tf  [([3])] TJ ET
BT 112.421 430.572 Td /F1 9.8 Tf  [([26])] TJ ET
BT 128.684 430.572 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 144.947 430.572 Td /F1 9.8 Tf  [( ; and additional technologies are under development.)] TJ ET
40.337 410.385 m 
40.337 410.831 40.154 411.275 39.838 411.591 c
39.522 411.907 39.078 412.091 38.631 412.091 c
38.185 412.091 37.741 411.907 37.425 411.591 c
37.109 411.275 36.925 410.831 36.925 410.385 c
36.925 409.938 37.109 409.494 37.425 409.178 c
37.741 408.862 38.185 408.678 38.631 408.678 c
39.078 408.678 39.522 408.862 39.838 409.178 c
40.154 409.494 40.337 409.938 40.337 410.385 c f
BT 45.750 407.417 Td /F1 9.8 Tf  [(The analytic sensitivity and specificity of each DNA test for FH will depend on the particular mutations being assayed and )] TJ ET
BT 45.750 395.512 Td /F1 9.8 Tf  [(on the population\(s\) tested. \(Often, labs will initially test only for those mutations that are most prevalent in a particular )] TJ ET
BT 45.750 383.607 Td /F1 9.8 Tf  [(population.\))] TJ ET
40.337 363.420 m 
40.337 363.867 40.154 364.311 39.838 364.627 c
39.522 364.943 39.078 365.127 38.631 365.127 c
38.185 365.127 37.741 364.943 37.425 364.627 c
37.109 364.311 36.925 363.867 36.925 363.420 c
36.925 362.974 37.109 362.530 37.425 362.214 c
37.741 361.898 38.185 361.714 38.631 361.714 c
39.078 361.714 39.522 361.898 39.838 362.214 c
40.154 362.530 40.337 362.974 40.337 363.420 c f
BT 45.750 360.453 Td /F1 9.8 Tf  [(Because of the number of common polymorphisms that exist and because some scanning methods are not very efficient in )] TJ ET
BT 45.750 348.548 Td /F1 9.8 Tf  [(detecting large-scale genetic rearrangements, many diagnostic labs are switching to direct sequencing strategies to )] TJ ET
BT 45.750 336.643 Td /F1 9.8 Tf  [(improve the sensitivity of their mutation detection efforts )] TJ ET
0.267 0.267 0.267 rg
BT 289.061 336.643 Td /F1 9.8 Tf  [([26])] TJ ET
0.271 0.267 0.267 rg
BT 305.324 336.643 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 313.488 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 313.488 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 313.488 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying relatives of patients with FH \(predictive value\).)] TJ ET
40.337 297.051 m 
40.337 297.498 40.154 297.942 39.838 298.258 c
39.522 298.574 39.078 298.758 38.631 298.758 c
38.185 298.758 37.741 298.574 37.425 298.258 c
37.109 297.942 36.925 297.498 36.925 297.051 c
36.925 296.605 37.109 296.161 37.425 295.845 c
37.741 295.529 38.185 295.345 38.631 295.345 c
39.078 295.345 39.522 295.529 39.838 295.845 c
40.154 296.161 40.337 296.605 40.337 297.051 c f
BT 45.750 294.084 Td /F1 9.8 Tf  [(More than 1,000 mutations in the )] TJ ET
BT 190.996 294.084 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 215.917 294.084 Td /F1 9.8 Tf  [( gene have been identified in patients with FH )] TJ ET
0.267 0.267 0.267 rg
BT 415.899 294.084 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 432.162 294.084 Td /F1 9.8 Tf  [( ; and DNA testing on this gene )] TJ ET
BT 45.750 282.179 Td /F1 9.8 Tf  [(alone has been found to identify 70-80% of people with a definitive clinical diagnosis of FH and 20-30% of those whose )] TJ ET
BT 45.750 270.274 Td /F1 9.8 Tf  [(diagnosis is less certain )] TJ ET
0.267 0.267 0.267 rg
BT 151.411 270.274 Td /F1 9.8 Tf  [([3])] TJ ET
BT 162.253 270.274 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 178.516 270.274 Td /F1 9.8 Tf  [( . Researchers have estimated that mutations in the )] TJ ET
BT 403.955 270.274 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 431.050 270.274 Td /F1 9.8 Tf  [( and )] TJ ET
BT 452.735 270.274 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 484.705 270.274 Td /F1 9.8 Tf  [( genes account for )] TJ ET
BT 45.750 258.369 Td /F1 9.8 Tf  [(only about 5.5% and 1.5% of FH cases, respectively )] TJ ET
0.267 0.267 0.267 rg
BT 273.900 258.369 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 290.163 258.369 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 238.182 m 
40.337 238.629 40.154 239.073 39.838 239.389 c
39.522 239.705 39.078 239.889 38.631 239.889 c
38.185 239.889 37.741 239.705 37.425 239.389 c
37.109 239.073 36.925 238.629 36.925 238.182 c
36.925 237.736 37.109 237.292 37.425 236.976 c
37.741 236.660 38.185 236.476 38.631 236.476 c
39.078 236.476 39.522 236.660 39.838 236.976 c
40.154 237.292 40.337 237.736 40.337 238.182 c f
BT 45.750 235.215 Td /F1 9.8 Tf  [(Current DNA testing for FH is not 100% sensitive because the disorder may be caused by a mutation that is not assessed. )] TJ ET
BT 45.750 223.310 Td /F1 9.8 Tf  [(Therefore, )] TJ ET
BT 93.437 223.310 Td /F5 9.8 Tf  [(not)] TJ ET
BT 106.990 223.310 Td /F1 9.8 Tf  [( finding a mutation does not necessarily exclude a diagnosis of FH )] TJ ET
0.267 0.267 0.267 rg
BT 395.834 223.310 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 406.675 223.310 Td /F1 9.8 Tf  [( . Research has shown that ~15% of )] TJ ET
BT 45.750 211.405 Td /F1 9.8 Tf  [(people with FH do not have a mutation in their )] TJ ET
BT 247.351 211.405 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 272.272 211.405 Td /F1 9.8 Tf  [(, )] TJ ET
BT 277.693 211.405 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 304.788 211.405 Td /F1 9.8 Tf  [(, or )] TJ ET
BT 321.587 211.405 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 353.558 211.405 Td /F1 9.8 Tf  [(genes \(though reliable estimates range from 12% to )] TJ ET
BT 45.750 199.500 Td /F1 9.8 Tf  [(48%\) )] TJ ET
0.267 0.267 0.267 rg
BT 71.217 199.500 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 87.480 199.500 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 179.313 m 
40.337 179.760 40.154 180.204 39.838 180.520 c
39.522 180.836 39.078 181.020 38.631 181.020 c
38.185 181.020 37.741 180.836 37.425 180.520 c
37.109 180.204 36.925 179.760 36.925 179.313 c
36.925 178.867 37.109 178.423 37.425 178.107 c
37.741 177.791 38.185 177.607 38.631 177.607 c
39.078 177.607 39.522 177.791 39.838 178.107 c
40.154 178.423 40.337 178.867 40.337 179.313 c f
BT 45.750 176.346 Td /F1 9.8 Tf  [(Conversely, though mutation screening for FH is highly specific, it may produce false positives because some sequence )] TJ ET
BT 45.750 164.441 Td /F1 9.8 Tf  [(changes that are detected can be non-pathogenic )] TJ ET
0.267 0.267 0.267 rg
BT 263.097 164.441 Td /F1 9.8 Tf  [([26])] TJ ET
BT 279.360 164.441 Td /F1 9.8 Tf  [([27])] TJ ET
BT 295.623 164.441 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 311.886 164.441 Td /F1 9.8 Tf  [( . However, a false positive mutation will likely become )] TJ ET
BT 45.750 152.536 Td /F1 9.8 Tf  [(evident during cascade screening, since it should fail to consistently associate with the FH phenotype.)] TJ ET
40.337 132.349 m 
40.337 132.796 40.154 133.240 39.838 133.556 c
39.522 133.871 39.078 134.055 38.631 134.055 c
38.185 134.055 37.741 133.871 37.425 133.556 c
37.109 133.240 36.925 132.796 36.925 132.349 c
36.925 131.902 37.109 131.458 37.425 131.142 c
37.741 130.827 38.185 130.643 38.631 130.643 c
39.078 130.643 39.522 130.827 39.838 131.142 c
40.154 131.458 40.337 131.902 40.337 132.349 c f
BT 45.750 129.381 Td /F1 9.8 Tf  [(Since FH is a disease inherited in an autosomal dominant fashion, the identification of the true mutation responsible for the )] TJ ET
BT 45.750 117.477 Td /F1 9.8 Tf  [(disease in a family allows for the definitive diagnosis of biological relatives who have the mutation )] TJ ET
0.267 0.267 0.267 rg
BT 467.886 117.477 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 478.728 117.477 Td /F1 9.8 Tf  [( \(i.e., 100% positive )] TJ ET
BT 45.750 105.572 Td /F1 9.8 Tf  [(predictive value\).)] TJ ET
40.337 85.385 m 
40.337 85.831 40.154 86.275 39.838 86.591 c
39.522 86.907 39.078 87.091 38.631 87.091 c
38.185 87.091 37.741 86.907 37.425 86.591 c
37.109 86.275 36.925 85.831 36.925 85.385 c
36.925 84.938 37.109 84.494 37.425 84.178 c
37.741 83.862 38.185 83.679 38.631 83.679 c
39.078 83.679 39.522 83.862 39.838 84.178 c
40.154 84.494 40.337 84.938 40.337 85.385 c f
BT 45.750 82.417 Td /F1 9.8 Tf  [(If a familial FH mutation is not identified or if genetic testing is not available, relatives of an FH patient can be diagnosed )] TJ ET
BT 45.750 70.512 Td /F1 9.8 Tf  [(with the disorder on the basis of sex- and age-specific LDL cholesterol thresholds \(as recommended by NICE\) )] TJ ET
0.267 0.267 0.267 rg
BT 522.603 70.512 Td /F1 9.8 Tf  [([3])] TJ ET
BT 533.445 70.512 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 549.708 70.512 Td /F1 9.8 Tf  [( . )] TJ ET
BT 45.750 58.608 Td /F1 9.8 Tf  [(However, because of an overlap in LDL cholesterol levels between people with FH and those without, there is still )] TJ ET
BT 45.750 46.703 Td /F1 9.8 Tf  [(diagnostic uncertainty in over 15% of individuals )] TJ ET
0.267 0.267 0.267 rg
BT 256.009 46.703 Td /F1 9.8 Tf  [([3])] TJ ET
BT 266.851 46.703 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 283.114 46.703 Td /F1 9.8 Tf  [( . Relatives can also be diagnosed on the basis of specific clinical )] TJ ET
Q
q
15.000 32.417 577.500 744.583 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 748.071 Td /F4 9.8 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 728.667 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 709.262 Td /F1 9.8 Tf  [(A systematic evidence review )] TJ ET
0.267 0.267 0.267 rg
BT 156.832 709.262 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 167.674 709.262 Td /F1 9.8 Tf  [( was conducted during the formulation of guidelines from the National Institute for Health and )] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(Clinical Excellence \(NICE\) in the United Kingdom \(see next subsection\).)] TJ ET
BT 26.250 677.952 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 658.548 Td /F1 9.8 Tf  [(The NICE guidelines on the identification and management of FH recommend cascade screening using a combination of )] TJ ET
BT 26.250 646.643 Td /F1 9.8 Tf  [(genetic testing and LDL cholesterol concentration measurement �is recommended to identify affected relatives of those index )] TJ ET
BT 26.250 634.738 Td /F1 9.8 Tf  [(individuals with a clinical diagnosis of FH. This should include at least the first- and second- and, when possible, third-degree )] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(biological relatives� )] TJ ET
0.267 0.267 0.267 rg
BT 111.855 622.833 Td /F1 9.8 Tf  [([3])] TJ ET
BT 122.697 622.833 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 138.960 622.833 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 603.429 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 584.024 Td /F1 9.8 Tf  [(Until recently, there were no formal clinical guidelines or recommendations in the United States regarding cascade screening for )] TJ ET
BT 26.250 572.119 Td /F1 9.8 Tf  [(FH. However, in June 2011, the National Lipid Association issued guidelines strongly encouraging the use of cascade screening )] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(to identify persons with FH )] TJ ET
0.267 0.267 0.267 rg
BT 143.835 560.214 Td /F1 9.8 Tf  [([23])] TJ ET
BT 160.098 560.214 Td /F1 9.8 Tf  [([24])] TJ ET
0.271 0.267 0.267 rg
BT 176.361 560.214 Td /F1 9.8 Tf  [( . Also in June 2011, the European Society of Cardiology and the European Atherosclerosis )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(Society jointly issued guidelines recommending family screening \(and cascade screening, if resources are available\) for the )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(detection of FH )] TJ ET
0.267 0.267 0.267 rg
BT 95.075 536.405 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 111.338 536.405 Td /F1 9.8 Tf  [( . In both of these guidelines, cascade screening does not necessarily incorporate genetic testing, though )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(DNA analysis is noted as being useful in some cases )] TJ ET
0.267 0.267 0.267 rg
BT 257.637 524.500 Td /F1 9.8 Tf  [([23])] TJ ET
BT 273.900 524.500 Td /F1 9.8 Tf  [([24])] TJ ET
0.271 0.267 0.267 rg
BT 290.163 524.500 Td /F1 9.8 Tf  [( or is recommended whenever resources are available )] TJ ET
0.267 0.267 0.267 rg
BT 527.497 524.500 Td /F1 9.8 Tf  [([25])] TJ ET
0.271 0.267 0.267 rg
BT 543.760 524.500 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 505.095 Td /F4 9.8 Tf  [(Evidence Overview)] TJ ET
BT 26.250 485.691 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 485.691 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 485.691 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the genomic markers of interest� mutations in the )] TJ ET
BT 515.008 485.691 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 539.929 485.691 Td /F1 9.8 Tf  [( , )] TJ ET
BT 548.060 485.691 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(, or )] TJ ET
BT 43.049 473.786 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 75.019 473.786 Td /F1 9.8 Tf  [(genes \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 457.349 m 
40.337 457.795 40.154 458.239 39.838 458.555 c
39.522 458.871 39.078 459.055 38.631 459.055 c
38.185 459.055 37.741 458.871 37.425 458.555 c
37.109 458.239 36.925 457.795 36.925 457.349 c
36.925 456.902 37.109 456.458 37.425 456.142 c
37.741 455.826 38.185 455.642 38.631 455.642 c
39.078 455.642 39.522 455.826 39.838 456.142 c
40.154 456.458 40.337 456.902 40.337 457.349 c f
BT 45.750 454.381 Td /F1 9.8 Tf  [(Mutations known to cause FH have been found in the LDL receptor )] TJ ET
BT 337.860 454.381 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 362.781 454.381 Td /F1 9.8 Tf  [(\), apolipoprotein B \()] TJ ET
BT 447.860 454.381 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 474.955 454.381 Td /F1 9.8 Tf  [(\), and proprotein )] TJ ET
BT 45.750 442.476 Td /F1 9.8 Tf  [(convertase subtilisin/kexin type 9 \()] TJ ET
BT 194.223 442.476 Td /F5 9.8 Tf  [(PCSK9\))] TJ ET
BT 229.440 442.476 Td /F1 9.8 Tf  [(genes. Several methods are currently used to identify sequence changes in )] TJ ET
BT 45.750 430.572 Td /F1 9.8 Tf  [(these genes )] TJ ET
0.267 0.267 0.267 rg
BT 101.578 430.572 Td /F1 9.8 Tf  [([3])] TJ ET
BT 112.421 430.572 Td /F1 9.8 Tf  [([26])] TJ ET
BT 128.684 430.572 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 144.947 430.572 Td /F1 9.8 Tf  [( ; and additional technologies are under development.)] TJ ET
40.337 410.385 m 
40.337 410.831 40.154 411.275 39.838 411.591 c
39.522 411.907 39.078 412.091 38.631 412.091 c
38.185 412.091 37.741 411.907 37.425 411.591 c
37.109 411.275 36.925 410.831 36.925 410.385 c
36.925 409.938 37.109 409.494 37.425 409.178 c
37.741 408.862 38.185 408.678 38.631 408.678 c
39.078 408.678 39.522 408.862 39.838 409.178 c
40.154 409.494 40.337 409.938 40.337 410.385 c f
BT 45.750 407.417 Td /F1 9.8 Tf  [(The analytic sensitivity and specificity of each DNA test for FH will depend on the particular mutations being assayed and )] TJ ET
BT 45.750 395.512 Td /F1 9.8 Tf  [(on the population\(s\) tested. \(Often, labs will initially test only for those mutations that are most prevalent in a particular )] TJ ET
BT 45.750 383.607 Td /F1 9.8 Tf  [(population.\))] TJ ET
40.337 363.420 m 
40.337 363.867 40.154 364.311 39.838 364.627 c
39.522 364.943 39.078 365.127 38.631 365.127 c
38.185 365.127 37.741 364.943 37.425 364.627 c
37.109 364.311 36.925 363.867 36.925 363.420 c
36.925 362.974 37.109 362.530 37.425 362.214 c
37.741 361.898 38.185 361.714 38.631 361.714 c
39.078 361.714 39.522 361.898 39.838 362.214 c
40.154 362.530 40.337 362.974 40.337 363.420 c f
BT 45.750 360.453 Td /F1 9.8 Tf  [(Because of the number of common polymorphisms that exist and because some scanning methods are not very efficient in )] TJ ET
BT 45.750 348.548 Td /F1 9.8 Tf  [(detecting large-scale genetic rearrangements, many diagnostic labs are switching to direct sequencing strategies to )] TJ ET
BT 45.750 336.643 Td /F1 9.8 Tf  [(improve the sensitivity of their mutation detection efforts )] TJ ET
0.267 0.267 0.267 rg
BT 289.061 336.643 Td /F1 9.8 Tf  [([26])] TJ ET
0.271 0.267 0.267 rg
BT 305.324 336.643 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 313.488 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 313.488 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 313.488 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying relatives of patients with FH \(predictive value\).)] TJ ET
40.337 297.051 m 
40.337 297.498 40.154 297.942 39.838 298.258 c
39.522 298.574 39.078 298.758 38.631 298.758 c
38.185 298.758 37.741 298.574 37.425 298.258 c
37.109 297.942 36.925 297.498 36.925 297.051 c
36.925 296.605 37.109 296.161 37.425 295.845 c
37.741 295.529 38.185 295.345 38.631 295.345 c
39.078 295.345 39.522 295.529 39.838 295.845 c
40.154 296.161 40.337 296.605 40.337 297.051 c f
BT 45.750 294.084 Td /F1 9.8 Tf  [(More than 1,000 mutations in the )] TJ ET
BT 190.996 294.084 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 215.917 294.084 Td /F1 9.8 Tf  [( gene have been identified in patients with FH )] TJ ET
0.267 0.267 0.267 rg
BT 415.899 294.084 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 432.162 294.084 Td /F1 9.8 Tf  [( ; and DNA testing on this gene )] TJ ET
BT 45.750 282.179 Td /F1 9.8 Tf  [(alone has been found to identify 70-80% of people with a definitive clinical diagnosis of FH and 20-30% of those whose )] TJ ET
BT 45.750 270.274 Td /F1 9.8 Tf  [(diagnosis is less certain )] TJ ET
0.267 0.267 0.267 rg
BT 151.411 270.274 Td /F1 9.8 Tf  [([3])] TJ ET
BT 162.253 270.274 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 178.516 270.274 Td /F1 9.8 Tf  [( . Researchers have estimated that mutations in the )] TJ ET
BT 403.955 270.274 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 431.050 270.274 Td /F1 9.8 Tf  [( and )] TJ ET
BT 452.735 270.274 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 484.705 270.274 Td /F1 9.8 Tf  [( genes account for )] TJ ET
BT 45.750 258.369 Td /F1 9.8 Tf  [(only about 5.5% and 1.5% of FH cases, respectively )] TJ ET
0.267 0.267 0.267 rg
BT 273.900 258.369 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 290.163 258.369 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 238.182 m 
40.337 238.629 40.154 239.073 39.838 239.389 c
39.522 239.705 39.078 239.889 38.631 239.889 c
38.185 239.889 37.741 239.705 37.425 239.389 c
37.109 239.073 36.925 238.629 36.925 238.182 c
36.925 237.736 37.109 237.292 37.425 236.976 c
37.741 236.660 38.185 236.476 38.631 236.476 c
39.078 236.476 39.522 236.660 39.838 236.976 c
40.154 237.292 40.337 237.736 40.337 238.182 c f
BT 45.750 235.215 Td /F1 9.8 Tf  [(Current DNA testing for FH is not 100% sensitive because the disorder may be caused by a mutation that is not assessed. )] TJ ET
BT 45.750 223.310 Td /F1 9.8 Tf  [(Therefore, )] TJ ET
BT 93.437 223.310 Td /F5 9.8 Tf  [(not)] TJ ET
BT 106.990 223.310 Td /F1 9.8 Tf  [( finding a mutation does not necessarily exclude a diagnosis of FH )] TJ ET
0.267 0.267 0.267 rg
BT 395.834 223.310 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 406.675 223.310 Td /F1 9.8 Tf  [( . Research has shown that ~15% of )] TJ ET
BT 45.750 211.405 Td /F1 9.8 Tf  [(people with FH do not have a mutation in their )] TJ ET
BT 247.351 211.405 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 272.272 211.405 Td /F1 9.8 Tf  [(, )] TJ ET
BT 277.693 211.405 Td /F5 9.8 Tf  [(APOB)] TJ ET
BT 304.788 211.405 Td /F1 9.8 Tf  [(, or )] TJ ET
BT 321.587 211.405 Td /F5 9.8 Tf  [(PCSK9)] TJ ET
BT 353.558 211.405 Td /F1 9.8 Tf  [(genes \(though reliable estimates range from 12% to )] TJ ET
BT 45.750 199.500 Td /F1 9.8 Tf  [(48%\) )] TJ ET
0.267 0.267 0.267 rg
BT 71.217 199.500 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 87.480 199.500 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 179.313 m 
40.337 179.760 40.154 180.204 39.838 180.520 c
39.522 180.836 39.078 181.020 38.631 181.020 c
38.185 181.020 37.741 180.836 37.425 180.520 c
37.109 180.204 36.925 179.760 36.925 179.313 c
36.925 178.867 37.109 178.423 37.425 178.107 c
37.741 177.791 38.185 177.607 38.631 177.607 c
39.078 177.607 39.522 177.791 39.838 178.107 c
40.154 178.423 40.337 178.867 40.337 179.313 c f
BT 45.750 176.346 Td /F1 9.8 Tf  [(Conversely, though mutation screening for FH is highly specific, it may produce false positives because some sequence )] TJ ET
BT 45.750 164.441 Td /F1 9.8 Tf  [(changes that are detected can be non-pathogenic )] TJ ET
0.267 0.267 0.267 rg
BT 263.097 164.441 Td /F1 9.8 Tf  [([26])] TJ ET
BT 279.360 164.441 Td /F1 9.8 Tf  [([27])] TJ ET
BT 295.623 164.441 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 311.886 164.441 Td /F1 9.8 Tf  [( . However, a false positive mutation will likely become )] TJ ET
BT 45.750 152.536 Td /F1 9.8 Tf  [(evident during cascade screening, since it should fail to consistently associate with the FH phenotype.)] TJ ET
40.337 132.349 m 
40.337 132.796 40.154 133.240 39.838 133.556 c
39.522 133.871 39.078 134.055 38.631 134.055 c
38.185 134.055 37.741 133.871 37.425 133.556 c
37.109 133.240 36.925 132.796 36.925 132.349 c
36.925 131.902 37.109 131.458 37.425 131.142 c
37.741 130.827 38.185 130.643 38.631 130.643 c
39.078 130.643 39.522 130.827 39.838 131.142 c
40.154 131.458 40.337 131.902 40.337 132.349 c f
BT 45.750 129.381 Td /F1 9.8 Tf  [(Since FH is a disease inherited in an autosomal dominant fashion, the identification of the true mutation responsible for the )] TJ ET
BT 45.750 117.477 Td /F1 9.8 Tf  [(disease in a family allows for the definitive diagnosis of biological relatives who have the mutation )] TJ ET
0.267 0.267 0.267 rg
BT 467.886 117.477 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 478.728 117.477 Td /F1 9.8 Tf  [( \(i.e., 100% positive )] TJ ET
BT 45.750 105.572 Td /F1 9.8 Tf  [(predictive value\).)] TJ ET
40.337 85.385 m 
40.337 85.831 40.154 86.275 39.838 86.591 c
39.522 86.907 39.078 87.091 38.631 87.091 c
38.185 87.091 37.741 86.907 37.425 86.591 c
37.109 86.275 36.925 85.831 36.925 85.385 c
36.925 84.938 37.109 84.494 37.425 84.178 c
37.741 83.862 38.185 83.679 38.631 83.679 c
39.078 83.679 39.522 83.862 39.838 84.178 c
40.154 84.494 40.337 84.938 40.337 85.385 c f
BT 45.750 82.417 Td /F1 9.8 Tf  [(If a familial FH mutation is not identified or if genetic testing is not available, relatives of an FH patient can be diagnosed )] TJ ET
BT 45.750 70.512 Td /F1 9.8 Tf  [(with the disorder on the basis of sex- and age-specific LDL cholesterol thresholds \(as recommended by NICE\) )] TJ ET
0.267 0.267 0.267 rg
BT 522.603 70.512 Td /F1 9.8 Tf  [([3])] TJ ET
BT 533.445 70.512 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 549.708 70.512 Td /F1 9.8 Tf  [( . )] TJ ET
BT 45.750 58.608 Td /F1 9.8 Tf  [(However, because of an overlap in LDL cholesterol levels between people with FH and those without, there is still )] TJ ET
BT 45.750 46.703 Td /F1 9.8 Tf  [(diagnostic uncertainty in over 15% of individuals )] TJ ET
0.267 0.267 0.267 rg
BT 256.009 46.703 Td /F1 9.8 Tf  [([3])] TJ ET
BT 266.851 46.703 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 283.114 46.703 Td /F1 9.8 Tf  [( . Relatives can also be diagnosed on the basis of specific clinical )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(2)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 45.750 767.476 Td /F1 9.8 Tf  [(characteristics, such as the presence of xanthomas \(though these are not present in all persons with FH\).)] TJ ET
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40.337 747.289 m 
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BT 45.750 744.321 Td /F1 9.8 Tf  [(Published studies on the clinical validity of diagnosing relatives using DNA-based criteria compared to clinical criteria have )] TJ ET
BT 45.750 732.417 Td /F1 9.8 Tf  [(shown that a clinical diagnosis is less sensitive and leads to under-diagnosis )] TJ ET
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BT 377.933 732.417 Td /F1 9.8 Tf  [([15])] TJ ET
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BT 442.984 732.417 Td /F1 9.8 Tf  [( , raising the possibility that )] TJ ET
BT 45.750 720.512 Td /F1 9.8 Tf  [(relatives diagnosed by clinical criteria may, in fact, have another form of dyslipidemia \(i.e., they may have been )] TJ ET
BT 45.750 708.607 Td /F1 9.8 Tf  [(misdiagnosed\).)] TJ ET
BT 26.250 685.452 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 685.452 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 685.452 Td /F1 9.8 Tf  [( Net benefit of cascade screening in improving health outcomes.)] TJ ET
40.337 669.015 m 
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BT 45.750 666.048 Td /F1 9.8 Tf  [(Data from the U.K. has shown that cascade screening reduces the average age at which FH patients are diagnosed )] TJ ET
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BT 547.582 666.048 Td /F1 9.8 Tf  [([3])] TJ ET
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BT 558.424 666.048 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 645.861 m 
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BT 45.750 642.893 Td /F1 9.8 Tf  [(Cascade screening has also resulted in increased percentages of people with FH on statins and has, subsequently, )] TJ ET
BT 45.750 630.988 Td /F1 9.8 Tf  [(resulted in decreased lipid levels in these people )] TJ ET
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BT 258.183 630.988 Td /F1 9.8 Tf  [([3])] TJ ET
BT 269.025 630.988 Td /F1 9.8 Tf  [([30])] TJ ET
BT 285.288 630.988 Td /F1 9.8 Tf  [([33])] TJ ET
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BT 301.551 630.988 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 610.801 m 
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BT 45.750 607.833 Td /F1 9.8 Tf  [(Statin use has been shown to reduce both total cholesterol and LDL cholesterol in adults with FH; and early detection and )] TJ ET
BT 45.750 595.929 Td /F1 9.8 Tf  [(treatment with statins have been shown to reduce morbidity and mortality among those with heterozygous FH )] TJ ET
0.267 0.267 0.267 rg
BT 519.912 595.929 Td /F1 9.8 Tf  [([3])] TJ ET
BT 530.754 595.929 Td /F1 9.8 Tf  [([4])] TJ ET
BT 541.596 595.929 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 557.859 595.929 Td /F1 9.8 Tf  [( . In )] TJ ET
BT 45.750 584.024 Td /F1 9.8 Tf  [(one of the few long-term cohort studies of FH patients, there was an ~80% reduction in the risk of first onset of CHD among )] TJ ET
BT 45.750 572.119 Td /F1 9.8 Tf  [(those treated with statins compared to untreated patients )] TJ ET
0.267 0.267 0.267 rg
BT 293.966 572.119 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 310.228 572.119 Td /F1 9.8 Tf  [( . This study mimicked a placebo-controlled primary )] TJ ET
BT 45.750 560.214 Td /F1 9.8 Tf  [(prevention trial and is the highest quality evidence of the effect of statin treatment in FH patients. Results from another long-)] TJ ET
BT 45.750 548.310 Td /F1 9.8 Tf  [(term prospective study examined mortality in heterozygous FH patients aged 20-79 years old and showed an overall 37% )] TJ ET
BT 45.750 536.405 Td /F1 9.8 Tf  [(reduction in deaths from CHD since statins became widely available. \(The reduction in coronary mortality was greater for )] TJ ET
BT 45.750 524.500 Td /F1 9.8 Tf  [(primary CHD prevention than for secondary CHD prevention� 48% versus 25% reduction\) )] TJ ET
0.267 0.267 0.267 rg
BT 440.216 524.500 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 451.058 524.500 Td /F1 9.8 Tf  [( . Other researchers used the )] TJ ET
BT 45.750 512.595 Td /F1 9.8 Tf  [(concept of population attributable fraction to estimate the proportion of the 5-year risk for CHD mortality that could )] TJ ET
BT 45.750 500.691 Td /F1 9.8 Tf  [(potentially be prevented among first-degree relatives of FH patients by treating the hypercholesterolemia among the )] TJ ET
BT 45.750 488.786 Td /F1 9.8 Tf  [(affected relatives. This proportion was 44% among male, and 57% among female, first-degree relatives aged 20-79 years )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 476.881 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 476.881 Td /F1 9.8 Tf  [( . Remarkably, this analysis estimated that 96-98% of the deaths due to CHD among those under the age of 40 could )] TJ ET
BT 45.750 464.976 Td /F1 9.8 Tf  [(be prevented with cholesterol reduction )] TJ ET
0.267 0.267 0.267 rg
BT 218.081 464.976 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 234.344 464.976 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 444.789 m 
40.337 445.236 40.154 445.680 39.838 445.996 c
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40.154 443.899 40.337 444.343 40.337 444.789 c f
BT 45.750 441.822 Td /F1 9.8 Tf  [(Statin treatment has been shown to decrease total and LDL cholesterol concentrations in children with FH )] TJ ET
0.267 0.267 0.267 rg
BT 504.214 441.822 Td /F1 9.8 Tf  [([3])] TJ ET
BT 515.056 441.822 Td /F1 9.8 Tf  [([36])] TJ ET
BT 531.319 441.822 Td /F1 9.8 Tf  [([37])] TJ ET
BT 547.582 441.822 Td /F1 9.8 Tf  [([38])] TJ ET
BT 563.845 441.822 Td /F1 9.8 Tf  [([39])] TJ ET
BT 45.750 429.917 Td /F1 9.8 Tf  [([40])] TJ ET
BT 62.013 429.917 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 78.276 429.917 Td /F1 9.8 Tf  [( . However, there is no evidence of the long-term health benefits of statin treatment in children with FH \(such as )] TJ ET
BT 45.750 418.012 Td /F1 9.8 Tf  [(delayed onset of, or reduced risk for, CHD\), nor evidence of any benefits compared to the detection and treatment of the )] TJ ET
BT 45.750 406.107 Td /F1 9.8 Tf  [(disorder in adulthood )] TJ ET
0.267 0.267 0.267 rg
BT 139.506 406.107 Td /F1 9.8 Tf  [([38])] TJ ET
BT 155.769 406.107 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 172.032 406.107 Td /F1 9.8 Tf  [( . Nevertheless, there are studies that support cholesterol lowering in children based on )] TJ ET
BT 45.750 394.203 Td /F1 9.8 Tf  [(surrogate markers of cardiovascular disease [such as carotid intima-media thickness \(IMT\)] )] TJ ET
0.267 0.267 0.267 rg
BT 441.824 394.203 Td /F1 9.8 Tf  [([43])] TJ ET
BT 458.087 394.203 Td /F1 9.8 Tf  [([44])] TJ ET
BT 474.350 394.203 Td /F1 9.8 Tf  [([45])] TJ ET
BT 490.613 394.203 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 506.876 394.203 Td /F1 9.8 Tf  [( , some of which )] TJ ET
BT 45.750 382.298 Td /F1 9.8 Tf  [(note a significant deviation in carotid IMT from the age of 12 years in children with FH \(compared to unaffected siblings\) )] TJ ET
0.267 0.267 0.267 rg
BT 563.260 382.298 Td /F1 9.8 Tf  [([45])] TJ ET
0.271 0.267 0.267 rg
BT 45.750 370.393 Td /F1 9.8 Tf  [(. Increased carotid IMT is reversible by statins, though we lack information regarding when such changes become )] TJ ET
BT 45.750 358.488 Td /F1 9.8 Tf  [(irreversible.)] TJ ET
40.337 338.301 m 
40.337 338.748 40.154 339.192 39.838 339.508 c
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38.185 340.008 37.741 339.824 37.425 339.508 c
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39.078 336.595 39.522 336.779 39.838 337.095 c
40.154 337.411 40.337 337.855 40.337 338.301 c f
BT 45.750 335.334 Td /F1 9.8 Tf  [(Because cascade screening may identify fewer than 50% of people with FH \(at least as estimated for the U.K. population\) )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 323.429 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 56.592 323.429 Td /F1 9.8 Tf  [( , research is needed to compare the utility of other strategies for identifying those with FH.)] TJ ET
40.337 303.242 m 
40.337 303.688 40.154 304.132 39.838 304.448 c
39.522 304.764 39.078 304.948 38.631 304.948 c
38.185 304.948 37.741 304.764 37.425 304.448 c
37.109 304.132 36.925 303.688 36.925 303.242 c
36.925 302.795 37.109 302.351 37.425 302.035 c
37.741 301.719 38.185 301.536 38.631 301.536 c
39.078 301.536 39.522 301.719 39.838 302.035 c
40.154 302.351 40.337 302.795 40.337 303.242 c f
BT 45.750 300.274 Td /F1 9.8 Tf  [(There are no published data on the clinical utility of cascade screening that includes DNA testing compared to cascade )] TJ ET
BT 45.750 288.369 Td /F1 9.8 Tf  [(screening without genetic analysis. The National Lipid Association has identified several areas related to FH where further )] TJ ET
BT 45.750 276.465 Td /F1 9.8 Tf  [(research is needed, including the cost-effectiveness of genetic screening )] TJ ET
0.267 0.267 0.267 rg
BT 362.235 276.465 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 378.498 276.465 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 256.278 m 
40.337 256.724 40.154 257.168 39.838 257.484 c
39.522 257.800 39.078 257.984 38.631 257.984 c
38.185 257.984 37.741 257.800 37.425 257.484 c
37.109 257.168 36.925 256.724 36.925 256.278 c
36.925 255.831 37.109 255.387 37.425 255.071 c
37.741 254.755 38.185 254.571 38.631 254.571 c
39.078 254.571 39.522 254.755 39.838 255.071 c
40.154 255.387 40.337 255.831 40.337 256.278 c f
BT 45.750 253.310 Td /F1 9.8 Tf  [(Hard data are also lacking regarding whether FH identification by cascade screening \(and subsequent treatment of FH )] TJ ET
BT 45.750 241.405 Td /F1 9.8 Tf  [(patients\) is more effective in improving health outcomes of these patients compared to other identification methods \(e.g., )] TJ ET
BT 45.750 229.500 Td /F1 9.8 Tf  [(general physician note searching, use of secondary care registries, or population screening\).)] TJ ET
40.337 209.313 m 
40.337 209.760 40.154 210.204 39.838 210.520 c
39.522 210.836 39.078 211.020 38.631 211.020 c
38.185 211.020 37.741 210.836 37.425 210.520 c
37.109 210.204 36.925 209.760 36.925 209.313 c
36.925 208.867 37.109 208.423 37.425 208.107 c
37.741 207.791 38.185 207.607 38.631 207.607 c
39.078 207.607 39.522 207.791 39.838 208.107 c
40.154 208.423 40.337 208.867 40.337 209.313 c f
BT 45.750 206.346 Td /F1 9.8 Tf  [(The following issues may also affect the ability of cascade screening to reduce CHD and CHD-related deaths among )] TJ ET
BT 45.750 194.441 Td /F1 9.8 Tf  [(relatives of FH patients: )] TJ ET
0.39 w 1 J 1 j
59.837 181.754 m 
59.837 182.200 59.654 182.644 59.338 182.960 c
59.022 183.276 58.578 183.460 58.131 183.460 c
57.685 183.460 57.241 183.276 56.925 182.960 c
56.609 182.644 56.425 182.200 56.425 181.754 c
56.425 181.307 56.609 180.863 56.925 180.547 c
57.241 180.231 57.685 180.048 58.131 180.048 c
58.578 180.048 59.022 180.231 59.338 180.547 c
59.654 180.863 59.837 181.307 59.837 181.754 c s
BT 65.250 178.786 Td /F4 9.8 Tf  [(The identification and diagnosis of index cases.)] TJ ET
BT 286.858 178.786 Td /F1 9.8 Tf  [(It is unclear whether a screening program should be implemented )] TJ ET
BT 65.250 166.881 Td /F1 9.8 Tf  [(to find FH index cases and, if so, what type of program would be best \(e.g., population-based or opportunistic )] TJ ET
BT 65.250 154.977 Td /F1 9.8 Tf  [(screening of adults; universal or targeted lipid screening of children\) )] TJ ET
0.267 0.267 0.267 rg
BT 360.041 154.977 Td /F1 9.8 Tf  [([11])] TJ ET
BT 376.304 154.977 Td /F1 9.8 Tf  [([12])] TJ ET
BT 392.567 154.977 Td /F1 9.8 Tf  [([38])] TJ ET
BT 408.830 154.977 Td /F1 9.8 Tf  [([48])] TJ ET
BT 425.093 154.977 Td /F1 9.8 Tf  [([49])] TJ ET
BT 441.356 154.977 Td /F1 9.8 Tf  [([50])] TJ ET
BT 457.619 154.977 Td /F1 9.8 Tf  [([51])] TJ ET
BT 473.882 154.977 Td /F1 9.8 Tf  [([52])] TJ ET
BT 490.145 154.977 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 506.408 154.977 Td /F1 9.8 Tf  [( . In addition, )] TJ ET
BT 65.250 143.072 Td /F1 9.8 Tf  [(three groups have developed diagnostic criteria for FH. These criteria differ in their need for \(and the sufficiency of\) )] TJ ET
BT 65.250 131.167 Td /F1 9.8 Tf  [(DNA testing and in their diagnostic effectiveness )] TJ ET
0.267 0.267 0.267 rg
BT 277.137 131.167 Td /F1 9.8 Tf  [([1])] TJ ET
BT 287.979 131.167 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 298.821 131.167 Td /F1 9.8 Tf  [( .)] TJ ET
0.39 w 1 J 1 j
59.837 118.480 m 
59.837 118.927 59.654 119.371 59.338 119.687 c
59.022 120.002 58.578 120.186 58.131 120.186 c
57.685 120.186 57.241 120.002 56.925 119.687 c
56.609 119.371 56.425 118.927 56.425 118.480 c
56.425 118.033 56.609 117.589 56.925 117.273 c
57.241 116.958 57.685 116.774 58.131 116.774 c
58.578 116.774 59.022 116.958 59.338 117.273 c
59.654 117.589 59.837 118.033 59.837 118.480 c s
BT 65.250 115.512 Td /F4 9.8 Tf  [(The possibility of variation in the severity of FH phenotypes according to the type of mutation \(the genotype-)] TJ ET
BT 65.250 103.608 Td /F4 9.8 Tf  [(phenotype relationship\), particularly for )] TJ ET
BT 252.167 103.608 Td /F6 9.8 Tf  [(LDLR)] TJ ET
BT 278.161 103.608 Td /F4 9.8 Tf  [( . )] TJ ET
BT 286.292 103.608 Td /F1 9.8 Tf  [( For example, LDL receptor-null mutations have been associated )] TJ ET
BT 65.250 91.703 Td /F1 9.8 Tf  [(with higher blood LDL cholesterol levels compared with LDL receptor-defective mutations )] TJ ET
0.267 0.267 0.267 rg
BT 452.149 91.703 Td /F1 9.8 Tf  [([2])] TJ ET
BT 462.991 91.703 Td /F1 9.8 Tf  [([46])] TJ ET
BT 479.254 91.703 Td /F1 9.8 Tf  [([54])] TJ ET
BT 495.517 91.703 Td /F1 9.8 Tf  [([55])] TJ ET
BT 511.780 91.703 Td /F1 9.8 Tf  [([56])] TJ ET
0.271 0.267 0.267 rg
BT 528.043 91.703 Td /F1 9.8 Tf  [( . However, )] TJ ET
BT 65.250 79.798 Td /F1 9.8 Tf  [(family-based and population-based studies have largely found that statin treatment efficacy or the risks of CHD or CHD-)] TJ ET
BT 65.250 67.893 Td /F1 9.8 Tf  [(related mortality are not affected by )] TJ ET
BT 220.782 67.893 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 245.703 67.893 Td /F1 9.8 Tf  [( mutation type )] TJ ET
0.267 0.267 0.267 rg
BT 309.653 67.893 Td /F1 9.8 Tf  [([54])] TJ ET
BT 325.916 67.893 Td /F1 9.8 Tf  [([57])] TJ ET
BT 342.179 67.893 Td /F1 9.8 Tf  [([58])] TJ ET
0.271 0.267 0.267 rg
BT 358.442 67.893 Td /F1 9.8 Tf  [( . Of note, the only subgroup analysis performed in )] TJ ET
BT 65.250 55.989 Td /F1 9.8 Tf  [(a randomized, double-blinded trial showed that )] TJ ET
BT 270.097 55.989 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 295.019 55.989 Td /F1 9.8 Tf  [( mutation type altered the LDL-lowering effect of the investigated )] TJ ET
BT 65.250 44.084 Td /F1 9.8 Tf  [(statin, but this trend was not statistically significant )] TJ ET
0.267 0.267 0.267 rg
BT 285.259 44.084 Td /F1 9.8 Tf  [([55])] TJ ET
0.271 0.267 0.267 rg
BT 301.522 44.084 Td /F1 9.8 Tf  [( .)] TJ ET
Q
q
15.000 37.953 577.500 739.047 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(characteristics, such as the presence of xanthomas \(though these are not present in all persons with FH\).)] TJ ET
0.271 0.267 0.267 RG
40.337 747.289 m 
40.337 747.736 40.154 748.180 39.838 748.496 c
39.522 748.811 39.078 748.995 38.631 748.995 c
38.185 748.995 37.741 748.811 37.425 748.496 c
37.109 748.180 36.925 747.736 36.925 747.289 c
36.925 746.842 37.109 746.398 37.425 746.082 c
37.741 745.767 38.185 745.583 38.631 745.583 c
39.078 745.583 39.522 745.767 39.838 746.082 c
40.154 746.398 40.337 746.842 40.337 747.289 c f
BT 45.750 744.321 Td /F1 9.8 Tf  [(Published studies on the clinical validity of diagnosing relatives using DNA-based criteria compared to clinical criteria have )] TJ ET
BT 45.750 732.417 Td /F1 9.8 Tf  [(shown that a clinical diagnosis is less sensitive and leads to under-diagnosis )] TJ ET
0.267 0.267 0.267 rg
BT 377.933 732.417 Td /F1 9.8 Tf  [([15])] TJ ET
BT 394.195 732.417 Td /F1 9.8 Tf  [([30])] TJ ET
BT 410.458 732.417 Td /F1 9.8 Tf  [([31])] TJ ET
BT 426.721 732.417 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 442.984 732.417 Td /F1 9.8 Tf  [( , raising the possibility that )] TJ ET
BT 45.750 720.512 Td /F1 9.8 Tf  [(relatives diagnosed by clinical criteria may, in fact, have another form of dyslipidemia \(i.e., they may have been )] TJ ET
BT 45.750 708.607 Td /F1 9.8 Tf  [(misdiagnosed\).)] TJ ET
BT 26.250 685.452 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 685.452 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 685.452 Td /F1 9.8 Tf  [( Net benefit of cascade screening in improving health outcomes.)] TJ ET
40.337 669.015 m 
40.337 669.462 40.154 669.906 39.838 670.222 c
39.522 670.538 39.078 670.721 38.631 670.721 c
38.185 670.721 37.741 670.538 37.425 670.222 c
37.109 669.906 36.925 669.462 36.925 669.015 c
36.925 668.569 37.109 668.125 37.425 667.809 c
37.741 667.493 38.185 667.309 38.631 667.309 c
39.078 667.309 39.522 667.493 39.838 667.809 c
40.154 668.125 40.337 668.569 40.337 669.015 c f
BT 45.750 666.048 Td /F1 9.8 Tf  [(Data from the U.K. has shown that cascade screening reduces the average age at which FH patients are diagnosed )] TJ ET
0.267 0.267 0.267 rg
BT 547.582 666.048 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 558.424 666.048 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 645.861 m 
40.337 646.307 40.154 646.751 39.838 647.067 c
39.522 647.383 39.078 647.567 38.631 647.567 c
38.185 647.567 37.741 647.383 37.425 647.067 c
37.109 646.751 36.925 646.307 36.925 645.861 c
36.925 645.414 37.109 644.970 37.425 644.654 c
37.741 644.338 38.185 644.154 38.631 644.154 c
39.078 644.154 39.522 644.338 39.838 644.654 c
40.154 644.970 40.337 645.414 40.337 645.861 c f
BT 45.750 642.893 Td /F1 9.8 Tf  [(Cascade screening has also resulted in increased percentages of people with FH on statins and has, subsequently, )] TJ ET
BT 45.750 630.988 Td /F1 9.8 Tf  [(resulted in decreased lipid levels in these people )] TJ ET
0.267 0.267 0.267 rg
BT 258.183 630.988 Td /F1 9.8 Tf  [([3])] TJ ET
BT 269.025 630.988 Td /F1 9.8 Tf  [([30])] TJ ET
BT 285.288 630.988 Td /F1 9.8 Tf  [([33])] TJ ET
0.271 0.267 0.267 rg
BT 301.551 630.988 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 610.801 m 
40.337 611.248 40.154 611.692 39.838 612.008 c
39.522 612.323 39.078 612.507 38.631 612.507 c
38.185 612.507 37.741 612.323 37.425 612.008 c
37.109 611.692 36.925 611.248 36.925 610.801 c
36.925 610.354 37.109 609.910 37.425 609.594 c
37.741 609.279 38.185 609.095 38.631 609.095 c
39.078 609.095 39.522 609.279 39.838 609.594 c
40.154 609.910 40.337 610.354 40.337 610.801 c f
BT 45.750 607.833 Td /F1 9.8 Tf  [(Statin use has been shown to reduce both total cholesterol and LDL cholesterol in adults with FH; and early detection and )] TJ ET
BT 45.750 595.929 Td /F1 9.8 Tf  [(treatment with statins have been shown to reduce morbidity and mortality among those with heterozygous FH )] TJ ET
0.267 0.267 0.267 rg
BT 519.912 595.929 Td /F1 9.8 Tf  [([3])] TJ ET
BT 530.754 595.929 Td /F1 9.8 Tf  [([4])] TJ ET
BT 541.596 595.929 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 557.859 595.929 Td /F1 9.8 Tf  [( . In )] TJ ET
BT 45.750 584.024 Td /F1 9.8 Tf  [(one of the few long-term cohort studies of FH patients, there was an ~80% reduction in the risk of first onset of CHD among )] TJ ET
BT 45.750 572.119 Td /F1 9.8 Tf  [(those treated with statins compared to untreated patients )] TJ ET
0.267 0.267 0.267 rg
BT 293.966 572.119 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 310.228 572.119 Td /F1 9.8 Tf  [( . This study mimicked a placebo-controlled primary )] TJ ET
BT 45.750 560.214 Td /F1 9.8 Tf  [(prevention trial and is the highest quality evidence of the effect of statin treatment in FH patients. Results from another long-)] TJ ET
BT 45.750 548.310 Td /F1 9.8 Tf  [(term prospective study examined mortality in heterozygous FH patients aged 20-79 years old and showed an overall 37% )] TJ ET
BT 45.750 536.405 Td /F1 9.8 Tf  [(reduction in deaths from CHD since statins became widely available. \(The reduction in coronary mortality was greater for )] TJ ET
BT 45.750 524.500 Td /F1 9.8 Tf  [(primary CHD prevention than for secondary CHD prevention� 48% versus 25% reduction\) )] TJ ET
0.267 0.267 0.267 rg
BT 440.216 524.500 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 451.058 524.500 Td /F1 9.8 Tf  [( . Other researchers used the )] TJ ET
BT 45.750 512.595 Td /F1 9.8 Tf  [(concept of population attributable fraction to estimate the proportion of the 5-year risk for CHD mortality that could )] TJ ET
BT 45.750 500.691 Td /F1 9.8 Tf  [(potentially be prevented among first-degree relatives of FH patients by treating the hypercholesterolemia among the )] TJ ET
BT 45.750 488.786 Td /F1 9.8 Tf  [(affected relatives. This proportion was 44% among male, and 57% among female, first-degree relatives aged 20-79 years )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 476.881 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 476.881 Td /F1 9.8 Tf  [( . Remarkably, this analysis estimated that 96-98% of the deaths due to CHD among those under the age of 40 could )] TJ ET
BT 45.750 464.976 Td /F1 9.8 Tf  [(be prevented with cholesterol reduction )] TJ ET
0.267 0.267 0.267 rg
BT 218.081 464.976 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 234.344 464.976 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 444.789 m 
40.337 445.236 40.154 445.680 39.838 445.996 c
39.522 446.312 39.078 446.496 38.631 446.496 c
38.185 446.496 37.741 446.312 37.425 445.996 c
37.109 445.680 36.925 445.236 36.925 444.789 c
36.925 444.343 37.109 443.899 37.425 443.583 c
37.741 443.267 38.185 443.083 38.631 443.083 c
39.078 443.083 39.522 443.267 39.838 443.583 c
40.154 443.899 40.337 444.343 40.337 444.789 c f
BT 45.750 441.822 Td /F1 9.8 Tf  [(Statin treatment has been shown to decrease total and LDL cholesterol concentrations in children with FH )] TJ ET
0.267 0.267 0.267 rg
BT 504.214 441.822 Td /F1 9.8 Tf  [([3])] TJ ET
BT 515.056 441.822 Td /F1 9.8 Tf  [([36])] TJ ET
BT 531.319 441.822 Td /F1 9.8 Tf  [([37])] TJ ET
BT 547.582 441.822 Td /F1 9.8 Tf  [([38])] TJ ET
BT 563.845 441.822 Td /F1 9.8 Tf  [([39])] TJ ET
BT 45.750 429.917 Td /F1 9.8 Tf  [([40])] TJ ET
BT 62.013 429.917 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 78.276 429.917 Td /F1 9.8 Tf  [( . However, there is no evidence of the long-term health benefits of statin treatment in children with FH \(such as )] TJ ET
BT 45.750 418.012 Td /F1 9.8 Tf  [(delayed onset of, or reduced risk for, CHD\), nor evidence of any benefits compared to the detection and treatment of the )] TJ ET
BT 45.750 406.107 Td /F1 9.8 Tf  [(disorder in adulthood )] TJ ET
0.267 0.267 0.267 rg
BT 139.506 406.107 Td /F1 9.8 Tf  [([38])] TJ ET
BT 155.769 406.107 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 172.032 406.107 Td /F1 9.8 Tf  [( . Nevertheless, there are studies that support cholesterol lowering in children based on )] TJ ET
BT 45.750 394.203 Td /F1 9.8 Tf  [(surrogate markers of cardiovascular disease [such as carotid intima-media thickness \(IMT\)] )] TJ ET
0.267 0.267 0.267 rg
BT 441.824 394.203 Td /F1 9.8 Tf  [([43])] TJ ET
BT 458.087 394.203 Td /F1 9.8 Tf  [([44])] TJ ET
BT 474.350 394.203 Td /F1 9.8 Tf  [([45])] TJ ET
BT 490.613 394.203 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 506.876 394.203 Td /F1 9.8 Tf  [( , some of which )] TJ ET
BT 45.750 382.298 Td /F1 9.8 Tf  [(note a significant deviation in carotid IMT from the age of 12 years in children with FH \(compared to unaffected siblings\) )] TJ ET
0.267 0.267 0.267 rg
BT 563.260 382.298 Td /F1 9.8 Tf  [([45])] TJ ET
0.271 0.267 0.267 rg
BT 45.750 370.393 Td /F1 9.8 Tf  [(. Increased carotid IMT is reversible by statins, though we lack information regarding when such changes become )] TJ ET
BT 45.750 358.488 Td /F1 9.8 Tf  [(irreversible.)] TJ ET
40.337 338.301 m 
40.337 338.748 40.154 339.192 39.838 339.508 c
39.522 339.824 39.078 340.008 38.631 340.008 c
38.185 340.008 37.741 339.824 37.425 339.508 c
37.109 339.192 36.925 338.748 36.925 338.301 c
36.925 337.855 37.109 337.411 37.425 337.095 c
37.741 336.779 38.185 336.595 38.631 336.595 c
39.078 336.595 39.522 336.779 39.838 337.095 c
40.154 337.411 40.337 337.855 40.337 338.301 c f
BT 45.750 335.334 Td /F1 9.8 Tf  [(Because cascade screening may identify fewer than 50% of people with FH \(at least as estimated for the U.K. population\) )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 323.429 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 56.592 323.429 Td /F1 9.8 Tf  [( , research is needed to compare the utility of other strategies for identifying those with FH.)] TJ ET
40.337 303.242 m 
40.337 303.688 40.154 304.132 39.838 304.448 c
39.522 304.764 39.078 304.948 38.631 304.948 c
38.185 304.948 37.741 304.764 37.425 304.448 c
37.109 304.132 36.925 303.688 36.925 303.242 c
36.925 302.795 37.109 302.351 37.425 302.035 c
37.741 301.719 38.185 301.536 38.631 301.536 c
39.078 301.536 39.522 301.719 39.838 302.035 c
40.154 302.351 40.337 302.795 40.337 303.242 c f
BT 45.750 300.274 Td /F1 9.8 Tf  [(There are no published data on the clinical utility of cascade screening that includes DNA testing compared to cascade )] TJ ET
BT 45.750 288.369 Td /F1 9.8 Tf  [(screening without genetic analysis. The National Lipid Association has identified several areas related to FH where further )] TJ ET
BT 45.750 276.465 Td /F1 9.8 Tf  [(research is needed, including the cost-effectiveness of genetic screening )] TJ ET
0.267 0.267 0.267 rg
BT 362.235 276.465 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 378.498 276.465 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 256.278 m 
40.337 256.724 40.154 257.168 39.838 257.484 c
39.522 257.800 39.078 257.984 38.631 257.984 c
38.185 257.984 37.741 257.800 37.425 257.484 c
37.109 257.168 36.925 256.724 36.925 256.278 c
36.925 255.831 37.109 255.387 37.425 255.071 c
37.741 254.755 38.185 254.571 38.631 254.571 c
39.078 254.571 39.522 254.755 39.838 255.071 c
40.154 255.387 40.337 255.831 40.337 256.278 c f
BT 45.750 253.310 Td /F1 9.8 Tf  [(Hard data are also lacking regarding whether FH identification by cascade screening \(and subsequent treatment of FH )] TJ ET
BT 45.750 241.405 Td /F1 9.8 Tf  [(patients\) is more effective in improving health outcomes of these patients compared to other identification methods \(e.g., )] TJ ET
BT 45.750 229.500 Td /F1 9.8 Tf  [(general physician note searching, use of secondary care registries, or population screening\).)] TJ ET
40.337 209.313 m 
40.337 209.760 40.154 210.204 39.838 210.520 c
39.522 210.836 39.078 211.020 38.631 211.020 c
38.185 211.020 37.741 210.836 37.425 210.520 c
37.109 210.204 36.925 209.760 36.925 209.313 c
36.925 208.867 37.109 208.423 37.425 208.107 c
37.741 207.791 38.185 207.607 38.631 207.607 c
39.078 207.607 39.522 207.791 39.838 208.107 c
40.154 208.423 40.337 208.867 40.337 209.313 c f
BT 45.750 206.346 Td /F1 9.8 Tf  [(The following issues may also affect the ability of cascade screening to reduce CHD and CHD-related deaths among )] TJ ET
BT 45.750 194.441 Td /F1 9.8 Tf  [(relatives of FH patients: )] TJ ET
0.39 w 1 J 1 j
59.837 181.754 m 
59.837 182.200 59.654 182.644 59.338 182.960 c
59.022 183.276 58.578 183.460 58.131 183.460 c
57.685 183.460 57.241 183.276 56.925 182.960 c
56.609 182.644 56.425 182.200 56.425 181.754 c
56.425 181.307 56.609 180.863 56.925 180.547 c
57.241 180.231 57.685 180.048 58.131 180.048 c
58.578 180.048 59.022 180.231 59.338 180.547 c
59.654 180.863 59.837 181.307 59.837 181.754 c s
BT 65.250 178.786 Td /F4 9.8 Tf  [(The identification and diagnosis of index cases.)] TJ ET
BT 286.858 178.786 Td /F1 9.8 Tf  [(It is unclear whether a screening program should be implemented )] TJ ET
BT 65.250 166.881 Td /F1 9.8 Tf  [(to find FH index cases and, if so, what type of program would be best \(e.g., population-based or opportunistic )] TJ ET
BT 65.250 154.977 Td /F1 9.8 Tf  [(screening of adults; universal or targeted lipid screening of children\) )] TJ ET
0.267 0.267 0.267 rg
BT 360.041 154.977 Td /F1 9.8 Tf  [([11])] TJ ET
BT 376.304 154.977 Td /F1 9.8 Tf  [([12])] TJ ET
BT 392.567 154.977 Td /F1 9.8 Tf  [([38])] TJ ET
BT 408.830 154.977 Td /F1 9.8 Tf  [([48])] TJ ET
BT 425.093 154.977 Td /F1 9.8 Tf  [([49])] TJ ET
BT 441.356 154.977 Td /F1 9.8 Tf  [([50])] TJ ET
BT 457.619 154.977 Td /F1 9.8 Tf  [([51])] TJ ET
BT 473.882 154.977 Td /F1 9.8 Tf  [([52])] TJ ET
BT 490.145 154.977 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 506.408 154.977 Td /F1 9.8 Tf  [( . In addition, )] TJ ET
BT 65.250 143.072 Td /F1 9.8 Tf  [(three groups have developed diagnostic criteria for FH. These criteria differ in their need for \(and the sufficiency of\) )] TJ ET
BT 65.250 131.167 Td /F1 9.8 Tf  [(DNA testing and in their diagnostic effectiveness )] TJ ET
0.267 0.267 0.267 rg
BT 277.137 131.167 Td /F1 9.8 Tf  [([1])] TJ ET
BT 287.979 131.167 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 298.821 131.167 Td /F1 9.8 Tf  [( .)] TJ ET
0.39 w 1 J 1 j
59.837 118.480 m 
59.837 118.927 59.654 119.371 59.338 119.687 c
59.022 120.002 58.578 120.186 58.131 120.186 c
57.685 120.186 57.241 120.002 56.925 119.687 c
56.609 119.371 56.425 118.927 56.425 118.480 c
56.425 118.033 56.609 117.589 56.925 117.273 c
57.241 116.958 57.685 116.774 58.131 116.774 c
58.578 116.774 59.022 116.958 59.338 117.273 c
59.654 117.589 59.837 118.033 59.837 118.480 c s
BT 65.250 115.512 Td /F4 9.8 Tf  [(The possibility of variation in the severity of FH phenotypes according to the type of mutation \(the genotype-)] TJ ET
BT 65.250 103.608 Td /F4 9.8 Tf  [(phenotype relationship\), particularly for )] TJ ET
BT 252.167 103.608 Td /F6 9.8 Tf  [(LDLR)] TJ ET
BT 278.161 103.608 Td /F4 9.8 Tf  [( . )] TJ ET
BT 286.292 103.608 Td /F1 9.8 Tf  [( For example, LDL receptor-null mutations have been associated )] TJ ET
BT 65.250 91.703 Td /F1 9.8 Tf  [(with higher blood LDL cholesterol levels compared with LDL receptor-defective mutations )] TJ ET
0.267 0.267 0.267 rg
BT 452.149 91.703 Td /F1 9.8 Tf  [([2])] TJ ET
BT 462.991 91.703 Td /F1 9.8 Tf  [([46])] TJ ET
BT 479.254 91.703 Td /F1 9.8 Tf  [([54])] TJ ET
BT 495.517 91.703 Td /F1 9.8 Tf  [([55])] TJ ET
BT 511.780 91.703 Td /F1 9.8 Tf  [([56])] TJ ET
0.271 0.267 0.267 rg
BT 528.043 91.703 Td /F1 9.8 Tf  [( . However, )] TJ ET
BT 65.250 79.798 Td /F1 9.8 Tf  [(family-based and population-based studies have largely found that statin treatment efficacy or the risks of CHD or CHD-)] TJ ET
BT 65.250 67.893 Td /F1 9.8 Tf  [(related mortality are not affected by )] TJ ET
BT 220.782 67.893 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 245.703 67.893 Td /F1 9.8 Tf  [( mutation type )] TJ ET
0.267 0.267 0.267 rg
BT 309.653 67.893 Td /F1 9.8 Tf  [([54])] TJ ET
BT 325.916 67.893 Td /F1 9.8 Tf  [([57])] TJ ET
BT 342.179 67.893 Td /F1 9.8 Tf  [([58])] TJ ET
0.271 0.267 0.267 rg
BT 358.442 67.893 Td /F1 9.8 Tf  [( . Of note, the only subgroup analysis performed in )] TJ ET
BT 65.250 55.989 Td /F1 9.8 Tf  [(a randomized, double-blinded trial showed that )] TJ ET
BT 270.097 55.989 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 295.019 55.989 Td /F1 9.8 Tf  [( mutation type altered the LDL-lowering effect of the investigated )] TJ ET
BT 65.250 44.084 Td /F1 9.8 Tf  [(statin, but this trend was not statistically significant )] TJ ET
0.267 0.267 0.267 rg
BT 285.259 44.084 Td /F1 9.8 Tf  [([55])] TJ ET
0.271 0.267 0.267 rg
BT 301.522 44.084 Td /F1 9.8 Tf  [( .)] TJ ET
Q
q
15.000 37.953 577.500 739.047 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(characteristics, such as the presence of xanthomas \(though these are not present in all persons with FH\).)] TJ ET
0.271 0.267 0.267 RG
40.337 747.289 m 
40.337 747.736 40.154 748.180 39.838 748.496 c
39.522 748.811 39.078 748.995 38.631 748.995 c
38.185 748.995 37.741 748.811 37.425 748.496 c
37.109 748.180 36.925 747.736 36.925 747.289 c
36.925 746.842 37.109 746.398 37.425 746.082 c
37.741 745.767 38.185 745.583 38.631 745.583 c
39.078 745.583 39.522 745.767 39.838 746.082 c
40.154 746.398 40.337 746.842 40.337 747.289 c f
BT 45.750 744.321 Td /F1 9.8 Tf  [(Published studies on the clinical validity of diagnosing relatives using DNA-based criteria compared to clinical criteria have )] TJ ET
BT 45.750 732.417 Td /F1 9.8 Tf  [(shown that a clinical diagnosis is less sensitive and leads to under-diagnosis )] TJ ET
0.267 0.267 0.267 rg
BT 377.933 732.417 Td /F1 9.8 Tf  [([15])] TJ ET
BT 394.195 732.417 Td /F1 9.8 Tf  [([30])] TJ ET
BT 410.458 732.417 Td /F1 9.8 Tf  [([31])] TJ ET
BT 426.721 732.417 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 442.984 732.417 Td /F1 9.8 Tf  [( , raising the possibility that )] TJ ET
BT 45.750 720.512 Td /F1 9.8 Tf  [(relatives diagnosed by clinical criteria may, in fact, have another form of dyslipidemia \(i.e., they may have been )] TJ ET
BT 45.750 708.607 Td /F1 9.8 Tf  [(misdiagnosed\).)] TJ ET
BT 26.250 685.452 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 685.452 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 685.452 Td /F1 9.8 Tf  [( Net benefit of cascade screening in improving health outcomes.)] TJ ET
40.337 669.015 m 
40.337 669.462 40.154 669.906 39.838 670.222 c
39.522 670.538 39.078 670.721 38.631 670.721 c
38.185 670.721 37.741 670.538 37.425 670.222 c
37.109 669.906 36.925 669.462 36.925 669.015 c
36.925 668.569 37.109 668.125 37.425 667.809 c
37.741 667.493 38.185 667.309 38.631 667.309 c
39.078 667.309 39.522 667.493 39.838 667.809 c
40.154 668.125 40.337 668.569 40.337 669.015 c f
BT 45.750 666.048 Td /F1 9.8 Tf  [(Data from the U.K. has shown that cascade screening reduces the average age at which FH patients are diagnosed )] TJ ET
0.267 0.267 0.267 rg
BT 547.582 666.048 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 558.424 666.048 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 645.861 m 
40.337 646.307 40.154 646.751 39.838 647.067 c
39.522 647.383 39.078 647.567 38.631 647.567 c
38.185 647.567 37.741 647.383 37.425 647.067 c
37.109 646.751 36.925 646.307 36.925 645.861 c
36.925 645.414 37.109 644.970 37.425 644.654 c
37.741 644.338 38.185 644.154 38.631 644.154 c
39.078 644.154 39.522 644.338 39.838 644.654 c
40.154 644.970 40.337 645.414 40.337 645.861 c f
BT 45.750 642.893 Td /F1 9.8 Tf  [(Cascade screening has also resulted in increased percentages of people with FH on statins and has, subsequently, )] TJ ET
BT 45.750 630.988 Td /F1 9.8 Tf  [(resulted in decreased lipid levels in these people )] TJ ET
0.267 0.267 0.267 rg
BT 258.183 630.988 Td /F1 9.8 Tf  [([3])] TJ ET
BT 269.025 630.988 Td /F1 9.8 Tf  [([30])] TJ ET
BT 285.288 630.988 Td /F1 9.8 Tf  [([33])] TJ ET
0.271 0.267 0.267 rg
BT 301.551 630.988 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 610.801 m 
40.337 611.248 40.154 611.692 39.838 612.008 c
39.522 612.323 39.078 612.507 38.631 612.507 c
38.185 612.507 37.741 612.323 37.425 612.008 c
37.109 611.692 36.925 611.248 36.925 610.801 c
36.925 610.354 37.109 609.910 37.425 609.594 c
37.741 609.279 38.185 609.095 38.631 609.095 c
39.078 609.095 39.522 609.279 39.838 609.594 c
40.154 609.910 40.337 610.354 40.337 610.801 c f
BT 45.750 607.833 Td /F1 9.8 Tf  [(Statin use has been shown to reduce both total cholesterol and LDL cholesterol in adults with FH; and early detection and )] TJ ET
BT 45.750 595.929 Td /F1 9.8 Tf  [(treatment with statins have been shown to reduce morbidity and mortality among those with heterozygous FH )] TJ ET
0.267 0.267 0.267 rg
BT 519.912 595.929 Td /F1 9.8 Tf  [([3])] TJ ET
BT 530.754 595.929 Td /F1 9.8 Tf  [([4])] TJ ET
BT 541.596 595.929 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 557.859 595.929 Td /F1 9.8 Tf  [( . In )] TJ ET
BT 45.750 584.024 Td /F1 9.8 Tf  [(one of the few long-term cohort studies of FH patients, there was an ~80% reduction in the risk of first onset of CHD among )] TJ ET
BT 45.750 572.119 Td /F1 9.8 Tf  [(those treated with statins compared to untreated patients )] TJ ET
0.267 0.267 0.267 rg
BT 293.966 572.119 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 310.228 572.119 Td /F1 9.8 Tf  [( . This study mimicked a placebo-controlled primary )] TJ ET
BT 45.750 560.214 Td /F1 9.8 Tf  [(prevention trial and is the highest quality evidence of the effect of statin treatment in FH patients. Results from another long-)] TJ ET
BT 45.750 548.310 Td /F1 9.8 Tf  [(term prospective study examined mortality in heterozygous FH patients aged 20-79 years old and showed an overall 37% )] TJ ET
BT 45.750 536.405 Td /F1 9.8 Tf  [(reduction in deaths from CHD since statins became widely available. \(The reduction in coronary mortality was greater for )] TJ ET
BT 45.750 524.500 Td /F1 9.8 Tf  [(primary CHD prevention than for secondary CHD prevention� 48% versus 25% reduction\) )] TJ ET
0.267 0.267 0.267 rg
BT 440.216 524.500 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 451.058 524.500 Td /F1 9.8 Tf  [( . Other researchers used the )] TJ ET
BT 45.750 512.595 Td /F1 9.8 Tf  [(concept of population attributable fraction to estimate the proportion of the 5-year risk for CHD mortality that could )] TJ ET
BT 45.750 500.691 Td /F1 9.8 Tf  [(potentially be prevented among first-degree relatives of FH patients by treating the hypercholesterolemia among the )] TJ ET
BT 45.750 488.786 Td /F1 9.8 Tf  [(affected relatives. This proportion was 44% among male, and 57% among female, first-degree relatives aged 20-79 years )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 476.881 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 476.881 Td /F1 9.8 Tf  [( . Remarkably, this analysis estimated that 96-98% of the deaths due to CHD among those under the age of 40 could )] TJ ET
BT 45.750 464.976 Td /F1 9.8 Tf  [(be prevented with cholesterol reduction )] TJ ET
0.267 0.267 0.267 rg
BT 218.081 464.976 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 234.344 464.976 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 444.789 m 
40.337 445.236 40.154 445.680 39.838 445.996 c
39.522 446.312 39.078 446.496 38.631 446.496 c
38.185 446.496 37.741 446.312 37.425 445.996 c
37.109 445.680 36.925 445.236 36.925 444.789 c
36.925 444.343 37.109 443.899 37.425 443.583 c
37.741 443.267 38.185 443.083 38.631 443.083 c
39.078 443.083 39.522 443.267 39.838 443.583 c
40.154 443.899 40.337 444.343 40.337 444.789 c f
BT 45.750 441.822 Td /F1 9.8 Tf  [(Statin treatment has been shown to decrease total and LDL cholesterol concentrations in children with FH )] TJ ET
0.267 0.267 0.267 rg
BT 504.214 441.822 Td /F1 9.8 Tf  [([3])] TJ ET
BT 515.056 441.822 Td /F1 9.8 Tf  [([36])] TJ ET
BT 531.319 441.822 Td /F1 9.8 Tf  [([37])] TJ ET
BT 547.582 441.822 Td /F1 9.8 Tf  [([38])] TJ ET
BT 563.845 441.822 Td /F1 9.8 Tf  [([39])] TJ ET
BT 45.750 429.917 Td /F1 9.8 Tf  [([40])] TJ ET
BT 62.013 429.917 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 78.276 429.917 Td /F1 9.8 Tf  [( . However, there is no evidence of the long-term health benefits of statin treatment in children with FH \(such as )] TJ ET
BT 45.750 418.012 Td /F1 9.8 Tf  [(delayed onset of, or reduced risk for, CHD\), nor evidence of any benefits compared to the detection and treatment of the )] TJ ET
BT 45.750 406.107 Td /F1 9.8 Tf  [(disorder in adulthood )] TJ ET
0.267 0.267 0.267 rg
BT 139.506 406.107 Td /F1 9.8 Tf  [([38])] TJ ET
BT 155.769 406.107 Td /F1 9.8 Tf  [([42])] TJ ET
0.271 0.267 0.267 rg
BT 172.032 406.107 Td /F1 9.8 Tf  [( . Nevertheless, there are studies that support cholesterol lowering in children based on )] TJ ET
BT 45.750 394.203 Td /F1 9.8 Tf  [(surrogate markers of cardiovascular disease [such as carotid intima-media thickness \(IMT\)] )] TJ ET
0.267 0.267 0.267 rg
BT 441.824 394.203 Td /F1 9.8 Tf  [([43])] TJ ET
BT 458.087 394.203 Td /F1 9.8 Tf  [([44])] TJ ET
BT 474.350 394.203 Td /F1 9.8 Tf  [([45])] TJ ET
BT 490.613 394.203 Td /F1 9.8 Tf  [([46])] TJ ET
0.271 0.267 0.267 rg
BT 506.876 394.203 Td /F1 9.8 Tf  [( , some of which )] TJ ET
BT 45.750 382.298 Td /F1 9.8 Tf  [(note a significant deviation in carotid IMT from the age of 12 years in children with FH \(compared to unaffected siblings\) )] TJ ET
0.267 0.267 0.267 rg
BT 563.260 382.298 Td /F1 9.8 Tf  [([45])] TJ ET
0.271 0.267 0.267 rg
BT 45.750 370.393 Td /F1 9.8 Tf  [(. Increased carotid IMT is reversible by statins, though we lack information regarding when such changes become )] TJ ET
BT 45.750 358.488 Td /F1 9.8 Tf  [(irreversible.)] TJ ET
40.337 338.301 m 
40.337 338.748 40.154 339.192 39.838 339.508 c
39.522 339.824 39.078 340.008 38.631 340.008 c
38.185 340.008 37.741 339.824 37.425 339.508 c
37.109 339.192 36.925 338.748 36.925 338.301 c
36.925 337.855 37.109 337.411 37.425 337.095 c
37.741 336.779 38.185 336.595 38.631 336.595 c
39.078 336.595 39.522 336.779 39.838 337.095 c
40.154 337.411 40.337 337.855 40.337 338.301 c f
BT 45.750 335.334 Td /F1 9.8 Tf  [(Because cascade screening may identify fewer than 50% of people with FH \(at least as estimated for the U.K. population\) )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 323.429 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 56.592 323.429 Td /F1 9.8 Tf  [( , research is needed to compare the utility of other strategies for identifying those with FH.)] TJ ET
40.337 303.242 m 
40.337 303.688 40.154 304.132 39.838 304.448 c
39.522 304.764 39.078 304.948 38.631 304.948 c
38.185 304.948 37.741 304.764 37.425 304.448 c
37.109 304.132 36.925 303.688 36.925 303.242 c
36.925 302.795 37.109 302.351 37.425 302.035 c
37.741 301.719 38.185 301.536 38.631 301.536 c
39.078 301.536 39.522 301.719 39.838 302.035 c
40.154 302.351 40.337 302.795 40.337 303.242 c f
BT 45.750 300.274 Td /F1 9.8 Tf  [(There are no published data on the clinical utility of cascade screening that includes DNA testing compared to cascade )] TJ ET
BT 45.750 288.369 Td /F1 9.8 Tf  [(screening without genetic analysis. The National Lipid Association has identified several areas related to FH where further )] TJ ET
BT 45.750 276.465 Td /F1 9.8 Tf  [(research is needed, including the cost-effectiveness of genetic screening )] TJ ET
0.267 0.267 0.267 rg
BT 362.235 276.465 Td /F1 9.8 Tf  [([47])] TJ ET
0.271 0.267 0.267 rg
BT 378.498 276.465 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 256.278 m 
40.337 256.724 40.154 257.168 39.838 257.484 c
39.522 257.800 39.078 257.984 38.631 257.984 c
38.185 257.984 37.741 257.800 37.425 257.484 c
37.109 257.168 36.925 256.724 36.925 256.278 c
36.925 255.831 37.109 255.387 37.425 255.071 c
37.741 254.755 38.185 254.571 38.631 254.571 c
39.078 254.571 39.522 254.755 39.838 255.071 c
40.154 255.387 40.337 255.831 40.337 256.278 c f
BT 45.750 253.310 Td /F1 9.8 Tf  [(Hard data are also lacking regarding whether FH identification by cascade screening \(and subsequent treatment of FH )] TJ ET
BT 45.750 241.405 Td /F1 9.8 Tf  [(patients\) is more effective in improving health outcomes of these patients compared to other identification methods \(e.g., )] TJ ET
BT 45.750 229.500 Td /F1 9.8 Tf  [(general physician note searching, use of secondary care registries, or population screening\).)] TJ ET
40.337 209.313 m 
40.337 209.760 40.154 210.204 39.838 210.520 c
39.522 210.836 39.078 211.020 38.631 211.020 c
38.185 211.020 37.741 210.836 37.425 210.520 c
37.109 210.204 36.925 209.760 36.925 209.313 c
36.925 208.867 37.109 208.423 37.425 208.107 c
37.741 207.791 38.185 207.607 38.631 207.607 c
39.078 207.607 39.522 207.791 39.838 208.107 c
40.154 208.423 40.337 208.867 40.337 209.313 c f
BT 45.750 206.346 Td /F1 9.8 Tf  [(The following issues may also affect the ability of cascade screening to reduce CHD and CHD-related deaths among )] TJ ET
BT 45.750 194.441 Td /F1 9.8 Tf  [(relatives of FH patients: )] TJ ET
0.39 w 1 J 1 j
59.837 181.754 m 
59.837 182.200 59.654 182.644 59.338 182.960 c
59.022 183.276 58.578 183.460 58.131 183.460 c
57.685 183.460 57.241 183.276 56.925 182.960 c
56.609 182.644 56.425 182.200 56.425 181.754 c
56.425 181.307 56.609 180.863 56.925 180.547 c
57.241 180.231 57.685 180.048 58.131 180.048 c
58.578 180.048 59.022 180.231 59.338 180.547 c
59.654 180.863 59.837 181.307 59.837 181.754 c s
BT 65.250 178.786 Td /F4 9.8 Tf  [(The identification and diagnosis of index cases.)] TJ ET
BT 286.858 178.786 Td /F1 9.8 Tf  [(It is unclear whether a screening program should be implemented )] TJ ET
BT 65.250 166.881 Td /F1 9.8 Tf  [(to find FH index cases and, if so, what type of program would be best \(e.g., population-based or opportunistic )] TJ ET
BT 65.250 154.977 Td /F1 9.8 Tf  [(screening of adults; universal or targeted lipid screening of children\) )] TJ ET
0.267 0.267 0.267 rg
BT 360.041 154.977 Td /F1 9.8 Tf  [([11])] TJ ET
BT 376.304 154.977 Td /F1 9.8 Tf  [([12])] TJ ET
BT 392.567 154.977 Td /F1 9.8 Tf  [([38])] TJ ET
BT 408.830 154.977 Td /F1 9.8 Tf  [([48])] TJ ET
BT 425.093 154.977 Td /F1 9.8 Tf  [([49])] TJ ET
BT 441.356 154.977 Td /F1 9.8 Tf  [([50])] TJ ET
BT 457.619 154.977 Td /F1 9.8 Tf  [([51])] TJ ET
BT 473.882 154.977 Td /F1 9.8 Tf  [([52])] TJ ET
BT 490.145 154.977 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 506.408 154.977 Td /F1 9.8 Tf  [( . In addition, )] TJ ET
BT 65.250 143.072 Td /F1 9.8 Tf  [(three groups have developed diagnostic criteria for FH. These criteria differ in their need for \(and the sufficiency of\) )] TJ ET
BT 65.250 131.167 Td /F1 9.8 Tf  [(DNA testing and in their diagnostic effectiveness )] TJ ET
0.267 0.267 0.267 rg
BT 277.137 131.167 Td /F1 9.8 Tf  [([1])] TJ ET
BT 287.979 131.167 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 298.821 131.167 Td /F1 9.8 Tf  [( .)] TJ ET
0.39 w 1 J 1 j
59.837 118.480 m 
59.837 118.927 59.654 119.371 59.338 119.687 c
59.022 120.002 58.578 120.186 58.131 120.186 c
57.685 120.186 57.241 120.002 56.925 119.687 c
56.609 119.371 56.425 118.927 56.425 118.480 c
56.425 118.033 56.609 117.589 56.925 117.273 c
57.241 116.958 57.685 116.774 58.131 116.774 c
58.578 116.774 59.022 116.958 59.338 117.273 c
59.654 117.589 59.837 118.033 59.837 118.480 c s
BT 65.250 115.512 Td /F4 9.8 Tf  [(The possibility of variation in the severity of FH phenotypes according to the type of mutation \(the genotype-)] TJ ET
BT 65.250 103.608 Td /F4 9.8 Tf  [(phenotype relationship\), particularly for )] TJ ET
BT 252.167 103.608 Td /F6 9.8 Tf  [(LDLR)] TJ ET
BT 278.161 103.608 Td /F4 9.8 Tf  [( . )] TJ ET
BT 286.292 103.608 Td /F1 9.8 Tf  [( For example, LDL receptor-null mutations have been associated )] TJ ET
BT 65.250 91.703 Td /F1 9.8 Tf  [(with higher blood LDL cholesterol levels compared with LDL receptor-defective mutations )] TJ ET
0.267 0.267 0.267 rg
BT 452.149 91.703 Td /F1 9.8 Tf  [([2])] TJ ET
BT 462.991 91.703 Td /F1 9.8 Tf  [([46])] TJ ET
BT 479.254 91.703 Td /F1 9.8 Tf  [([54])] TJ ET
BT 495.517 91.703 Td /F1 9.8 Tf  [([55])] TJ ET
BT 511.780 91.703 Td /F1 9.8 Tf  [([56])] TJ ET
0.271 0.267 0.267 rg
BT 528.043 91.703 Td /F1 9.8 Tf  [( . However, )] TJ ET
BT 65.250 79.798 Td /F1 9.8 Tf  [(family-based and population-based studies have largely found that statin treatment efficacy or the risks of CHD or CHD-)] TJ ET
BT 65.250 67.893 Td /F1 9.8 Tf  [(related mortality are not affected by )] TJ ET
BT 220.782 67.893 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 245.703 67.893 Td /F1 9.8 Tf  [( mutation type )] TJ ET
0.267 0.267 0.267 rg
BT 309.653 67.893 Td /F1 9.8 Tf  [([54])] TJ ET
BT 325.916 67.893 Td /F1 9.8 Tf  [([57])] TJ ET
BT 342.179 67.893 Td /F1 9.8 Tf  [([58])] TJ ET
0.271 0.267 0.267 rg
BT 358.442 67.893 Td /F1 9.8 Tf  [( . Of note, the only subgroup analysis performed in )] TJ ET
BT 65.250 55.989 Td /F1 9.8 Tf  [(a randomized, double-blinded trial showed that )] TJ ET
BT 270.097 55.989 Td /F5 9.8 Tf  [(LDLR)] TJ ET
BT 295.019 55.989 Td /F1 9.8 Tf  [( mutation type altered the LDL-lowering effect of the investigated )] TJ ET
BT 65.250 44.084 Td /F1 9.8 Tf  [(statin, but this trend was not statistically significant )] TJ ET
0.267 0.267 0.267 rg
BT 285.259 44.084 Td /F1 9.8 Tf  [([55])] TJ ET
0.271 0.267 0.267 rg
BT 301.522 44.084 Td /F1 9.8 Tf  [( .)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(3)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
Q
endstream
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BT 65.250 767.476 Td /F4 9.8 Tf  [(Uncertainty surrounding when and how to pharmacologically treat lipid disorders in children.)] TJ ET
BT 497.604 767.476 Td /F1 9.8 Tf  [(As noted )] TJ ET
BT 65.250 755.571 Td /F1 9.8 Tf  [(previously, there is no evidence of the long-term health benefits or safety of statin treatment in children, as the longest )] TJ ET
BT 65.250 743.667 Td /F1 9.8 Tf  [(follow-up period in studies was 2 years )] TJ ET
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BT 235.397 743.667 Td /F1 9.8 Tf  [([36])] TJ ET
BT 251.660 743.667 Td /F1 9.8 Tf  [([37])] TJ ET
BT 267.923 743.667 Td /F1 9.8 Tf  [([39])] TJ ET
BT 284.186 743.667 Td /F1 9.8 Tf  [([40])] TJ ET
BT 300.449 743.667 Td /F1 9.8 Tf  [([41])] TJ ET
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BT 316.712 743.667 Td /F1 9.8 Tf  [( . Therefore, even if a child with FH is identified through )] TJ ET
BT 65.250 731.762 Td /F1 9.8 Tf  [(cascade screening, the issue of when to start drug therapy is not straightforward. The U.S. Preventive Services Task )] TJ ET
BT 65.250 719.857 Td /F1 9.8 Tf  [(Force \(USPSTF\) has not issued specific recommendations for the treatment of children with FH, although it did note )] TJ ET
BT 65.250 707.952 Td /F1 9.8 Tf  [(that statins are effective for reducing total and LDL cholesterol levels in these children )] TJ ET
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BT 437.008 707.952 Td /F1 9.8 Tf  [([38])] TJ ET
BT 453.271 707.952 Td /F1 9.8 Tf  [([48])] TJ ET
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BT 469.534 707.952 Td /F1 9.8 Tf  [( . The American )] TJ ET
BT 65.250 696.048 Td /F1 9.8 Tf  [(Academy of Pediatrics recommends that in children and adolescents with heterozygous FH, initial intervention �is )] TJ ET
BT 65.250 684.143 Td /F1 9.8 Tf  [(focused on changing the diet. However, if this approach does not lower LDL to an acceptable concentration, these )] TJ ET
BT 65.250 672.238 Td /F1 9.8 Tf  [(children may be candidates for pharmacologic intervention� )] TJ ET
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BT 323.186 672.238 Td /F1 9.8 Tf  [([50])] TJ ET
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BT 339.449 672.238 Td /F1 9.8 Tf  [( . The American Heart Association is more aggressive, )] TJ ET
BT 65.250 660.333 Td /F1 9.8 Tf  [(recommending the consideration of lipid-lowering therapy for children aged ?10 years \(and after the onset of menses )] TJ ET
BT 65.250 648.429 Td /F1 9.8 Tf  [(for girls\) whose LDL levels are �severely elevated� and that the age or LDL cutpoint at which such therapy is initiated )] TJ ET
BT 65.250 636.524 Td /F1 9.8 Tf  [(may be even lower for children with additional cardiovascular risk factors )] TJ ET
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BT 380.604 636.524 Td /F1 9.8 Tf  [([52])] TJ ET
BT 396.867 636.524 Td /F1 9.8 Tf  [([59])] TJ ET
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BT 413.130 636.524 Td /F1 9.8 Tf  [( . The National Lipid Association says )] TJ ET
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BT 65.250 612.714 Td /F1 9.8 Tf  [([53])] TJ ET
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BT 81.513 612.714 Td /F1 9.8 Tf  [( . The recommendation from NICE is similar: �lipid-modifying drug therapy for a child or young person with )] TJ ET
BT 65.250 600.810 Td /F1 9.8 Tf  [(\(heterozygous\) FH should usually be considered by the age of 10 years�, taking into account the presence of other )] TJ ET
BT 65.250 588.905 Td /F1 9.8 Tf  [(cardiovascular risk factors and the family history of CHD )] TJ ET
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BT 310.150 588.905 Td /F1 9.8 Tf  [([3])] TJ ET
BT 320.993 588.905 Td /F1 9.8 Tf  [([22])] TJ ET
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BT 337.255 588.905 Td /F1 9.8 Tf  [( .It is important to note, however, that lifestyle )] TJ ET
BT 65.250 577.000 Td /F1 9.8 Tf  [(interventions are also an important component of the medical management of FH for both children and adults )] TJ ET
0.267 0.267 0.267 rg
BT 538.349 577.000 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 554.612 577.000 Td /F1 9.8 Tf  [( , )] TJ ET
BT 65.250 565.095 Td /F1 9.8 Tf  [(since environmental and metabolic factors can influence the FH phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 390.403 565.095 Td /F1 9.8 Tf  [([5])] TJ ET
BT 401.245 565.095 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 412.087 565.095 Td /F1 9.8 Tf  [( . FH patients \(including children\) are )] TJ ET
BT 65.250 553.191 Td /F1 9.8 Tf  [(encouraged to get adequate physical activity, eat a healthy diet, and to refrain from smoking. Of note, however, a )] TJ ET
BT 65.250 541.286 Td /F1 9.8 Tf  [(recent Cochrane review of randomized controlled trials found that currently available data are insufficient to reach any )] TJ ET
BT 65.250 529.381 Td /F1 9.8 Tf  [(conclusions regarding the efficacy of different dietary interventions for FH patients, including a lack of data on the )] TJ ET
BT 65.250 517.476 Td /F1 9.8 Tf  [(usefulness of dietary modification over and above lipid-lowering drug therapy )] TJ ET
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BT 399.061 517.476 Td /F1 9.8 Tf  [([60])] TJ ET
0.271 0.267 0.267 rg
BT 415.324 517.476 Td /F1 9.8 Tf  [( .)] TJ ET
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BT 65.250 501.822 Td /F4 9.8 Tf  [(The best means by which to contact relatives of an FH index case.)] TJ ET
BT 371.936 501.822 Td /F1 9.8 Tf  [(This subject is currently under debate )] TJ ET
0.267 0.267 0.267 rg
BT 536.672 501.822 Td /F1 9.8 Tf  [([61])] TJ ET
BT 552.935 501.822 Td /F1 9.8 Tf  [([62])] TJ ET
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BT 569.198 501.822 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 474.917 Td /F1 9.8 Tf  [(In summary, the clinical validity and utility of cascade screening for FH is dependent on a number of factors, including the )] TJ ET
BT 26.250 463.012 Td /F1 9.8 Tf  [(criterion used to diagnose the disorder in the index case, the use of DNA testing in the index case and in relatives, and the )] TJ ET
BT 26.250 451.107 Td /F1 9.8 Tf  [(nature of the benefit and possible harms of identifying and pharmacologically treating the disorder in childhood. Nevertheless, )] TJ ET
BT 26.250 439.203 Td /F1 9.8 Tf  [(cascade screening is a straightforward and highly effective way to identify persons who have FH.)] TJ ET
BT 26.250 419.798 Td /F4 9.8 Tf  [(Links)] TJ ET
40.337 403.361 m 
40.337 403.807 40.154 404.251 39.838 404.567 c
39.522 404.883 39.078 405.067 38.631 405.067 c
38.185 405.067 37.741 404.883 37.425 404.567 c
37.109 404.251 36.925 403.807 36.925 403.361 c
36.925 402.914 37.109 402.470 37.425 402.154 c
37.741 401.838 38.185 401.654 38.631 401.654 c
39.078 401.654 39.522 401.838 39.838 402.154 c
40.154 402.470 40.337 402.914 40.337 403.361 c f
BT 45.750 400.393 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man \(OMIM\) entry on Hypercholesterolemia, Autosomal Dominant: )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 388.488 Td /F1 9.8 Tf  [(https://www.ncbi.nlm.nih.gov/omim/143890)] TJ ET
0.271 0.267 0.267 rg
BT 226.193 388.488 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 368.301 m 
40.337 368.748 40.154 369.192 39.838 369.508 c
39.522 369.824 39.078 370.007 38.631 370.007 c
38.185 370.007 37.741 369.824 37.425 369.508 c
37.109 369.192 36.925 368.748 36.925 368.301 c
36.925 367.855 37.109 367.411 37.425 367.095 c
37.741 366.779 38.185 366.595 38.631 366.595 c
39.078 366.595 39.522 366.779 39.838 367.095 c
40.154 367.411 40.337 367.855 40.337 368.301 c f
BT 45.750 365.334 Td /F1 9.8 Tf  [(NICE guidelines: )] TJ ET
0.267 0.267 0.267 rg
BT 121.069 365.334 Td /F1 9.8 Tf  [(https://www.nice.org.uk/guidance/CG71)] TJ ET
0.271 0.267 0.267 rg
BT 287.433 365.334 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 345.147 m 
40.337 345.593 40.154 346.037 39.838 346.353 c
39.522 346.669 39.078 346.853 38.631 346.853 c
38.185 346.853 37.741 346.669 37.425 346.353 c
37.109 346.037 36.925 345.593 36.925 345.147 c
36.925 344.700 37.109 344.256 37.425 343.940 c
37.741 343.624 38.185 343.440 38.631 343.440 c
39.078 343.440 39.522 343.624 39.838 343.940 c
40.154 344.256 40.337 344.700 40.337 345.147 c f
BT 45.750 342.179 Td /F1 9.8 Tf  [(Make Early Diagnosis to Prevent Early Death \(MEDPED\): )] TJ ET
0.267 0.267 0.267 rg
BT 297.154 342.179 Td /F1 9.8 Tf  [(www.medped.org)] TJ ET
0.271 0.267 0.267 rg
BT 373.009 342.179 Td /F1 9.8 Tf  [( ; )] TJ ET
0.267 0.267 0.267 rg
BT 381.140 342.179 Td /F1 9.8 Tf  [([63])] TJ ET
0.271 0.267 0.267 rg
BT 397.403 342.179 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 329.492 m 
40.337 329.938 40.154 330.382 39.838 330.698 c
39.522 331.014 39.078 331.198 38.631 331.198 c
38.185 331.198 37.741 331.014 37.425 330.698 c
37.109 330.382 36.925 329.938 36.925 329.492 c
36.925 329.045 37.109 328.601 37.425 328.285 c
37.741 327.969 38.185 327.786 38.631 327.786 c
39.078 327.786 39.522 327.969 39.838 328.285 c
40.154 328.601 40.337 329.045 40.337 329.492 c f
BT 45.750 326.524 Td /F1 9.8 Tf  [(CDC podcast on cascade screening for FH: )] TJ ET
0.267 0.267 0.267 rg
BT 236.489 326.524 Td /F1 9.8 Tf  [(https://www.cdc.gov/genomics/resources/video/RNed/index.htm)] TJ ET
0.271 0.267 0.267 rg
BT 506.876 326.524 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 303.369 Td /F1 9.8 Tf  [(Last updated: July 1, 2011)] TJ ET
BT 26.250 283.965 Td /F4 9.8 Tf  [(Acknowledgments)] TJ ET
BT 26.250 264.560 Td /F1 9.8 Tf  [(We would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics )] TJ ET
BT 26.250 252.655 Td /F1 9.8 Tf  [(\(OPHG\) at CDC for comments and guidance.)] TJ ET
BT 26.250 233.250 Td /F4 9.8 Tf  [(Funding information)] TJ ET
BT 26.250 213.846 Td /F1 9.8 Tf  [(This work was supported by the Office of Public Health Genomics \(OPHG\), Office of Surveillance, Epidemiology, and )] TJ ET
BT 26.250 201.941 Td /F1 9.8 Tf  [(Laboratory Services \(OSELS\), Centers for Disease Control and Prevention \(CDC\).)] TJ ET
BT 26.250 182.536 Td /F4 9.8 Tf  [(Competing interests)] TJ ET
BT 26.250 163.131 Td /F1 9.8 Tf  [(The authors declare that no competing interests exist.)] TJ ET
BT 26.250 143.727 Td /F4 9.8 Tf  [(Disclaimers)] TJ ET
BT 26.250 124.322 Td /F1 9.8 Tf  [(The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers )] TJ ET
BT 26.250 112.417 Td /F1 9.8 Tf  [(for Disease Control and Prevention \(CDC\).)] TJ ET
BT 26.250 93.012 Td /F1 9.8 Tf  [(The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we )] TJ ET
BT 26.250 81.108 Td /F1 9.8 Tf  [(suggest that you discuss them with your health care provider.)] TJ ET
Q
q
15.000 34.075 577.500 742.925 re W n
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
0.39 w 1 J 1 j
59.837 770.444 m 
59.837 770.890 59.654 771.334 59.338 771.650 c
59.022 771.966 58.578 772.150 58.131 772.150 c
57.685 772.150 57.241 771.966 56.925 771.650 c
56.609 771.334 56.425 770.890 56.425 770.444 c
56.425 769.997 56.609 769.553 56.925 769.237 c
57.241 768.921 57.685 768.738 58.131 768.738 c
58.578 768.738 59.022 768.921 59.338 769.237 c
59.654 769.553 59.837 769.997 59.837 770.444 c s
BT 65.250 767.476 Td /F4 9.8 Tf  [(Uncertainty surrounding when and how to pharmacologically treat lipid disorders in children.)] TJ ET
BT 497.604 767.476 Td /F1 9.8 Tf  [(As noted )] TJ ET
BT 65.250 755.571 Td /F1 9.8 Tf  [(previously, there is no evidence of the long-term health benefits or safety of statin treatment in children, as the longest )] TJ ET
BT 65.250 743.667 Td /F1 9.8 Tf  [(follow-up period in studies was 2 years )] TJ ET
0.267 0.267 0.267 rg
BT 235.397 743.667 Td /F1 9.8 Tf  [([36])] TJ ET
BT 251.660 743.667 Td /F1 9.8 Tf  [([37])] TJ ET
BT 267.923 743.667 Td /F1 9.8 Tf  [([39])] TJ ET
BT 284.186 743.667 Td /F1 9.8 Tf  [([40])] TJ ET
BT 300.449 743.667 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 316.712 743.667 Td /F1 9.8 Tf  [( . Therefore, even if a child with FH is identified through )] TJ ET
BT 65.250 731.762 Td /F1 9.8 Tf  [(cascade screening, the issue of when to start drug therapy is not straightforward. The U.S. Preventive Services Task )] TJ ET
BT 65.250 719.857 Td /F1 9.8 Tf  [(Force \(USPSTF\) has not issued specific recommendations for the treatment of children with FH, although it did note )] TJ ET
BT 65.250 707.952 Td /F1 9.8 Tf  [(that statins are effective for reducing total and LDL cholesterol levels in these children )] TJ ET
0.267 0.267 0.267 rg
BT 437.008 707.952 Td /F1 9.8 Tf  [([38])] TJ ET
BT 453.271 707.952 Td /F1 9.8 Tf  [([48])] TJ ET
0.271 0.267 0.267 rg
BT 469.534 707.952 Td /F1 9.8 Tf  [( . The American )] TJ ET
BT 65.250 696.048 Td /F1 9.8 Tf  [(Academy of Pediatrics recommends that in children and adolescents with heterozygous FH, initial intervention �is )] TJ ET
BT 65.250 684.143 Td /F1 9.8 Tf  [(focused on changing the diet. However, if this approach does not lower LDL to an acceptable concentration, these )] TJ ET
BT 65.250 672.238 Td /F1 9.8 Tf  [(children may be candidates for pharmacologic intervention� )] TJ ET
0.267 0.267 0.267 rg
BT 323.186 672.238 Td /F1 9.8 Tf  [([50])] TJ ET
0.271 0.267 0.267 rg
BT 339.449 672.238 Td /F1 9.8 Tf  [( . The American Heart Association is more aggressive, )] TJ ET
BT 65.250 660.333 Td /F1 9.8 Tf  [(recommending the consideration of lipid-lowering therapy for children aged ?10 years \(and after the onset of menses )] TJ ET
BT 65.250 648.429 Td /F1 9.8 Tf  [(for girls\) whose LDL levels are �severely elevated� and that the age or LDL cutpoint at which such therapy is initiated )] TJ ET
BT 65.250 636.524 Td /F1 9.8 Tf  [(may be even lower for children with additional cardiovascular risk factors )] TJ ET
0.267 0.267 0.267 rg
BT 380.604 636.524 Td /F1 9.8 Tf  [([52])] TJ ET
BT 396.867 636.524 Td /F1 9.8 Tf  [([59])] TJ ET
0.271 0.267 0.267 rg
BT 413.130 636.524 Td /F1 9.8 Tf  [( . The National Lipid Association says )] TJ ET
BT 65.250 624.619 Td /F1 9.8 Tf  [(that consideration should be given to starting treatment in children with \(heterozygous\) FH at 8 years of age or older )] TJ ET
0.267 0.267 0.267 rg
BT 65.250 612.714 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 81.513 612.714 Td /F1 9.8 Tf  [( . The recommendation from NICE is similar: �lipid-modifying drug therapy for a child or young person with )] TJ ET
BT 65.250 600.810 Td /F1 9.8 Tf  [(\(heterozygous\) FH should usually be considered by the age of 10 years�, taking into account the presence of other )] TJ ET
BT 65.250 588.905 Td /F1 9.8 Tf  [(cardiovascular risk factors and the family history of CHD )] TJ ET
0.267 0.267 0.267 rg
BT 310.150 588.905 Td /F1 9.8 Tf  [([3])] TJ ET
BT 320.993 588.905 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 337.255 588.905 Td /F1 9.8 Tf  [( .It is important to note, however, that lifestyle )] TJ ET
BT 65.250 577.000 Td /F1 9.8 Tf  [(interventions are also an important component of the medical management of FH for both children and adults )] TJ ET
0.267 0.267 0.267 rg
BT 538.349 577.000 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 554.612 577.000 Td /F1 9.8 Tf  [( , )] TJ ET
BT 65.250 565.095 Td /F1 9.8 Tf  [(since environmental and metabolic factors can influence the FH phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 390.403 565.095 Td /F1 9.8 Tf  [([5])] TJ ET
BT 401.245 565.095 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 412.087 565.095 Td /F1 9.8 Tf  [( . FH patients \(including children\) are )] TJ ET
BT 65.250 553.191 Td /F1 9.8 Tf  [(encouraged to get adequate physical activity, eat a healthy diet, and to refrain from smoking. Of note, however, a )] TJ ET
BT 65.250 541.286 Td /F1 9.8 Tf  [(recent Cochrane review of randomized controlled trials found that currently available data are insufficient to reach any )] TJ ET
BT 65.250 529.381 Td /F1 9.8 Tf  [(conclusions regarding the efficacy of different dietary interventions for FH patients, including a lack of data on the )] TJ ET
BT 65.250 517.476 Td /F1 9.8 Tf  [(usefulness of dietary modification over and above lipid-lowering drug therapy )] TJ ET
0.267 0.267 0.267 rg
BT 399.061 517.476 Td /F1 9.8 Tf  [([60])] TJ ET
0.271 0.267 0.267 rg
BT 415.324 517.476 Td /F1 9.8 Tf  [( .)] TJ ET
0.39 w 1 J 1 j
59.837 504.789 m 
59.837 505.236 59.654 505.680 59.338 505.996 c
59.022 506.312 58.578 506.495 58.131 506.495 c
57.685 506.495 57.241 506.312 56.925 505.996 c
56.609 505.680 56.425 505.236 56.425 504.789 c
56.425 504.343 56.609 503.899 56.925 503.583 c
57.241 503.267 57.685 503.083 58.131 503.083 c
58.578 503.083 59.022 503.267 59.338 503.583 c
59.654 503.899 59.837 504.343 59.837 504.789 c s
BT 65.250 501.822 Td /F4 9.8 Tf  [(The best means by which to contact relatives of an FH index case.)] TJ ET
BT 371.936 501.822 Td /F1 9.8 Tf  [(This subject is currently under debate )] TJ ET
0.267 0.267 0.267 rg
BT 536.672 501.822 Td /F1 9.8 Tf  [([61])] TJ ET
BT 552.935 501.822 Td /F1 9.8 Tf  [([62])] TJ ET
0.271 0.267 0.267 rg
BT 569.198 501.822 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 474.917 Td /F1 9.8 Tf  [(In summary, the clinical validity and utility of cascade screening for FH is dependent on a number of factors, including the )] TJ ET
BT 26.250 463.012 Td /F1 9.8 Tf  [(criterion used to diagnose the disorder in the index case, the use of DNA testing in the index case and in relatives, and the )] TJ ET
BT 26.250 451.107 Td /F1 9.8 Tf  [(nature of the benefit and possible harms of identifying and pharmacologically treating the disorder in childhood. Nevertheless, )] TJ ET
BT 26.250 439.203 Td /F1 9.8 Tf  [(cascade screening is a straightforward and highly effective way to identify persons who have FH.)] TJ ET
BT 26.250 419.798 Td /F4 9.8 Tf  [(Links)] TJ ET
40.337 403.361 m 
40.337 403.807 40.154 404.251 39.838 404.567 c
39.522 404.883 39.078 405.067 38.631 405.067 c
38.185 405.067 37.741 404.883 37.425 404.567 c
37.109 404.251 36.925 403.807 36.925 403.361 c
36.925 402.914 37.109 402.470 37.425 402.154 c
37.741 401.838 38.185 401.654 38.631 401.654 c
39.078 401.654 39.522 401.838 39.838 402.154 c
40.154 402.470 40.337 402.914 40.337 403.361 c f
BT 45.750 400.393 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man \(OMIM\) entry on Hypercholesterolemia, Autosomal Dominant: )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 388.488 Td /F1 9.8 Tf  [(https://www.ncbi.nlm.nih.gov/omim/143890)] TJ ET
0.271 0.267 0.267 rg
BT 226.193 388.488 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 368.301 m 
40.337 368.748 40.154 369.192 39.838 369.508 c
39.522 369.824 39.078 370.007 38.631 370.007 c
38.185 370.007 37.741 369.824 37.425 369.508 c
37.109 369.192 36.925 368.748 36.925 368.301 c
36.925 367.855 37.109 367.411 37.425 367.095 c
37.741 366.779 38.185 366.595 38.631 366.595 c
39.078 366.595 39.522 366.779 39.838 367.095 c
40.154 367.411 40.337 367.855 40.337 368.301 c f
BT 45.750 365.334 Td /F1 9.8 Tf  [(NICE guidelines: )] TJ ET
0.267 0.267 0.267 rg
BT 121.069 365.334 Td /F1 9.8 Tf  [(https://www.nice.org.uk/guidance/CG71)] TJ ET
0.271 0.267 0.267 rg
BT 287.433 365.334 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 345.147 m 
40.337 345.593 40.154 346.037 39.838 346.353 c
39.522 346.669 39.078 346.853 38.631 346.853 c
38.185 346.853 37.741 346.669 37.425 346.353 c
37.109 346.037 36.925 345.593 36.925 345.147 c
36.925 344.700 37.109 344.256 37.425 343.940 c
37.741 343.624 38.185 343.440 38.631 343.440 c
39.078 343.440 39.522 343.624 39.838 343.940 c
40.154 344.256 40.337 344.700 40.337 345.147 c f
BT 45.750 342.179 Td /F1 9.8 Tf  [(Make Early Diagnosis to Prevent Early Death \(MEDPED\): )] TJ ET
0.267 0.267 0.267 rg
BT 297.154 342.179 Td /F1 9.8 Tf  [(www.medped.org)] TJ ET
0.271 0.267 0.267 rg
BT 373.009 342.179 Td /F1 9.8 Tf  [( ; )] TJ ET
0.267 0.267 0.267 rg
BT 381.140 342.179 Td /F1 9.8 Tf  [([63])] TJ ET
0.271 0.267 0.267 rg
BT 397.403 342.179 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 329.492 m 
40.337 329.938 40.154 330.382 39.838 330.698 c
39.522 331.014 39.078 331.198 38.631 331.198 c
38.185 331.198 37.741 331.014 37.425 330.698 c
37.109 330.382 36.925 329.938 36.925 329.492 c
36.925 329.045 37.109 328.601 37.425 328.285 c
37.741 327.969 38.185 327.786 38.631 327.786 c
39.078 327.786 39.522 327.969 39.838 328.285 c
40.154 328.601 40.337 329.045 40.337 329.492 c f
BT 45.750 326.524 Td /F1 9.8 Tf  [(CDC podcast on cascade screening for FH: )] TJ ET
0.267 0.267 0.267 rg
BT 236.489 326.524 Td /F1 9.8 Tf  [(https://www.cdc.gov/genomics/resources/video/RNed/index.htm)] TJ ET
0.271 0.267 0.267 rg
BT 506.876 326.524 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 303.369 Td /F1 9.8 Tf  [(Last updated: July 1, 2011)] TJ ET
BT 26.250 283.965 Td /F4 9.8 Tf  [(Acknowledgments)] TJ ET
BT 26.250 264.560 Td /F1 9.8 Tf  [(We would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics )] TJ ET
BT 26.250 252.655 Td /F1 9.8 Tf  [(\(OPHG\) at CDC for comments and guidance.)] TJ ET
BT 26.250 233.250 Td /F4 9.8 Tf  [(Funding information)] TJ ET
BT 26.250 213.846 Td /F1 9.8 Tf  [(This work was supported by the Office of Public Health Genomics \(OPHG\), Office of Surveillance, Epidemiology, and )] TJ ET
BT 26.250 201.941 Td /F1 9.8 Tf  [(Laboratory Services \(OSELS\), Centers for Disease Control and Prevention \(CDC\).)] TJ ET
BT 26.250 182.536 Td /F4 9.8 Tf  [(Competing interests)] TJ ET
BT 26.250 163.131 Td /F1 9.8 Tf  [(The authors declare that no competing interests exist.)] TJ ET
BT 26.250 143.727 Td /F4 9.8 Tf  [(Disclaimers)] TJ ET
BT 26.250 124.322 Td /F1 9.8 Tf  [(The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers )] TJ ET
BT 26.250 112.417 Td /F1 9.8 Tf  [(for Disease Control and Prevention \(CDC\).)] TJ ET
BT 26.250 93.012 Td /F1 9.8 Tf  [(The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we )] TJ ET
BT 26.250 81.108 Td /F1 9.8 Tf  [(suggest that you discuss them with your health care provider.)] TJ ET
Q
q
15.000 34.075 577.500 742.925 re W n
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
0.39 w 1 J 1 j
59.837 770.444 m 
59.837 770.890 59.654 771.334 59.338 771.650 c
59.022 771.966 58.578 772.150 58.131 772.150 c
57.685 772.150 57.241 771.966 56.925 771.650 c
56.609 771.334 56.425 770.890 56.425 770.444 c
56.425 769.997 56.609 769.553 56.925 769.237 c
57.241 768.921 57.685 768.738 58.131 768.738 c
58.578 768.738 59.022 768.921 59.338 769.237 c
59.654 769.553 59.837 769.997 59.837 770.444 c s
BT 65.250 767.476 Td /F4 9.8 Tf  [(Uncertainty surrounding when and how to pharmacologically treat lipid disorders in children.)] TJ ET
BT 497.604 767.476 Td /F1 9.8 Tf  [(As noted )] TJ ET
BT 65.250 755.571 Td /F1 9.8 Tf  [(previously, there is no evidence of the long-term health benefits or safety of statin treatment in children, as the longest )] TJ ET
BT 65.250 743.667 Td /F1 9.8 Tf  [(follow-up period in studies was 2 years )] TJ ET
0.267 0.267 0.267 rg
BT 235.397 743.667 Td /F1 9.8 Tf  [([36])] TJ ET
BT 251.660 743.667 Td /F1 9.8 Tf  [([37])] TJ ET
BT 267.923 743.667 Td /F1 9.8 Tf  [([39])] TJ ET
BT 284.186 743.667 Td /F1 9.8 Tf  [([40])] TJ ET
BT 300.449 743.667 Td /F1 9.8 Tf  [([41])] TJ ET
0.271 0.267 0.267 rg
BT 316.712 743.667 Td /F1 9.8 Tf  [( . Therefore, even if a child with FH is identified through )] TJ ET
BT 65.250 731.762 Td /F1 9.8 Tf  [(cascade screening, the issue of when to start drug therapy is not straightforward. The U.S. Preventive Services Task )] TJ ET
BT 65.250 719.857 Td /F1 9.8 Tf  [(Force \(USPSTF\) has not issued specific recommendations for the treatment of children with FH, although it did note )] TJ ET
BT 65.250 707.952 Td /F1 9.8 Tf  [(that statins are effective for reducing total and LDL cholesterol levels in these children )] TJ ET
0.267 0.267 0.267 rg
BT 437.008 707.952 Td /F1 9.8 Tf  [([38])] TJ ET
BT 453.271 707.952 Td /F1 9.8 Tf  [([48])] TJ ET
0.271 0.267 0.267 rg
BT 469.534 707.952 Td /F1 9.8 Tf  [( . The American )] TJ ET
BT 65.250 696.048 Td /F1 9.8 Tf  [(Academy of Pediatrics recommends that in children and adolescents with heterozygous FH, initial intervention �is )] TJ ET
BT 65.250 684.143 Td /F1 9.8 Tf  [(focused on changing the diet. However, if this approach does not lower LDL to an acceptable concentration, these )] TJ ET
BT 65.250 672.238 Td /F1 9.8 Tf  [(children may be candidates for pharmacologic intervention� )] TJ ET
0.267 0.267 0.267 rg
BT 323.186 672.238 Td /F1 9.8 Tf  [([50])] TJ ET
0.271 0.267 0.267 rg
BT 339.449 672.238 Td /F1 9.8 Tf  [( . The American Heart Association is more aggressive, )] TJ ET
BT 65.250 660.333 Td /F1 9.8 Tf  [(recommending the consideration of lipid-lowering therapy for children aged ?10 years \(and after the onset of menses )] TJ ET
BT 65.250 648.429 Td /F1 9.8 Tf  [(for girls\) whose LDL levels are �severely elevated� and that the age or LDL cutpoint at which such therapy is initiated )] TJ ET
BT 65.250 636.524 Td /F1 9.8 Tf  [(may be even lower for children with additional cardiovascular risk factors )] TJ ET
0.267 0.267 0.267 rg
BT 380.604 636.524 Td /F1 9.8 Tf  [([52])] TJ ET
BT 396.867 636.524 Td /F1 9.8 Tf  [([59])] TJ ET
0.271 0.267 0.267 rg
BT 413.130 636.524 Td /F1 9.8 Tf  [( . The National Lipid Association says )] TJ ET
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0.267 0.267 0.267 rg
BT 65.250 612.714 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 81.513 612.714 Td /F1 9.8 Tf  [( . The recommendation from NICE is similar: �lipid-modifying drug therapy for a child or young person with )] TJ ET
BT 65.250 600.810 Td /F1 9.8 Tf  [(\(heterozygous\) FH should usually be considered by the age of 10 years�, taking into account the presence of other )] TJ ET
BT 65.250 588.905 Td /F1 9.8 Tf  [(cardiovascular risk factors and the family history of CHD )] TJ ET
0.267 0.267 0.267 rg
BT 310.150 588.905 Td /F1 9.8 Tf  [([3])] TJ ET
BT 320.993 588.905 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 337.255 588.905 Td /F1 9.8 Tf  [( .It is important to note, however, that lifestyle )] TJ ET
BT 65.250 577.000 Td /F1 9.8 Tf  [(interventions are also an important component of the medical management of FH for both children and adults )] TJ ET
0.267 0.267 0.267 rg
BT 538.349 577.000 Td /F1 9.8 Tf  [([22])] TJ ET
0.271 0.267 0.267 rg
BT 554.612 577.000 Td /F1 9.8 Tf  [( , )] TJ ET
BT 65.250 565.095 Td /F1 9.8 Tf  [(since environmental and metabolic factors can influence the FH phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 390.403 565.095 Td /F1 9.8 Tf  [([5])] TJ ET
BT 401.245 565.095 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 412.087 565.095 Td /F1 9.8 Tf  [( . FH patients \(including children\) are )] TJ ET
BT 65.250 553.191 Td /F1 9.8 Tf  [(encouraged to get adequate physical activity, eat a healthy diet, and to refrain from smoking. Of note, however, a )] TJ ET
BT 65.250 541.286 Td /F1 9.8 Tf  [(recent Cochrane review of randomized controlled trials found that currently available data are insufficient to reach any )] TJ ET
BT 65.250 529.381 Td /F1 9.8 Tf  [(conclusions regarding the efficacy of different dietary interventions for FH patients, including a lack of data on the )] TJ ET
BT 65.250 517.476 Td /F1 9.8 Tf  [(usefulness of dietary modification over and above lipid-lowering drug therapy )] TJ ET
0.267 0.267 0.267 rg
BT 399.061 517.476 Td /F1 9.8 Tf  [([60])] TJ ET
0.271 0.267 0.267 rg
BT 415.324 517.476 Td /F1 9.8 Tf  [( .)] TJ ET
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59.837 504.789 m 
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BT 65.250 501.822 Td /F4 9.8 Tf  [(The best means by which to contact relatives of an FH index case.)] TJ ET
BT 371.936 501.822 Td /F1 9.8 Tf  [(This subject is currently under debate )] TJ ET
0.267 0.267 0.267 rg
BT 536.672 501.822 Td /F1 9.8 Tf  [([61])] TJ ET
BT 552.935 501.822 Td /F1 9.8 Tf  [([62])] TJ ET
0.271 0.267 0.267 rg
BT 569.198 501.822 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 474.917 Td /F1 9.8 Tf  [(In summary, the clinical validity and utility of cascade screening for FH is dependent on a number of factors, including the )] TJ ET
BT 26.250 463.012 Td /F1 9.8 Tf  [(criterion used to diagnose the disorder in the index case, the use of DNA testing in the index case and in relatives, and the )] TJ ET
BT 26.250 451.107 Td /F1 9.8 Tf  [(nature of the benefit and possible harms of identifying and pharmacologically treating the disorder in childhood. Nevertheless, )] TJ ET
BT 26.250 439.203 Td /F1 9.8 Tf  [(cascade screening is a straightforward and highly effective way to identify persons who have FH.)] TJ ET
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40.337 403.361 m 
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BT 45.750 400.393 Td /F1 9.8 Tf  [(Online Mendelian Inheritance in Man \(OMIM\) entry on Hypercholesterolemia, Autosomal Dominant: )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 388.488 Td /F1 9.8 Tf  [(https://www.ncbi.nlm.nih.gov/omim/143890)] TJ ET
0.271 0.267 0.267 rg
BT 226.193 388.488 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 368.301 m 
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38.185 370.007 37.741 369.824 37.425 369.508 c
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39.078 366.595 39.522 366.779 39.838 367.095 c
40.154 367.411 40.337 367.855 40.337 368.301 c f
BT 45.750 365.334 Td /F1 9.8 Tf  [(NICE guidelines: )] TJ ET
0.267 0.267 0.267 rg
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0.271 0.267 0.267 rg
BT 287.433 365.334 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 345.147 m 
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40.154 344.256 40.337 344.700 40.337 345.147 c f
BT 45.750 342.179 Td /F1 9.8 Tf  [(Make Early Diagnosis to Prevent Early Death \(MEDPED\): )] TJ ET
0.267 0.267 0.267 rg
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0.271 0.267 0.267 rg
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0.267 0.267 0.267 rg
BT 381.140 342.179 Td /F1 9.8 Tf  [([63])] TJ ET
0.271 0.267 0.267 rg
BT 397.403 342.179 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 329.492 m 
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38.185 331.198 37.741 331.014 37.425 330.698 c
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39.078 327.786 39.522 327.969 39.838 328.285 c
40.154 328.601 40.337 329.045 40.337 329.492 c f
BT 45.750 326.524 Td /F1 9.8 Tf  [(CDC podcast on cascade screening for FH: )] TJ ET
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BT 26.250 303.369 Td /F1 9.8 Tf  [(Last updated: July 1, 2011)] TJ ET
BT 26.250 283.965 Td /F4 9.8 Tf  [(Acknowledgments)] TJ ET
BT 26.250 264.560 Td /F1 9.8 Tf  [(We would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics )] TJ ET
BT 26.250 252.655 Td /F1 9.8 Tf  [(\(OPHG\) at CDC for comments and guidance.)] TJ ET
BT 26.250 233.250 Td /F4 9.8 Tf  [(Funding information)] TJ ET
BT 26.250 213.846 Td /F1 9.8 Tf  [(This work was supported by the Office of Public Health Genomics \(OPHG\), Office of Surveillance, Epidemiology, and )] TJ ET
BT 26.250 201.941 Td /F1 9.8 Tf  [(Laboratory Services \(OSELS\), Centers for Disease Control and Prevention \(CDC\).)] TJ ET
BT 26.250 182.536 Td /F4 9.8 Tf  [(Competing interests)] TJ ET
BT 26.250 163.131 Td /F1 9.8 Tf  [(The authors declare that no competing interests exist.)] TJ ET
BT 26.250 143.727 Td /F4 9.8 Tf  [(Disclaimers)] TJ ET
BT 26.250 124.322 Td /F1 9.8 Tf  [(The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers )] TJ ET
BT 26.250 112.417 Td /F1 9.8 Tf  [(for Disease Control and Prevention \(CDC\).)] TJ ET
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BT 26.250 581.277 Td /F1 9.8 Tf  [(and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. )] TJ ET
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BT 38.132 549.967 Td /F1 9.8 Tf  [(Jansen AC, van Aalst-Cohen ES, Tanck MW, Trip MD, Lansberg PJ, Liem AH, van Lennep HW, Sijbrands EJ, Kastelein JJ. )] TJ ET
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BT 38.132 506.753 Td /F1 9.8 Tf  [(Jansen AC, van Wissen S, Defesche JC, Kastelein JJ. Phenotypic variability in familial hypercholesterolaemia: an update. )] TJ ET
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BT 26.250 475.443 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 475.443 Td /F1 9.8 Tf  [(World Health Organization \(WHO\). Familial Hypercholesterolaemia \(FH\): Report of a second WHO Consultation. 1999. )] TJ ET
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BT 38.132 444.134 Td /F1 9.8 Tf  [(Neil HA, Hammond T, Huxley R, Matthews DR, Humphries SE. Extent of underdiagnosis of familial hypercholesterolaemia in )] TJ ET
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BT 26.250 420.324 Td /F1 9.8 Tf  [(PMCID: PMC27432.)] TJ ET
BT 26.250 400.920 Td /F1 9.8 Tf  [(9.)] TJ ET
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BT 26.250 389.015 Td /F1 9.8 Tf  [(Preventing Early Deaths. Berg K, Boulyjenkov, V, Christen, Y \(editors\). Genetic Approaches to Noncommunicable Diseases. )] TJ ET
BT 26.250 377.110 Td /F1 9.8 Tf  [(1996. Berlin: Springer Verlag. pp. 35-46.)] TJ ET
BT 26.250 357.705 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 357.705 Td /F1 9.8 Tf  [(Hopkins PN. Defining the challenges of familial hypercholesterolemia screening: introduction. J Clin Lipidol. 2010 Sep-)] TJ ET
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BT 43.553 326.396 Td /F1 9.8 Tf  [(Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Screening for hypercholesterolaemia versus )] TJ ET
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BT 26.250 271.277 Td /F1 9.8 Tf  [(approaches of screening for familial hypercholesterolaemia. BMJ. 2002 Jun 1;324\(7349\):1303. PubMed PMID: 12039822; )] TJ ET
BT 26.250 259.372 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC113765.)] TJ ET
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BT 43.553 208.658 Td /F1 9.8 Tf  [(Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. Advanced method for the identification of patients with )] TJ ET
BT 26.250 196.753 Td /F1 9.8 Tf  [(inherited hypercholesterolemia. Semin Vasc Med. 2004 Feb;4\(1\):59-65. Review. PubMed PMID: 15199434.)] TJ ET
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BT 26.250 146.039 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 146.039 Td /F1 9.8 Tf  [(Hamilton-Craig I. Case-finding for familial hypercholesterolemia in the Asia-Pacific region. Semin Vasc Med. 2004 )] TJ ET
BT 26.250 134.134 Td /F1 9.8 Tf  [(Feb;4\(1\):87-92. PubMed PMID: 15199437.)] TJ ET
BT 26.250 114.729 Td /F1 9.8 Tf  [(17.)] TJ ET
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BT 26.250 71.515 Td /F1 9.8 Tf  [(18.)] TJ ET
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BT 38.132 722.824 Td /F1 9.8 Tf  [(Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial )] TJ ET
BT 26.250 710.919 Td /F1 9.8 Tf  [(hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004 Sep 1;160\(5\):407-20. Review. PubMed PMID: )] TJ ET
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BT 26.250 667.705 Td /F1 9.8 Tf  [(association review. Am J Epidemiol. 2004 Sep 1;160\(5\):421-9. Review. PubMed PMID: 15321838.)] TJ ET
BT 26.250 648.300 Td /F1 9.8 Tf  [(3.)] TJ ET
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BT 26.250 636.396 Td /F1 9.8 Tf  [(Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical Guidelines and Evidence Review for )] TJ ET
BT 26.250 624.491 Td /F1 9.8 Tf  [(Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. )] TJ ET
BT 26.250 612.586 Td /F1 9.8 Tf  [(2008. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners.)] TJ ET
BT 26.250 593.181 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 593.181 Td /F1 9.8 Tf  [(Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE. Reductions in all-cause, cancer, )] TJ ET
BT 26.250 581.277 Td /F1 9.8 Tf  [(and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. )] TJ ET
BT 26.250 569.372 Td /F1 9.8 Tf  [(Eur Heart J. 2008 Nov;29\(21\):2625-33. Epub 2008 Oct 7. PubMed PMID: 18840879; PubMed Central PMCID: PMC2577142.)] TJ ET
BT 26.250 549.967 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 549.967 Td /F1 9.8 Tf  [(Jansen AC, van Aalst-Cohen ES, Tanck MW, Trip MD, Lansberg PJ, Liem AH, van Lennep HW, Sijbrands EJ, Kastelein JJ. )] TJ ET
BT 26.250 538.062 Td /F1 9.8 Tf  [(The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J )] TJ ET
BT 26.250 526.158 Td /F1 9.8 Tf  [(Intern Med. 2004 Dec;256\(6\):482-90. PubMed PMID: 15554949.)] TJ ET
BT 26.250 506.753 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 506.753 Td /F1 9.8 Tf  [(Jansen AC, van Wissen S, Defesche JC, Kastelein JJ. Phenotypic variability in familial hypercholesterolaemia: an update. )] TJ ET
BT 26.250 494.848 Td /F1 9.8 Tf  [(Curr Opin Lipidol. 2002 Apr;13\(2\):165-71. Review. PubMed PMID: 11891419.)] TJ ET
BT 26.250 475.443 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 475.443 Td /F1 9.8 Tf  [(World Health Organization \(WHO\). Familial Hypercholesterolaemia \(FH\): Report of a second WHO Consultation. 1999. )] TJ ET
BT 26.250 463.539 Td /F1 9.8 Tf  [(Geneva.)] TJ ET
BT 26.250 444.134 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 444.134 Td /F1 9.8 Tf  [(Neil HA, Hammond T, Huxley R, Matthews DR, Humphries SE. Extent of underdiagnosis of familial hypercholesterolaemia in )] TJ ET
BT 26.250 432.229 Td /F1 9.8 Tf  [(routine practice: prospective registry study. BMJ. 2000 Jul 15;321\(7254\):148. PubMed PMID: 10894692; PubMed Central )] TJ ET
BT 26.250 420.324 Td /F1 9.8 Tf  [(PMCID: PMC27432.)] TJ ET
BT 26.250 400.920 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 400.920 Td /F1 9.8 Tf  [(Williams RR, Hamilton-Craig I, Kostner G, Hegele RA, Hayden MR, et al. MEDPED: An Integrated Genetic Strategy for )] TJ ET
BT 26.250 389.015 Td /F1 9.8 Tf  [(Preventing Early Deaths. Berg K, Boulyjenkov, V, Christen, Y \(editors\). Genetic Approaches to Noncommunicable Diseases. )] TJ ET
BT 26.250 377.110 Td /F1 9.8 Tf  [(1996. Berlin: Springer Verlag. pp. 35-46.)] TJ ET
BT 26.250 357.705 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 357.705 Td /F1 9.8 Tf  [(Hopkins PN. Defining the challenges of familial hypercholesterolemia screening: introduction. J Clin Lipidol. 2010 Sep-)] TJ ET
BT 26.250 345.801 Td /F1 9.8 Tf  [(Oct;4\(5\):342-5. Epub 2010 Aug 20. PubMed PMID: 21122675.)] TJ ET
BT 26.250 326.396 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 326.396 Td /F1 9.8 Tf  [(Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Screening for hypercholesterolaemia versus )] TJ ET
BT 26.250 314.491 Td /F1 9.8 Tf  [(case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis. Health Technol Assess. )] TJ ET
BT 26.250 302.586 Td /F1 9.8 Tf  [(2000;4\(29\):1-123. Review. PubMed PMID: 11109029.)] TJ ET
BT 26.250 283.182 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 283.182 Td /F1 9.8 Tf  [(Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Cost effectiveness analysis of different )] TJ ET
BT 26.250 271.277 Td /F1 9.8 Tf  [(approaches of screening for familial hypercholesterolaemia. BMJ. 2002 Jun 1;324\(7349\):1303. PubMed PMID: 12039822; )] TJ ET
BT 26.250 259.372 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC113765.)] TJ ET
BT 26.250 239.967 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 239.967 Td /F1 9.8 Tf  [(Datta BN, McDowell IF, Rees A. Integrating provision of specialist lipid services with cascade testing for familial )] TJ ET
BT 26.250 228.063 Td /F1 9.8 Tf  [(hypercholesterolaemia. Curr Opin Lipidol. 2010 Aug;21\(4\):366-71. Review. PubMed PMID: 20613514.)] TJ ET
BT 26.250 208.658 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 208.658 Td /F1 9.8 Tf  [(Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. Advanced method for the identification of patients with )] TJ ET
BT 26.250 196.753 Td /F1 9.8 Tf  [(inherited hypercholesterolemia. Semin Vasc Med. 2004 Feb;4\(1\):59-65. Review. PubMed PMID: 15199434.)] TJ ET
BT 26.250 177.348 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 177.348 Td /F1 9.8 Tf  [(Umans-Eckenhausen MA, Defesche JC, Sijbrands EJ, Scheerder RL, Kastelein JJ. Review of first 5 years of screening for )] TJ ET
BT 26.250 165.444 Td /F1 9.8 Tf  [(familial hypercholesterolaemia in the Netherlands. Lancet. 2001 Jan 20;357\(9251\):165-8. PubMed PMID: 11213091.)] TJ ET
BT 26.250 146.039 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 146.039 Td /F1 9.8 Tf  [(Hamilton-Craig I. Case-finding for familial hypercholesterolemia in the Asia-Pacific region. Semin Vasc Med. 2004 )] TJ ET
BT 26.250 134.134 Td /F1 9.8 Tf  [(Feb;4\(1\):87-92. PubMed PMID: 15199437.)] TJ ET
BT 26.250 114.729 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 114.729 Td /F1 9.8 Tf  [(Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, S�rensen S, Bakken KS. Application of molecular )] TJ ET
BT 26.250 102.825 Td /F1 9.8 Tf  [(genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. Semin Vasc )] TJ ET
BT 26.250 90.920 Td /F1 9.8 Tf  [(Med. 2004 Feb;4\(1\):75-85. Review. PubMed PMID: 15199436.)] TJ ET
BT 26.250 71.515 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 71.515 Td /F1 9.8 Tf  [(Marais AD, Firth JC, Blom DJ. Familial hypercholesterolemia in South Africa. Semin Vasc Med. 2004 Feb;4\(1\):93-5. )] TJ ET
BT 26.250 59.610 Td /F1 9.8 Tf  [(PubMed PMID: 15199438.)] TJ ET
Q
q
15.000 49.729 577.500 727.271 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 722.824 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 722.824 Td /F1 9.8 Tf  [(Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial )] TJ ET
BT 26.250 710.919 Td /F1 9.8 Tf  [(hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004 Sep 1;160\(5\):407-20. Review. PubMed PMID: )] TJ ET
BT 26.250 699.015 Td /F1 9.8 Tf  [(15321837.)] TJ ET
BT 26.250 679.610 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 679.610 Td /F1 9.8 Tf  [(Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE )] TJ ET
BT 26.250 667.705 Td /F1 9.8 Tf  [(association review. Am J Epidemiol. 2004 Sep 1;160\(5\):421-9. Review. PubMed PMID: 15321838.)] TJ ET
BT 26.250 648.300 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 648.300 Td /F1 9.8 Tf  [(DeMott, K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, )] TJ ET
BT 26.250 636.396 Td /F1 9.8 Tf  [(Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical Guidelines and Evidence Review for )] TJ ET
BT 26.250 624.491 Td /F1 9.8 Tf  [(Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. )] TJ ET
BT 26.250 612.586 Td /F1 9.8 Tf  [(2008. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners.)] TJ ET
BT 26.250 593.181 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 593.181 Td /F1 9.8 Tf  [(Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE. Reductions in all-cause, cancer, )] TJ ET
BT 26.250 581.277 Td /F1 9.8 Tf  [(and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. )] TJ ET
BT 26.250 569.372 Td /F1 9.8 Tf  [(Eur Heart J. 2008 Nov;29\(21\):2625-33. Epub 2008 Oct 7. PubMed PMID: 18840879; PubMed Central PMCID: PMC2577142.)] TJ ET
BT 26.250 549.967 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 549.967 Td /F1 9.8 Tf  [(Jansen AC, van Aalst-Cohen ES, Tanck MW, Trip MD, Lansberg PJ, Liem AH, van Lennep HW, Sijbrands EJ, Kastelein JJ. )] TJ ET
BT 26.250 538.062 Td /F1 9.8 Tf  [(The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J )] TJ ET
BT 26.250 526.158 Td /F1 9.8 Tf  [(Intern Med. 2004 Dec;256\(6\):482-90. PubMed PMID: 15554949.)] TJ ET
BT 26.250 506.753 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 506.753 Td /F1 9.8 Tf  [(Jansen AC, van Wissen S, Defesche JC, Kastelein JJ. Phenotypic variability in familial hypercholesterolaemia: an update. )] TJ ET
BT 26.250 494.848 Td /F1 9.8 Tf  [(Curr Opin Lipidol. 2002 Apr;13\(2\):165-71. Review. PubMed PMID: 11891419.)] TJ ET
BT 26.250 475.443 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 475.443 Td /F1 9.8 Tf  [(World Health Organization \(WHO\). Familial Hypercholesterolaemia \(FH\): Report of a second WHO Consultation. 1999. )] TJ ET
BT 26.250 463.539 Td /F1 9.8 Tf  [(Geneva.)] TJ ET
BT 26.250 444.134 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 444.134 Td /F1 9.8 Tf  [(Neil HA, Hammond T, Huxley R, Matthews DR, Humphries SE. Extent of underdiagnosis of familial hypercholesterolaemia in )] TJ ET
BT 26.250 432.229 Td /F1 9.8 Tf  [(routine practice: prospective registry study. BMJ. 2000 Jul 15;321\(7254\):148. PubMed PMID: 10894692; PubMed Central )] TJ ET
BT 26.250 420.324 Td /F1 9.8 Tf  [(PMCID: PMC27432.)] TJ ET
BT 26.250 400.920 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 400.920 Td /F1 9.8 Tf  [(Williams RR, Hamilton-Craig I, Kostner G, Hegele RA, Hayden MR, et al. MEDPED: An Integrated Genetic Strategy for )] TJ ET
BT 26.250 389.015 Td /F1 9.8 Tf  [(Preventing Early Deaths. Berg K, Boulyjenkov, V, Christen, Y \(editors\). Genetic Approaches to Noncommunicable Diseases. )] TJ ET
BT 26.250 377.110 Td /F1 9.8 Tf  [(1996. Berlin: Springer Verlag. pp. 35-46.)] TJ ET
BT 26.250 357.705 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 357.705 Td /F1 9.8 Tf  [(Hopkins PN. Defining the challenges of familial hypercholesterolemia screening: introduction. J Clin Lipidol. 2010 Sep-)] TJ ET
BT 26.250 345.801 Td /F1 9.8 Tf  [(Oct;4\(5\):342-5. Epub 2010 Aug 20. PubMed PMID: 21122675.)] TJ ET
BT 26.250 326.396 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 326.396 Td /F1 9.8 Tf  [(Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Screening for hypercholesterolaemia versus )] TJ ET
BT 26.250 314.491 Td /F1 9.8 Tf  [(case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis. Health Technol Assess. )] TJ ET
BT 26.250 302.586 Td /F1 9.8 Tf  [(2000;4\(29\):1-123. Review. PubMed PMID: 11109029.)] TJ ET
BT 26.250 283.182 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 283.182 Td /F1 9.8 Tf  [(Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Cost effectiveness analysis of different )] TJ ET
BT 26.250 271.277 Td /F1 9.8 Tf  [(approaches of screening for familial hypercholesterolaemia. BMJ. 2002 Jun 1;324\(7349\):1303. PubMed PMID: 12039822; )] TJ ET
BT 26.250 259.372 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC113765.)] TJ ET
BT 26.250 239.967 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 239.967 Td /F1 9.8 Tf  [(Datta BN, McDowell IF, Rees A. Integrating provision of specialist lipid services with cascade testing for familial )] TJ ET
BT 26.250 228.063 Td /F1 9.8 Tf  [(hypercholesterolaemia. Curr Opin Lipidol. 2010 Aug;21\(4\):366-71. Review. PubMed PMID: 20613514.)] TJ ET
BT 26.250 208.658 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 208.658 Td /F1 9.8 Tf  [(Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. Advanced method for the identification of patients with )] TJ ET
BT 26.250 196.753 Td /F1 9.8 Tf  [(inherited hypercholesterolemia. Semin Vasc Med. 2004 Feb;4\(1\):59-65. Review. PubMed PMID: 15199434.)] TJ ET
BT 26.250 177.348 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 177.348 Td /F1 9.8 Tf  [(Umans-Eckenhausen MA, Defesche JC, Sijbrands EJ, Scheerder RL, Kastelein JJ. Review of first 5 years of screening for )] TJ ET
BT 26.250 165.444 Td /F1 9.8 Tf  [(familial hypercholesterolaemia in the Netherlands. Lancet. 2001 Jan 20;357\(9251\):165-8. PubMed PMID: 11213091.)] TJ ET
BT 26.250 146.039 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 146.039 Td /F1 9.8 Tf  [(Hamilton-Craig I. Case-finding for familial hypercholesterolemia in the Asia-Pacific region. Semin Vasc Med. 2004 )] TJ ET
BT 26.250 134.134 Td /F1 9.8 Tf  [(Feb;4\(1\):87-92. PubMed PMID: 15199437.)] TJ ET
BT 26.250 114.729 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 114.729 Td /F1 9.8 Tf  [(Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, S�rensen S, Bakken KS. Application of molecular )] TJ ET
BT 26.250 102.825 Td /F1 9.8 Tf  [(genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. Semin Vasc )] TJ ET
BT 26.250 90.920 Td /F1 9.8 Tf  [(Med. 2004 Feb;4\(1\):75-85. Review. PubMed PMID: 15199436.)] TJ ET
BT 26.250 71.515 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 71.515 Td /F1 9.8 Tf  [(Marais AD, Firth JC, Blom DJ. Familial hypercholesterolemia in South Africa. Semin Vasc Med. 2004 Feb;4\(1\):93-5. )] TJ ET
BT 26.250 59.610 Td /F1 9.8 Tf  [(PubMed PMID: 15199438.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(5)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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15.000 30.322 577.500 746.678 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Pocovi M, Civeira F, Alonso R, Mata P. Familial hypercholesterolemia in Spain: case-finding program, clinical and genetic )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(aspects. Semin Vasc Med. 2004 Feb;4\(1\):67-74. Review. PubMed PMID: 15199435.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Thorsson B, Sigurdsson G, Gudnason V. Systematic family screening for familial hypercholesterolemia in Iceland. )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(Arterioscler Thromb Vasc Biol. 2003 Feb 1;23\(2\):335-8. PubMed PMID: 12588780.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Watts GF, van Bockxmeer FM, Bates T, Burnett JR, Juniper A, O'Leary P. A new model of care for familial )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(hypercholesterolaemia from Western Australia: closing a major gap in preventive cardiology. Heart Lung Circ. 2010 )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(Jul;19\(7\):419-22. Epub 2010 Apr 3. PubMed PMID: 20363671.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia. NICE )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(clinical guideline CG71.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 633.752 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 615.202 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 615.202 Td /F1 9.8 Tf  [(Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito )] TJ ET
BT 26.250 603.297 Td /F1 9.8 Tf  [(MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE. Familial hypercholesterolemia: screening, diagnosis and )] TJ ET
BT 26.250 591.393 Td /F1 9.8 Tf  [(management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial )] TJ ET
BT 26.250 579.488 Td /F1 9.8 Tf  [(Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S1-8. Epub 2011 Apr 12. PubMed PMID: 21600525.)] TJ ET
BT 26.250 560.083 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 560.083 Td /F1 9.8 Tf  [(Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and )] TJ ET
BT 26.250 548.178 Td /F1 9.8 Tf  [(screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. )] TJ ET
BT 26.250 536.274 Td /F1 9.8 Tf  [(2011 Jun;5\(3 Suppl\):S9-17. Epub 2011 Apr 3. PubMed PMID: 21600530.)] TJ ET
BT 26.250 516.869 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 516.869 Td /F1 9.8 Tf  [(Developed with the special contribution of: European Association for Cardiovascular Prevention & Rehabilitation; )] TJ ET
BT 26.250 504.964 Td /F1 9.8 Tf  [(Authors/Task Force Members, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, )] TJ ET
BT 26.250 493.059 Td /F1 9.8 Tf  [(Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D; ESC )] TJ ET
BT 26.250 481.155 Td /F1 9.8 Tf  [(Committee for Practice Guidelines \(CPG\) 2008�2010 and 2010�2012 Committees, Bax J, Vahanian A, Auricchio A, )] TJ ET
BT 26.250 469.250 Td /F1 9.8 Tf  [(Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Filippatos G, Funck-Brentano C, Hasdai D, Hobbs R, Hoes A, Kearney )] TJ ET
BT 26.250 457.345 Td /F1 9.8 Tf  [(P, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki )] TJ ET
BT 26.250 445.440 Td /F1 9.8 Tf  [(A, Vardas P, Widimsky P, Windecker S; Document Reviewers:, Funck-Brentano C, Poldermans D, Berkenboom G, De Graaf J, )] TJ ET
BT 26.250 433.536 Td /F1 9.8 Tf  [(Descamps O, Gotcheva N, Griffith K, Guida GF, Gulec S, Henkin Y, Huber K, Kesaniemi YA, Lekakis J, Manolis AJ, Marques-)] TJ ET
BT 26.250 421.631 Td /F1 9.8 Tf  [(Vidal P, Masana L, McMurray J, Mendes M, Pagava Z, Pedersen T, Prescott E, Rato Q, Rosano G, Sans S, Stalenhoef A, )] TJ ET
BT 26.250 409.726 Td /F1 9.8 Tf  [(Tokgozoglu L, Viigimaa M, Wittekoek ME, Zamorano JL. ESC/EAS Guidelines for the management of dyslipidaemias: The Task )] TJ ET
BT 26.250 397.821 Td /F1 9.8 Tf  [(Force for the management of dyslipidaemias of the European Society of Cardiology \(ESC\) and the European Atherosclerosis )] TJ ET
BT 26.250 385.917 Td /F1 9.8 Tf  [(Society \(EAS\). Eur Heart J. 2011 Jun 28. [Epub ahead of print] PubMed PMID: 21712404.)] TJ ET
BT 26.250 366.512 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 366.512 Td /F1 9.8 Tf  [(Humphries SE, Norbury G, Leigh S, Hadfield SG, Nair D. What is the clinical utility of DNA testing in patients with familial )] TJ ET
BT 26.250 354.607 Td /F1 9.8 Tf  [(hypercholesterolaemia? Curr Opin Lipidol. 2008 Aug;19\(4\):362-8. Review. PubMed PMID: 18607183.)] TJ ET
BT 26.250 335.202 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 335.202 Td /F1 9.8 Tf  [(Varret M, Abifadel M, Rab�s JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin )] TJ ET
BT 26.250 323.298 Td /F1 9.8 Tf  [(Genet. 2008 Jan;73\(1\):1-13. Epub 2007 Nov 16. Review. PubMed PMID: 18028451.)] TJ ET
BT 26.250 303.893 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 303.893 Td /F1 9.8 Tf  [(Huijgen R, Kindt I, Fouchier SW, Defesche JC, Hutten BA, Kastelein JJ, Vissers MN. Functionality of sequence variants in )] TJ ET
BT 26.250 291.988 Td /F1 9.8 Tf  [(the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. )] TJ ET
BT 26.250 280.083 Td /F1 9.8 Tf  [(Hum Mutat. 2010 Jun;31\(6\):752-60. PubMed PMID: 20506408.)] TJ ET
BT 26.250 260.679 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 260.679 Td /F1 9.8 Tf  [(Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004 Dec;66\(6\):483-7. Review. )] TJ ET
BT 26.250 248.774 Td /F1 9.8 Tf  [(PubMed PMID: 15521974.)] TJ ET
BT 26.250 229.369 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 229.369 Td /F1 9.8 Tf  [(Leren TP, Finborud TH, Manshaus TE, Ose L, Berge KE. Diagnosis of familial hypercholesterolemia in general practice )] TJ ET
BT 26.250 217.464 Td /F1 9.8 Tf  [(using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet. 2008;11\(1\):26-35. )] TJ ET
BT 26.250 205.560 Td /F1 9.8 Tf  [(Epub 2008 Jan 15. PubMed PMID: 18196915.)] TJ ET
BT 26.250 186.155 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 186.155 Td /F1 9.8 Tf  [(Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O. The relationship )] TJ ET
BT 26.250 174.250 Td /F1 9.8 Tf  [(of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis. 2005 )] TJ ET
BT 26.250 162.345 Td /F1 9.8 Tf  [(May;180\(1\):155-60. Epub 2005 Jan 12. PubMed PMID: 15823288.)] TJ ET
BT 26.250 142.941 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 142.941 Td /F1 9.8 Tf  [(Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, )] TJ ET
BT 26.250 131.036 Td /F1 9.8 Tf  [(Wierzbicki AS. Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with )] TJ ET
BT 26.250 119.131 Td /F1 9.8 Tf  [(plasma lipid traits, heart disease risk and utility in relative tracing. J Mol Med. 2006 Mar;84\(3\):203-14. Epub 2005 Dec 31. )] TJ ET
BT 26.250 107.226 Td /F1 9.8 Tf  [(PubMed PMID: 16389549.)] TJ ET
BT 26.250 87.822 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 87.822 Td /F1 9.8 Tf  [(Huijgen R, Kindt I, Verhoeven SB, Sijbrands EJ, Vissers MN, Kastelein JJ, Hutten BA. Two years after molecular diagnosis )] TJ ET
BT 26.250 75.917 Td /F1 9.8 Tf  [(of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. PLoS One. )] TJ ET
BT 26.250 64.012 Td /F1 9.8 Tf  [(2010 Feb 15;5\(2\):e9220. PubMed PMID: 20169164; PubMed Central PMCID: PMC2821409.)] TJ ET
BT 26.250 44.607 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 44.607 Td /F1 9.8 Tf  [(Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg )] TJ ET
Q
q
15.000 30.322 577.500 746.678 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Pocovi M, Civeira F, Alonso R, Mata P. Familial hypercholesterolemia in Spain: case-finding program, clinical and genetic )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(aspects. Semin Vasc Med. 2004 Feb;4\(1\):67-74. Review. PubMed PMID: 15199435.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Thorsson B, Sigurdsson G, Gudnason V. Systematic family screening for familial hypercholesterolemia in Iceland. )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(Arterioscler Thromb Vasc Biol. 2003 Feb 1;23\(2\):335-8. PubMed PMID: 12588780.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Watts GF, van Bockxmeer FM, Bates T, Burnett JR, Juniper A, O'Leary P. A new model of care for familial )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(hypercholesterolaemia from Western Australia: closing a major gap in preventive cardiology. Heart Lung Circ. 2010 )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(Jul;19\(7\):419-22. Epub 2010 Apr 3. PubMed PMID: 20363671.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia. NICE )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(clinical guideline CG71.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 633.752 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 615.202 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 615.202 Td /F1 9.8 Tf  [(Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito )] TJ ET
BT 26.250 603.297 Td /F1 9.8 Tf  [(MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE. Familial hypercholesterolemia: screening, diagnosis and )] TJ ET
BT 26.250 591.393 Td /F1 9.8 Tf  [(management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial )] TJ ET
BT 26.250 579.488 Td /F1 9.8 Tf  [(Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S1-8. Epub 2011 Apr 12. PubMed PMID: 21600525.)] TJ ET
BT 26.250 560.083 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 560.083 Td /F1 9.8 Tf  [(Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and )] TJ ET
BT 26.250 548.178 Td /F1 9.8 Tf  [(screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. )] TJ ET
BT 26.250 536.274 Td /F1 9.8 Tf  [(2011 Jun;5\(3 Suppl\):S9-17. Epub 2011 Apr 3. PubMed PMID: 21600530.)] TJ ET
BT 26.250 516.869 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 516.869 Td /F1 9.8 Tf  [(Developed with the special contribution of: European Association for Cardiovascular Prevention & Rehabilitation; )] TJ ET
BT 26.250 504.964 Td /F1 9.8 Tf  [(Authors/Task Force Members, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, )] TJ ET
BT 26.250 493.059 Td /F1 9.8 Tf  [(Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D; ESC )] TJ ET
BT 26.250 481.155 Td /F1 9.8 Tf  [(Committee for Practice Guidelines \(CPG\) 2008�2010 and 2010�2012 Committees, Bax J, Vahanian A, Auricchio A, )] TJ ET
BT 26.250 469.250 Td /F1 9.8 Tf  [(Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Filippatos G, Funck-Brentano C, Hasdai D, Hobbs R, Hoes A, Kearney )] TJ ET
BT 26.250 457.345 Td /F1 9.8 Tf  [(P, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki )] TJ ET
BT 26.250 445.440 Td /F1 9.8 Tf  [(A, Vardas P, Widimsky P, Windecker S; Document Reviewers:, Funck-Brentano C, Poldermans D, Berkenboom G, De Graaf J, )] TJ ET
BT 26.250 433.536 Td /F1 9.8 Tf  [(Descamps O, Gotcheva N, Griffith K, Guida GF, Gulec S, Henkin Y, Huber K, Kesaniemi YA, Lekakis J, Manolis AJ, Marques-)] TJ ET
BT 26.250 421.631 Td /F1 9.8 Tf  [(Vidal P, Masana L, McMurray J, Mendes M, Pagava Z, Pedersen T, Prescott E, Rato Q, Rosano G, Sans S, Stalenhoef A, )] TJ ET
BT 26.250 409.726 Td /F1 9.8 Tf  [(Tokgozoglu L, Viigimaa M, Wittekoek ME, Zamorano JL. ESC/EAS Guidelines for the management of dyslipidaemias: The Task )] TJ ET
BT 26.250 397.821 Td /F1 9.8 Tf  [(Force for the management of dyslipidaemias of the European Society of Cardiology \(ESC\) and the European Atherosclerosis )] TJ ET
BT 26.250 385.917 Td /F1 9.8 Tf  [(Society \(EAS\). Eur Heart J. 2011 Jun 28. [Epub ahead of print] PubMed PMID: 21712404.)] TJ ET
BT 26.250 366.512 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 366.512 Td /F1 9.8 Tf  [(Humphries SE, Norbury G, Leigh S, Hadfield SG, Nair D. What is the clinical utility of DNA testing in patients with familial )] TJ ET
BT 26.250 354.607 Td /F1 9.8 Tf  [(hypercholesterolaemia? Curr Opin Lipidol. 2008 Aug;19\(4\):362-8. Review. PubMed PMID: 18607183.)] TJ ET
BT 26.250 335.202 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 335.202 Td /F1 9.8 Tf  [(Varret M, Abifadel M, Rab�s JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin )] TJ ET
BT 26.250 323.298 Td /F1 9.8 Tf  [(Genet. 2008 Jan;73\(1\):1-13. Epub 2007 Nov 16. Review. PubMed PMID: 18028451.)] TJ ET
BT 26.250 303.893 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 303.893 Td /F1 9.8 Tf  [(Huijgen R, Kindt I, Fouchier SW, Defesche JC, Hutten BA, Kastelein JJ, Vissers MN. Functionality of sequence variants in )] TJ ET
BT 26.250 291.988 Td /F1 9.8 Tf  [(the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. )] TJ ET
BT 26.250 280.083 Td /F1 9.8 Tf  [(Hum Mutat. 2010 Jun;31\(6\):752-60. PubMed PMID: 20506408.)] TJ ET
BT 26.250 260.679 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 260.679 Td /F1 9.8 Tf  [(Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004 Dec;66\(6\):483-7. Review. )] TJ ET
BT 26.250 248.774 Td /F1 9.8 Tf  [(PubMed PMID: 15521974.)] TJ ET
BT 26.250 229.369 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 229.369 Td /F1 9.8 Tf  [(Leren TP, Finborud TH, Manshaus TE, Ose L, Berge KE. Diagnosis of familial hypercholesterolemia in general practice )] TJ ET
BT 26.250 217.464 Td /F1 9.8 Tf  [(using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet. 2008;11\(1\):26-35. )] TJ ET
BT 26.250 205.560 Td /F1 9.8 Tf  [(Epub 2008 Jan 15. PubMed PMID: 18196915.)] TJ ET
BT 26.250 186.155 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 186.155 Td /F1 9.8 Tf  [(Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O. The relationship )] TJ ET
BT 26.250 174.250 Td /F1 9.8 Tf  [(of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis. 2005 )] TJ ET
BT 26.250 162.345 Td /F1 9.8 Tf  [(May;180\(1\):155-60. Epub 2005 Jan 12. PubMed PMID: 15823288.)] TJ ET
BT 26.250 142.941 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 142.941 Td /F1 9.8 Tf  [(Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, )] TJ ET
BT 26.250 131.036 Td /F1 9.8 Tf  [(Wierzbicki AS. Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with )] TJ ET
BT 26.250 119.131 Td /F1 9.8 Tf  [(plasma lipid traits, heart disease risk and utility in relative tracing. J Mol Med. 2006 Mar;84\(3\):203-14. Epub 2005 Dec 31. )] TJ ET
BT 26.250 107.226 Td /F1 9.8 Tf  [(PubMed PMID: 16389549.)] TJ ET
BT 26.250 87.822 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 87.822 Td /F1 9.8 Tf  [(Huijgen R, Kindt I, Verhoeven SB, Sijbrands EJ, Vissers MN, Kastelein JJ, Hutten BA. Two years after molecular diagnosis )] TJ ET
BT 26.250 75.917 Td /F1 9.8 Tf  [(of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. PLoS One. )] TJ ET
BT 26.250 64.012 Td /F1 9.8 Tf  [(2010 Feb 15;5\(2\):e9220. PubMed PMID: 20169164; PubMed Central PMCID: PMC2821409.)] TJ ET
BT 26.250 44.607 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 44.607 Td /F1 9.8 Tf  [(Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg )] TJ ET
Q
q
15.000 30.322 577.500 746.678 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Pocovi M, Civeira F, Alonso R, Mata P. Familial hypercholesterolemia in Spain: case-finding program, clinical and genetic )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(aspects. Semin Vasc Med. 2004 Feb;4\(1\):67-74. Review. PubMed PMID: 15199435.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Thorsson B, Sigurdsson G, Gudnason V. Systematic family screening for familial hypercholesterolemia in Iceland. )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(Arterioscler Thromb Vasc Biol. 2003 Feb 1;23\(2\):335-8. PubMed PMID: 12588780.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Watts GF, van Bockxmeer FM, Bates T, Burnett JR, Juniper A, O'Leary P. A new model of care for familial )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(hypercholesterolaemia from Western Australia: closing a major gap in preventive cardiology. Heart Lung Circ. 2010 )] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(Jul;19\(7\):419-22. Epub 2010 Apr 3. PubMed PMID: 20363671.)] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 654.143 Td /F1 9.8 Tf  [(National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia. NICE )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(clinical guideline CG71.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 633.752 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 615.202 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 615.202 Td /F1 9.8 Tf  [(Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito )] TJ ET
BT 26.250 603.297 Td /F1 9.8 Tf  [(MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE. Familial hypercholesterolemia: screening, diagnosis and )] TJ ET
BT 26.250 591.393 Td /F1 9.8 Tf  [(management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial )] TJ ET
BT 26.250 579.488 Td /F1 9.8 Tf  [(Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S1-8. Epub 2011 Apr 12. PubMed PMID: 21600525.)] TJ ET
BT 26.250 560.083 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 560.083 Td /F1 9.8 Tf  [(Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and )] TJ ET
BT 26.250 548.178 Td /F1 9.8 Tf  [(screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. )] TJ ET
BT 26.250 536.274 Td /F1 9.8 Tf  [(2011 Jun;5\(3 Suppl\):S9-17. Epub 2011 Apr 3. PubMed PMID: 21600530.)] TJ ET
BT 26.250 516.869 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 516.869 Td /F1 9.8 Tf  [(Developed with the special contribution of: European Association for Cardiovascular Prevention & Rehabilitation; )] TJ ET
BT 26.250 504.964 Td /F1 9.8 Tf  [(Authors/Task Force Members, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, )] TJ ET
BT 26.250 493.059 Td /F1 9.8 Tf  [(Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D; ESC )] TJ ET
BT 26.250 481.155 Td /F1 9.8 Tf  [(Committee for Practice Guidelines \(CPG\) 2008�2010 and 2010�2012 Committees, Bax J, Vahanian A, Auricchio A, )] TJ ET
BT 26.250 469.250 Td /F1 9.8 Tf  [(Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Filippatos G, Funck-Brentano C, Hasdai D, Hobbs R, Hoes A, Kearney )] TJ ET
BT 26.250 457.345 Td /F1 9.8 Tf  [(P, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki )] TJ ET
BT 26.250 445.440 Td /F1 9.8 Tf  [(A, Vardas P, Widimsky P, Windecker S; Document Reviewers:, Funck-Brentano C, Poldermans D, Berkenboom G, De Graaf J, )] TJ ET
BT 26.250 433.536 Td /F1 9.8 Tf  [(Descamps O, Gotcheva N, Griffith K, Guida GF, Gulec S, Henkin Y, Huber K, Kesaniemi YA, Lekakis J, Manolis AJ, Marques-)] TJ ET
BT 26.250 421.631 Td /F1 9.8 Tf  [(Vidal P, Masana L, McMurray J, Mendes M, Pagava Z, Pedersen T, Prescott E, Rato Q, Rosano G, Sans S, Stalenhoef A, )] TJ ET
BT 26.250 409.726 Td /F1 9.8 Tf  [(Tokgozoglu L, Viigimaa M, Wittekoek ME, Zamorano JL. ESC/EAS Guidelines for the management of dyslipidaemias: The Task )] TJ ET
BT 26.250 397.821 Td /F1 9.8 Tf  [(Force for the management of dyslipidaemias of the European Society of Cardiology \(ESC\) and the European Atherosclerosis )] TJ ET
BT 26.250 385.917 Td /F1 9.8 Tf  [(Society \(EAS\). Eur Heart J. 2011 Jun 28. [Epub ahead of print] PubMed PMID: 21712404.)] TJ ET
BT 26.250 366.512 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 366.512 Td /F1 9.8 Tf  [(Humphries SE, Norbury G, Leigh S, Hadfield SG, Nair D. What is the clinical utility of DNA testing in patients with familial )] TJ ET
BT 26.250 354.607 Td /F1 9.8 Tf  [(hypercholesterolaemia? Curr Opin Lipidol. 2008 Aug;19\(4\):362-8. Review. PubMed PMID: 18607183.)] TJ ET
BT 26.250 335.202 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 335.202 Td /F1 9.8 Tf  [(Varret M, Abifadel M, Rab�s JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin )] TJ ET
BT 26.250 323.298 Td /F1 9.8 Tf  [(Genet. 2008 Jan;73\(1\):1-13. Epub 2007 Nov 16. Review. PubMed PMID: 18028451.)] TJ ET
BT 26.250 303.893 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 303.893 Td /F1 9.8 Tf  [(Huijgen R, Kindt I, Fouchier SW, Defesche JC, Hutten BA, Kastelein JJ, Vissers MN. Functionality of sequence variants in )] TJ ET
BT 26.250 291.988 Td /F1 9.8 Tf  [(the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. )] TJ ET
BT 26.250 280.083 Td /F1 9.8 Tf  [(Hum Mutat. 2010 Jun;31\(6\):752-60. PubMed PMID: 20506408.)] TJ ET
BT 26.250 260.679 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 260.679 Td /F1 9.8 Tf  [(Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004 Dec;66\(6\):483-7. Review. )] TJ ET
BT 26.250 248.774 Td /F1 9.8 Tf  [(PubMed PMID: 15521974.)] TJ ET
BT 26.250 229.369 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 229.369 Td /F1 9.8 Tf  [(Leren TP, Finborud TH, Manshaus TE, Ose L, Berge KE. Diagnosis of familial hypercholesterolemia in general practice )] TJ ET
BT 26.250 217.464 Td /F1 9.8 Tf  [(using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet. 2008;11\(1\):26-35. )] TJ ET
BT 26.250 205.560 Td /F1 9.8 Tf  [(Epub 2008 Jan 15. PubMed PMID: 18196915.)] TJ ET
BT 26.250 186.155 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 186.155 Td /F1 9.8 Tf  [(Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O. The relationship )] TJ ET
BT 26.250 174.250 Td /F1 9.8 Tf  [(of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis. 2005 )] TJ ET
BT 26.250 162.345 Td /F1 9.8 Tf  [(May;180\(1\):155-60. Epub 2005 Jan 12. PubMed PMID: 15823288.)] TJ ET
BT 26.250 142.941 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 142.941 Td /F1 9.8 Tf  [(Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, )] TJ ET
BT 26.250 131.036 Td /F1 9.8 Tf  [(Wierzbicki AS. Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with )] TJ ET
BT 26.250 119.131 Td /F1 9.8 Tf  [(plasma lipid traits, heart disease risk and utility in relative tracing. J Mol Med. 2006 Mar;84\(3\):203-14. Epub 2005 Dec 31. )] TJ ET
BT 26.250 107.226 Td /F1 9.8 Tf  [(PubMed PMID: 16389549.)] TJ ET
BT 26.250 87.822 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 87.822 Td /F1 9.8 Tf  [(Huijgen R, Kindt I, Verhoeven SB, Sijbrands EJ, Vissers MN, Kastelein JJ, Hutten BA. Two years after molecular diagnosis )] TJ ET
BT 26.250 75.917 Td /F1 9.8 Tf  [(of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. PLoS One. )] TJ ET
BT 26.250 64.012 Td /F1 9.8 Tf  [(2010 Feb 15;5\(2\):e9220. PubMed PMID: 20169164; PubMed Central PMCID: PMC2821409.)] TJ ET
BT 26.250 44.607 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 44.607 Td /F1 9.8 Tf  [(Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg )] TJ ET
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BT 291.710 19.825 Td /F1 11.0 Tf  [(6)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(PJ, Kastelein JJ, Sijbrands EJ. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008 Nov )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(11;337:a2423. doi: 10.1136/bmj.a2423. PubMed PMID: 19001495; PubMed Central PMCID: PMC2583391.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Austin MA, Zimmern RL, Humphries SE. High "population attributable fraction" for coronary heart disease mortality among )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(relatives in monogenic familial hypercholesterolemia. Genet Med. 2002 Jul-Aug;4\(4\):275-8. PubMed PMID: 12172393.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Arambepola C, Farmer AJ, Perera R, Neil HA. Statin treatment for children and adolescents with heterozygous familial )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(hypercholesterolaemia: a systematic review and meta-analysis. Atherosclerosis. 2007 Dec;195\(2\):339-47. Epub 2006 Nov 13. )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(Review. PubMed PMID: 17097660.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, Hutten BA. A systematic review and meta-analysis of )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007 Aug;27\(8\):1803-10. Epub 2007 )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(Jun 14. Review. PubMed PMID: 17569881.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Haney EM, Huffman LH, Bougatsos C, Freeman M, Steiner RD, Nelson HD. Screening and treatment for lipid disorders in )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(children and adolescents: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2007 )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(Jul;120\(1\):e189-214. Review. PubMed PMID: 17606543.)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 575.214 Td /F1 9.8 Tf  [(O'Gorman CS, Higgins MF, O'Neill MB. Systematic review and metaanalysis of statins for heterozygous familial )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(hypercholesterolemia in children: evaluation of cholesterol changes and side effects. Pediatr Cardiol. 2009 May;30\(4\):482-9. )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Epub 2009 Feb 3. Review. PubMed PMID: 19189168.)] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 532.000 Td /F1 9.8 Tf  [(Shafiq N, Bhasin B, Pattanaik S, Pandhi P, Venkateshan SP, Singh M, Malhotra S. A meta-analysis to evaluate the efficacy )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(of statins in children with familial hypercholesterolemia. Int J Clin Pharmacol Ther. 2007 Oct;45\(10\):548-55. Erratum in: Int J )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Clin Pharmacol Ther. 2008 Jan;46\(1\):41. PubMed PMID: 17966840.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Strandberg T, Tonstad S, Gylling H. Statins for children with familial )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(hypercholesterolemia. Cochrane Database Syst Rev. 2010 Jul 7;\(7\):CD006401. Review. PubMed PMID: 20614444.)] TJ ET
BT 26.250 457.476 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 457.476 Td /F1 9.8 Tf  [(Calonge N, Guirguis-Blake J. Screening for familial hypercholesterolaemia. BMJ. 2007 Sep 22;335\(7620\):573-4. PubMed )] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(PMID: 17884865; PubMed Central PMCID: PMC1988985.)] TJ ET
BT 26.250 426.167 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 426.167 Td /F1 9.8 Tf  [(Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, Wijburg FA, Kastelein JJ, Hutten )] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(BA. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007 Aug 7;116\(6\):664-)] TJ ET
BT 26.250 402.357 Td /F1 9.8 Tf  [(8. Epub 2007 Jul 30. PubMed PMID: 17664376.)] TJ ET
BT 26.250 382.953 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 382.953 Td /F1 9.8 Tf  [(van der Graaf A, Kastelein JJ, Wiegman A. Heterozygous familial hypercholesterolaemia in childhood: cardiovascular risk )] TJ ET
BT 26.250 371.048 Td /F1 9.8 Tf  [(prevention. J Inherit Metab Dis. 2009 Dec;32\(6\):699-705. Epub 2009 Oct 31. Review. PubMed PMID: 19898954.)] TJ ET
BT 26.250 351.643 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 351.643 Td /F1 9.8 Tf  [(Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, Sijbrands EJ, Kastelein JJ. Arterial intima-media )] TJ ET
BT 26.250 339.738 Td /F1 9.8 Tf  [(thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004 Jan 31;363\(9406\):369-70. PubMed PMID: )] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(15070569.)] TJ ET
BT 26.250 308.429 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 308.429 Td /F1 9.8 Tf  [(Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, )] TJ ET
BT 26.250 296.524 Td /F1 9.8 Tf  [(Bertolini S. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J )] TJ ET
BT 26.250 284.619 Td /F1 9.8 Tf  [(Pediatr. 2009 Aug;155\(2\):199-204.e2. Epub 2009 May 15. PubMed PMID: 19446849.)] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 265.215 Td /F1 9.8 Tf  [(Goldberg AC, Robinson JG, Cromwell WC, Ross JL, Ziajka PE. Future issues, public policy, and public awareness of )] TJ ET
BT 26.250 253.310 Td /F1 9.8 Tf  [(familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial )] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S46-51. Epub 2011 Apr 8. PubMed PMID: 21600529.)] TJ ET
BT 26.250 222.000 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 222.000 Td /F1 9.8 Tf  [(US Preventive Services Task Force. Screening for lipid disorders in children: US Preventive Services Task Force )] TJ ET
BT 26.250 210.096 Td /F1 9.8 Tf  [(recommendation statement. Pediatrics. 2007 Jul;120\(1\):e215-9. PubMed PMID: 17606545.)] TJ ET
BT 26.250 190.691 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 190.691 Td /F1 9.8 Tf  [(Daniels SR. Screening for familial hypercholesterolemia: what is the most effective strategy? Nat Clin Pract Cardiovasc )] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(Med. 2008 Mar;5\(3\):130-1. Epub 2007 Dec 4. PubMed PMID: 18059381.)] TJ ET
BT 26.250 159.381 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 159.381 Td /F1 9.8 Tf  [(Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008 )] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(Jul;122\(1\):198-208. Review. PubMed PMID: 18596007.)] TJ ET
BT 26.250 128.072 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 128.072 Td /F1 9.8 Tf  [(Jenssen BP, Jacobson MS. Screening adolescents for lipid disorders: what is the best approach? Adolesc Med State Art )] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(Rev. 2008 Dec;19\(3\):507-20, x. Review. PubMed PMID: 19227389.)] TJ ET
BT 26.250 96.762 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 96.762 Td /F1 9.8 Tf  [(McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, Hayman LL, Daniels SR; American )] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing. Drug therapy of high-risk )] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, )] TJ ET
BT 26.250 49.143 Td /F1 9.8 Tf  [(Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on )] TJ ET
Q
q
15.000 34.858 577.500 742.142 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(PJ, Kastelein JJ, Sijbrands EJ. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008 Nov )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(11;337:a2423. doi: 10.1136/bmj.a2423. PubMed PMID: 19001495; PubMed Central PMCID: PMC2583391.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Austin MA, Zimmern RL, Humphries SE. High "population attributable fraction" for coronary heart disease mortality among )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(relatives in monogenic familial hypercholesterolemia. Genet Med. 2002 Jul-Aug;4\(4\):275-8. PubMed PMID: 12172393.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Arambepola C, Farmer AJ, Perera R, Neil HA. Statin treatment for children and adolescents with heterozygous familial )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(hypercholesterolaemia: a systematic review and meta-analysis. Atherosclerosis. 2007 Dec;195\(2\):339-47. Epub 2006 Nov 13. )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(Review. PubMed PMID: 17097660.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, Hutten BA. A systematic review and meta-analysis of )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007 Aug;27\(8\):1803-10. Epub 2007 )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(Jun 14. Review. PubMed PMID: 17569881.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Haney EM, Huffman LH, Bougatsos C, Freeman M, Steiner RD, Nelson HD. Screening and treatment for lipid disorders in )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(children and adolescents: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2007 )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(Jul;120\(1\):e189-214. Review. PubMed PMID: 17606543.)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 575.214 Td /F1 9.8 Tf  [(O'Gorman CS, Higgins MF, O'Neill MB. Systematic review and metaanalysis of statins for heterozygous familial )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(hypercholesterolemia in children: evaluation of cholesterol changes and side effects. Pediatr Cardiol. 2009 May;30\(4\):482-9. )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Epub 2009 Feb 3. Review. PubMed PMID: 19189168.)] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 532.000 Td /F1 9.8 Tf  [(Shafiq N, Bhasin B, Pattanaik S, Pandhi P, Venkateshan SP, Singh M, Malhotra S. A meta-analysis to evaluate the efficacy )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(of statins in children with familial hypercholesterolemia. Int J Clin Pharmacol Ther. 2007 Oct;45\(10\):548-55. Erratum in: Int J )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Clin Pharmacol Ther. 2008 Jan;46\(1\):41. PubMed PMID: 17966840.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Strandberg T, Tonstad S, Gylling H. Statins for children with familial )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(hypercholesterolemia. Cochrane Database Syst Rev. 2010 Jul 7;\(7\):CD006401. Review. PubMed PMID: 20614444.)] TJ ET
BT 26.250 457.476 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 457.476 Td /F1 9.8 Tf  [(Calonge N, Guirguis-Blake J. Screening for familial hypercholesterolaemia. BMJ. 2007 Sep 22;335\(7620\):573-4. PubMed )] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(PMID: 17884865; PubMed Central PMCID: PMC1988985.)] TJ ET
BT 26.250 426.167 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 426.167 Td /F1 9.8 Tf  [(Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, Wijburg FA, Kastelein JJ, Hutten )] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(BA. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007 Aug 7;116\(6\):664-)] TJ ET
BT 26.250 402.357 Td /F1 9.8 Tf  [(8. Epub 2007 Jul 30. PubMed PMID: 17664376.)] TJ ET
BT 26.250 382.953 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 382.953 Td /F1 9.8 Tf  [(van der Graaf A, Kastelein JJ, Wiegman A. Heterozygous familial hypercholesterolaemia in childhood: cardiovascular risk )] TJ ET
BT 26.250 371.048 Td /F1 9.8 Tf  [(prevention. J Inherit Metab Dis. 2009 Dec;32\(6\):699-705. Epub 2009 Oct 31. Review. PubMed PMID: 19898954.)] TJ ET
BT 26.250 351.643 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 351.643 Td /F1 9.8 Tf  [(Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, Sijbrands EJ, Kastelein JJ. Arterial intima-media )] TJ ET
BT 26.250 339.738 Td /F1 9.8 Tf  [(thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004 Jan 31;363\(9406\):369-70. PubMed PMID: )] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(15070569.)] TJ ET
BT 26.250 308.429 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 308.429 Td /F1 9.8 Tf  [(Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, )] TJ ET
BT 26.250 296.524 Td /F1 9.8 Tf  [(Bertolini S. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J )] TJ ET
BT 26.250 284.619 Td /F1 9.8 Tf  [(Pediatr. 2009 Aug;155\(2\):199-204.e2. Epub 2009 May 15. PubMed PMID: 19446849.)] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 265.215 Td /F1 9.8 Tf  [(Goldberg AC, Robinson JG, Cromwell WC, Ross JL, Ziajka PE. Future issues, public policy, and public awareness of )] TJ ET
BT 26.250 253.310 Td /F1 9.8 Tf  [(familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial )] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S46-51. Epub 2011 Apr 8. PubMed PMID: 21600529.)] TJ ET
BT 26.250 222.000 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 222.000 Td /F1 9.8 Tf  [(US Preventive Services Task Force. Screening for lipid disorders in children: US Preventive Services Task Force )] TJ ET
BT 26.250 210.096 Td /F1 9.8 Tf  [(recommendation statement. Pediatrics. 2007 Jul;120\(1\):e215-9. PubMed PMID: 17606545.)] TJ ET
BT 26.250 190.691 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 190.691 Td /F1 9.8 Tf  [(Daniels SR. Screening for familial hypercholesterolemia: what is the most effective strategy? Nat Clin Pract Cardiovasc )] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(Med. 2008 Mar;5\(3\):130-1. Epub 2007 Dec 4. PubMed PMID: 18059381.)] TJ ET
BT 26.250 159.381 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 159.381 Td /F1 9.8 Tf  [(Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008 )] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(Jul;122\(1\):198-208. Review. PubMed PMID: 18596007.)] TJ ET
BT 26.250 128.072 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 128.072 Td /F1 9.8 Tf  [(Jenssen BP, Jacobson MS. Screening adolescents for lipid disorders: what is the best approach? Adolesc Med State Art )] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(Rev. 2008 Dec;19\(3\):507-20, x. Review. PubMed PMID: 19227389.)] TJ ET
BT 26.250 96.762 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 96.762 Td /F1 9.8 Tf  [(McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, Hayman LL, Daniels SR; American )] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing. Drug therapy of high-risk )] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, )] TJ ET
BT 26.250 49.143 Td /F1 9.8 Tf  [(Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on )] TJ ET
Q
q
15.000 34.858 577.500 742.142 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(PJ, Kastelein JJ, Sijbrands EJ. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008 Nov )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(11;337:a2423. doi: 10.1136/bmj.a2423. PubMed PMID: 19001495; PubMed Central PMCID: PMC2583391.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Austin MA, Zimmern RL, Humphries SE. High "population attributable fraction" for coronary heart disease mortality among )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(relatives in monogenic familial hypercholesterolemia. Genet Med. 2002 Jul-Aug;4\(4\):275-8. PubMed PMID: 12172393.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Arambepola C, Farmer AJ, Perera R, Neil HA. Statin treatment for children and adolescents with heterozygous familial )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(hypercholesterolaemia: a systematic review and meta-analysis. Atherosclerosis. 2007 Dec;195\(2\):339-47. Epub 2006 Nov 13. )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(Review. PubMed PMID: 17097660.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, Hutten BA. A systematic review and meta-analysis of )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007 Aug;27\(8\):1803-10. Epub 2007 )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(Jun 14. Review. PubMed PMID: 17569881.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Haney EM, Huffman LH, Bougatsos C, Freeman M, Steiner RD, Nelson HD. Screening and treatment for lipid disorders in )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(children and adolescents: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2007 )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(Jul;120\(1\):e189-214. Review. PubMed PMID: 17606543.)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 575.214 Td /F1 9.8 Tf  [(O'Gorman CS, Higgins MF, O'Neill MB. Systematic review and metaanalysis of statins for heterozygous familial )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(hypercholesterolemia in children: evaluation of cholesterol changes and side effects. Pediatr Cardiol. 2009 May;30\(4\):482-9. )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Epub 2009 Feb 3. Review. PubMed PMID: 19189168.)] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 532.000 Td /F1 9.8 Tf  [(Shafiq N, Bhasin B, Pattanaik S, Pandhi P, Venkateshan SP, Singh M, Malhotra S. A meta-analysis to evaluate the efficacy )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(of statins in children with familial hypercholesterolemia. Int J Clin Pharmacol Ther. 2007 Oct;45\(10\):548-55. Erratum in: Int J )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Clin Pharmacol Ther. 2008 Jan;46\(1\):41. PubMed PMID: 17966840.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Strandberg T, Tonstad S, Gylling H. Statins for children with familial )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(hypercholesterolemia. Cochrane Database Syst Rev. 2010 Jul 7;\(7\):CD006401. Review. PubMed PMID: 20614444.)] TJ ET
BT 26.250 457.476 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 457.476 Td /F1 9.8 Tf  [(Calonge N, Guirguis-Blake J. Screening for familial hypercholesterolaemia. BMJ. 2007 Sep 22;335\(7620\):573-4. PubMed )] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(PMID: 17884865; PubMed Central PMCID: PMC1988985.)] TJ ET
BT 26.250 426.167 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 426.167 Td /F1 9.8 Tf  [(Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, Wijburg FA, Kastelein JJ, Hutten )] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(BA. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007 Aug 7;116\(6\):664-)] TJ ET
BT 26.250 402.357 Td /F1 9.8 Tf  [(8. Epub 2007 Jul 30. PubMed PMID: 17664376.)] TJ ET
BT 26.250 382.953 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 382.953 Td /F1 9.8 Tf  [(van der Graaf A, Kastelein JJ, Wiegman A. Heterozygous familial hypercholesterolaemia in childhood: cardiovascular risk )] TJ ET
BT 26.250 371.048 Td /F1 9.8 Tf  [(prevention. J Inherit Metab Dis. 2009 Dec;32\(6\):699-705. Epub 2009 Oct 31. Review. PubMed PMID: 19898954.)] TJ ET
BT 26.250 351.643 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 351.643 Td /F1 9.8 Tf  [(Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, Sijbrands EJ, Kastelein JJ. Arterial intima-media )] TJ ET
BT 26.250 339.738 Td /F1 9.8 Tf  [(thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004 Jan 31;363\(9406\):369-70. PubMed PMID: )] TJ ET
BT 26.250 327.834 Td /F1 9.8 Tf  [(15070569.)] TJ ET
BT 26.250 308.429 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 308.429 Td /F1 9.8 Tf  [(Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, )] TJ ET
BT 26.250 296.524 Td /F1 9.8 Tf  [(Bertolini S. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J )] TJ ET
BT 26.250 284.619 Td /F1 9.8 Tf  [(Pediatr. 2009 Aug;155\(2\):199-204.e2. Epub 2009 May 15. PubMed PMID: 19446849.)] TJ ET
BT 26.250 265.215 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 265.215 Td /F1 9.8 Tf  [(Goldberg AC, Robinson JG, Cromwell WC, Ross JL, Ziajka PE. Future issues, public policy, and public awareness of )] TJ ET
BT 26.250 253.310 Td /F1 9.8 Tf  [(familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial )] TJ ET
BT 26.250 241.405 Td /F1 9.8 Tf  [(Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S46-51. Epub 2011 Apr 8. PubMed PMID: 21600529.)] TJ ET
BT 26.250 222.000 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 222.000 Td /F1 9.8 Tf  [(US Preventive Services Task Force. Screening for lipid disorders in children: US Preventive Services Task Force )] TJ ET
BT 26.250 210.096 Td /F1 9.8 Tf  [(recommendation statement. Pediatrics. 2007 Jul;120\(1\):e215-9. PubMed PMID: 17606545.)] TJ ET
BT 26.250 190.691 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 190.691 Td /F1 9.8 Tf  [(Daniels SR. Screening for familial hypercholesterolemia: what is the most effective strategy? Nat Clin Pract Cardiovasc )] TJ ET
BT 26.250 178.786 Td /F1 9.8 Tf  [(Med. 2008 Mar;5\(3\):130-1. Epub 2007 Dec 4. PubMed PMID: 18059381.)] TJ ET
BT 26.250 159.381 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 159.381 Td /F1 9.8 Tf  [(Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008 )] TJ ET
BT 26.250 147.477 Td /F1 9.8 Tf  [(Jul;122\(1\):198-208. Review. PubMed PMID: 18596007.)] TJ ET
BT 26.250 128.072 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 128.072 Td /F1 9.8 Tf  [(Jenssen BP, Jacobson MS. Screening adolescents for lipid disorders: what is the best approach? Adolesc Med State Art )] TJ ET
BT 26.250 116.167 Td /F1 9.8 Tf  [(Rev. 2008 Dec;19\(3\):507-20, x. Review. PubMed PMID: 19227389.)] TJ ET
BT 26.250 96.762 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 96.762 Td /F1 9.8 Tf  [(McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, Hayman LL, Daniels SR; American )] TJ ET
BT 26.250 84.858 Td /F1 9.8 Tf  [(Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of )] TJ ET
BT 26.250 72.953 Td /F1 9.8 Tf  [(Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing. Drug therapy of high-risk )] TJ ET
BT 26.250 61.048 Td /F1 9.8 Tf  [(lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, )] TJ ET
BT 26.250 49.143 Td /F1 9.8 Tf  [(Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(7)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(Cardiovascular Nursing. Circulation. 2007 Apr 10;115\(14\):1948-67. Epub 2007 Mar 21. PubMed PMID: 17377073.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial hypercholesterolemias: recommendations from the )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S30-7. Epub 2011 )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Apr 5. PubMed PMID: 21600527.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJ, Sijbrands EJ. Effect of low-density lipoprotein )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study. Atherosclerosis. 2005 )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(May;180\(1\):93-9. Epub 2004 Dec 19. PubMed PMID: 15823280.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Koeijvoets KC, Rodenburg J, Hutten BA, Wiegman A, Kastelein JJ, Sijbrands EJ. Low-density lipoprotein receptor genotype )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(and response to pravastatin in children with familial hypercholesterolemia: substudy of an intima-media thickness trial. )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(Circulation. 2005 Nov 15;112\(20\):3168-73. PubMed PMID: 16286607.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Souverein OW, Defesche JC, Zwinderman AH, Kastelein JJ, Tanck MW. Influence of LDL-receptor mutation type on age at )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(first cardiovascular event in patients with familial hypercholesterolaemia. Eur Heart J. 2007 Feb;28\(3\):299-304. Epub 2006 Nov )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(7. PubMed PMID: 17090611.)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 575.214 Td /F1 9.8 Tf  [(Sijbrands EJ, Westendorp RG, Paola Lombardi M, Havekes LM, Frants RR, Kastelein JJ, Smelt AH. Additional risk factors )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(influence excess mortality in heterozygous familial hypercholesterolaemia. Atherosclerosis. 2000 Apr;149\(2\):421-5. PubMed )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(PMID: 10729393.)] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 532.000 Td /F1 9.8 Tf  [(Umans-Eckenhausen MA, Sijbrands EJ, Kastelein JJ, Defesche JC. Low-density lipoprotein receptor gene mutations and )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(cardiovascular risk in a large genetic cascade screening population. Circulation. 2002 Dec 10;106\(24\):3031-6. PubMed PMID: )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(12473547.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, Parekh RS, Steinberger J; American Heart )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(Association Expert Panel on Population and Prevention Science; American Heart Association Council on Cardiovascular )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(Disease in the Young; American Heart Association Council on Epidemiology and Prevention; American Heart Association )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(Council on Nutrition, Physical Activity and Metabolism; American Heart Association Council on High Blood Pressure Research; )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on the Kidney in Heart )] TJ ET
BT 26.250 429.262 Td /F1 9.8 Tf  [(Disease; Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk reduction in high-risk )] TJ ET
BT 26.250 417.357 Td /F1 9.8 Tf  [(pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention )] TJ ET
BT 26.250 405.453 Td /F1 9.8 Tf  [(Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and )] TJ ET
BT 26.250 393.548 Td /F1 9.8 Tf  [(Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary )] TJ ET
BT 26.250 381.643 Td /F1 9.8 Tf  [(Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. )] TJ ET
BT 26.250 369.738 Td /F1 9.8 Tf  [(2006 Dec 12;114\(24\):2710-38. Epub 2006 Nov 27. Review. PubMed PMID: 17130340.)] TJ ET
BT 26.250 350.334 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 350.334 Td /F1 9.8 Tf  [(Shafiq N, Singh M, Kaur S, Khosla P, Malhotra S. Dietary treatment for familial hypercholesterolaemia. Cochrane Database )] TJ ET
BT 26.250 338.429 Td /F1 9.8 Tf  [(Syst Rev. 2010 Jan 20;\(1\):CD001918. Review. PubMed PMID: 20091526.)] TJ ET
BT 26.250 319.024 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 319.024 Td /F1 9.8 Tf  [(Hadfield SG, Horara S, Starr BJ, Yazdgerdi S, Marks D, Bhatnagar D, Cramb R, Egan S, Everdell R, Ferns G, Jones A, )] TJ ET
BT 26.250 307.119 Td /F1 9.8 Tf  [(Marenah CB, Marples J, Prinsloo P, Sneyd A, Stewart MF, Sandle L, Wang T, Watson MS, Humphries SE; Steering Group for )] TJ ET
BT 26.250 295.215 Td /F1 9.8 Tf  [(the Department of Health Familial Hypercholesterolaemia Cascade Testing Audit Project. Family tracing to identify patients with )] TJ ET
BT 26.250 283.310 Td /F1 9.8 Tf  [(familial hypercholesterolaemia: the second audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing )] TJ ET
BT 26.250 271.405 Td /F1 9.8 Tf  [(Project. Ann Clin Biochem. 2009 Jan;46\(Pt 1\):24-32. Epub 2008 Nov 21. PubMed PMID: 19028807.)] TJ ET
BT 26.250 252.000 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 252.000 Td /F1 9.8 Tf  [(Newson AJ, Humphries SE. Cascade testing in familial hypercholesterolaemia: how should family members be contacted? )] TJ ET
BT 26.250 240.096 Td /F1 9.8 Tf  [(Eur J Hum Genet. 2005 Apr;13\(4\):401-8. Review. PubMed PMID: 15657617.)] TJ ET
BT 26.250 220.691 Td /F1 9.8 Tf  [(63.)] TJ ET
BT 43.553 220.691 Td /F1 9.8 Tf  [(Hopkins PN. Encouraging appropriate treatment for familial hypercholesterolemia. Clin Lipidol. 2010; 5:339-354.)] TJ ET
Q
q
15.000 203.310 577.500 573.690 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Cardiovascular Nursing. Circulation. 2007 Apr 10;115\(14\):1948-67. Epub 2007 Mar 21. PubMed PMID: 17377073.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial hypercholesterolemias: recommendations from the )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S30-7. Epub 2011 )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Apr 5. PubMed PMID: 21600527.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJ, Sijbrands EJ. Effect of low-density lipoprotein )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study. Atherosclerosis. 2005 )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(May;180\(1\):93-9. Epub 2004 Dec 19. PubMed PMID: 15823280.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Koeijvoets KC, Rodenburg J, Hutten BA, Wiegman A, Kastelein JJ, Sijbrands EJ. Low-density lipoprotein receptor genotype )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(and response to pravastatin in children with familial hypercholesterolemia: substudy of an intima-media thickness trial. )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(Circulation. 2005 Nov 15;112\(20\):3168-73. PubMed PMID: 16286607.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Souverein OW, Defesche JC, Zwinderman AH, Kastelein JJ, Tanck MW. Influence of LDL-receptor mutation type on age at )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(first cardiovascular event in patients with familial hypercholesterolaemia. Eur Heart J. 2007 Feb;28\(3\):299-304. Epub 2006 Nov )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(7. PubMed PMID: 17090611.)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 575.214 Td /F1 9.8 Tf  [(Sijbrands EJ, Westendorp RG, Paola Lombardi M, Havekes LM, Frants RR, Kastelein JJ, Smelt AH. Additional risk factors )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(influence excess mortality in heterozygous familial hypercholesterolaemia. Atherosclerosis. 2000 Apr;149\(2\):421-5. PubMed )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(PMID: 10729393.)] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 532.000 Td /F1 9.8 Tf  [(Umans-Eckenhausen MA, Sijbrands EJ, Kastelein JJ, Defesche JC. Low-density lipoprotein receptor gene mutations and )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(cardiovascular risk in a large genetic cascade screening population. Circulation. 2002 Dec 10;106\(24\):3031-6. PubMed PMID: )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(12473547.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, Parekh RS, Steinberger J; American Heart )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(Association Expert Panel on Population and Prevention Science; American Heart Association Council on Cardiovascular )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(Disease in the Young; American Heart Association Council on Epidemiology and Prevention; American Heart Association )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(Council on Nutrition, Physical Activity and Metabolism; American Heart Association Council on High Blood Pressure Research; )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on the Kidney in Heart )] TJ ET
BT 26.250 429.262 Td /F1 9.8 Tf  [(Disease; Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk reduction in high-risk )] TJ ET
BT 26.250 417.357 Td /F1 9.8 Tf  [(pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention )] TJ ET
BT 26.250 405.453 Td /F1 9.8 Tf  [(Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and )] TJ ET
BT 26.250 393.548 Td /F1 9.8 Tf  [(Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary )] TJ ET
BT 26.250 381.643 Td /F1 9.8 Tf  [(Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. )] TJ ET
BT 26.250 369.738 Td /F1 9.8 Tf  [(2006 Dec 12;114\(24\):2710-38. Epub 2006 Nov 27. Review. PubMed PMID: 17130340.)] TJ ET
BT 26.250 350.334 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 350.334 Td /F1 9.8 Tf  [(Shafiq N, Singh M, Kaur S, Khosla P, Malhotra S. Dietary treatment for familial hypercholesterolaemia. Cochrane Database )] TJ ET
BT 26.250 338.429 Td /F1 9.8 Tf  [(Syst Rev. 2010 Jan 20;\(1\):CD001918. Review. PubMed PMID: 20091526.)] TJ ET
BT 26.250 319.024 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 319.024 Td /F1 9.8 Tf  [(Hadfield SG, Horara S, Starr BJ, Yazdgerdi S, Marks D, Bhatnagar D, Cramb R, Egan S, Everdell R, Ferns G, Jones A, )] TJ ET
BT 26.250 307.119 Td /F1 9.8 Tf  [(Marenah CB, Marples J, Prinsloo P, Sneyd A, Stewart MF, Sandle L, Wang T, Watson MS, Humphries SE; Steering Group for )] TJ ET
BT 26.250 295.215 Td /F1 9.8 Tf  [(the Department of Health Familial Hypercholesterolaemia Cascade Testing Audit Project. Family tracing to identify patients with )] TJ ET
BT 26.250 283.310 Td /F1 9.8 Tf  [(familial hypercholesterolaemia: the second audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing )] TJ ET
BT 26.250 271.405 Td /F1 9.8 Tf  [(Project. Ann Clin Biochem. 2009 Jan;46\(Pt 1\):24-32. Epub 2008 Nov 21. PubMed PMID: 19028807.)] TJ ET
BT 26.250 252.000 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 252.000 Td /F1 9.8 Tf  [(Newson AJ, Humphries SE. Cascade testing in familial hypercholesterolaemia: how should family members be contacted? )] TJ ET
BT 26.250 240.096 Td /F1 9.8 Tf  [(Eur J Hum Genet. 2005 Apr;13\(4\):401-8. Review. PubMed PMID: 15657617.)] TJ ET
BT 26.250 220.691 Td /F1 9.8 Tf  [(63.)] TJ ET
BT 43.553 220.691 Td /F1 9.8 Tf  [(Hopkins PN. Encouraging appropriate treatment for familial hypercholesterolemia. Clin Lipidol. 2010; 5:339-354.)] TJ ET
Q
q
15.000 203.310 577.500 573.690 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(Cardiovascular Nursing. Circulation. 2007 Apr 10;115\(14\):1948-67. Epub 2007 Mar 21. PubMed PMID: 17377073.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial hypercholesterolemias: recommendations from the )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5\(3 Suppl\):S30-7. Epub 2011 )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Apr 5. PubMed PMID: 21600527.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJ, Sijbrands EJ. Effect of low-density lipoprotein )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study. Atherosclerosis. 2005 )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(May;180\(1\):93-9. Epub 2004 Dec 19. PubMed PMID: 15823280.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Koeijvoets KC, Rodenburg J, Hutten BA, Wiegman A, Kastelein JJ, Sijbrands EJ. Low-density lipoprotein receptor genotype )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(and response to pravastatin in children with familial hypercholesterolemia: substudy of an intima-media thickness trial. )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(Circulation. 2005 Nov 15;112\(20\):3168-73. PubMed PMID: 16286607.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Souverein OW, Defesche JC, Zwinderman AH, Kastelein JJ, Tanck MW. Influence of LDL-receptor mutation type on age at )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(first cardiovascular event in patients with familial hypercholesterolaemia. Eur Heart J. 2007 Feb;28\(3\):299-304. Epub 2006 Nov )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(7. PubMed PMID: 17090611.)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 575.214 Td /F1 9.8 Tf  [(Sijbrands EJ, Westendorp RG, Paola Lombardi M, Havekes LM, Frants RR, Kastelein JJ, Smelt AH. Additional risk factors )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(influence excess mortality in heterozygous familial hypercholesterolaemia. Atherosclerosis. 2000 Apr;149\(2\):421-5. PubMed )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(PMID: 10729393.)] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 532.000 Td /F1 9.8 Tf  [(Umans-Eckenhausen MA, Sijbrands EJ, Kastelein JJ, Defesche JC. Low-density lipoprotein receptor gene mutations and )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(cardiovascular risk in a large genetic cascade screening population. Circulation. 2002 Dec 10;106\(24\):3031-6. PubMed PMID: )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(12473547.)] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 488.786 Td /F1 9.8 Tf  [(Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, Parekh RS, Steinberger J; American Heart )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(Association Expert Panel on Population and Prevention Science; American Heart Association Council on Cardiovascular )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(Disease in the Young; American Heart Association Council on Epidemiology and Prevention; American Heart Association )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(Council on Nutrition, Physical Activity and Metabolism; American Heart Association Council on High Blood Pressure Research; )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on the Kidney in Heart )] TJ ET
BT 26.250 429.262 Td /F1 9.8 Tf  [(Disease; Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk reduction in high-risk )] TJ ET
BT 26.250 417.357 Td /F1 9.8 Tf  [(pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention )] TJ ET
BT 26.250 405.453 Td /F1 9.8 Tf  [(Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and )] TJ ET
BT 26.250 393.548 Td /F1 9.8 Tf  [(Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary )] TJ ET
BT 26.250 381.643 Td /F1 9.8 Tf  [(Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. )] TJ ET
BT 26.250 369.738 Td /F1 9.8 Tf  [(2006 Dec 12;114\(24\):2710-38. Epub 2006 Nov 27. Review. PubMed PMID: 17130340.)] TJ ET
BT 26.250 350.334 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 350.334 Td /F1 9.8 Tf  [(Shafiq N, Singh M, Kaur S, Khosla P, Malhotra S. Dietary treatment for familial hypercholesterolaemia. Cochrane Database )] TJ ET
BT 26.250 338.429 Td /F1 9.8 Tf  [(Syst Rev. 2010 Jan 20;\(1\):CD001918. Review. PubMed PMID: 20091526.)] TJ ET
BT 26.250 319.024 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 319.024 Td /F1 9.8 Tf  [(Hadfield SG, Horara S, Starr BJ, Yazdgerdi S, Marks D, Bhatnagar D, Cramb R, Egan S, Everdell R, Ferns G, Jones A, )] TJ ET
BT 26.250 307.119 Td /F1 9.8 Tf  [(Marenah CB, Marples J, Prinsloo P, Sneyd A, Stewart MF, Sandle L, Wang T, Watson MS, Humphries SE; Steering Group for )] TJ ET
BT 26.250 295.215 Td /F1 9.8 Tf  [(the Department of Health Familial Hypercholesterolaemia Cascade Testing Audit Project. Family tracing to identify patients with )] TJ ET
BT 26.250 283.310 Td /F1 9.8 Tf  [(familial hypercholesterolaemia: the second audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing )] TJ ET
BT 26.250 271.405 Td /F1 9.8 Tf  [(Project. Ann Clin Biochem. 2009 Jan;46\(Pt 1\):24-32. Epub 2008 Nov 21. PubMed PMID: 19028807.)] TJ ET
BT 26.250 252.000 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 252.000 Td /F1 9.8 Tf  [(Newson AJ, Humphries SE. Cascade testing in familial hypercholesterolaemia: how should family members be contacted? )] TJ ET
BT 26.250 240.096 Td /F1 9.8 Tf  [(Eur J Hum Genet. 2005 Apr;13\(4\):401-8. Review. PubMed PMID: 15657617.)] TJ ET
BT 26.250 220.691 Td /F1 9.8 Tf  [(63.)] TJ ET
BT 43.553 220.691 Td /F1 9.8 Tf  [(Hopkins PN. Encouraging appropriate treatment for familial hypercholesterolemia. Clin Lipidol. 2010; 5:339-354.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(8)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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trailer
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