%PDF-1.3
1 0 obj
<< /Type /Catalog
/Outlines 2 0 R
/Pages 3 0 R >>
endobj
2 0 obj
<< /Type /Outlines /Count 0 >>
endobj
3 0 obj
<< /Type /Pages
/Kids [6 0 R
165 0 R
306 0 R
398 0 R
406 0 R
]
/Count 5
/Resources <<
/ProcSet 4 0 R
/Font << 
/F1 8 0 R
/F2 9 0 R
/F3 10 0 R
/F4 11 0 R
/F5 12 0 R
/F6 167 0 R
>>
/XObject << 
/I1 13 0 R
/I2 14 0 R
>>
>>
/MediaBox [0.000 0.000 612.000 792.000]
 >>
endobj
4 0 obj
[/PDF /Text /ImageC ]
endobj
5 0 obj
<<
/Creator (DOMPDF)
/CreationDate (D:20170830072500+00'00')
/ModDate (D:20170830072500+00'00')
/Title (Use of the Afirma� Gene Expression Classifier for Preoperative Identification of Benign Thyroid Nodules with Indeterminate Fine Needle Aspiration Cytopathology � PLOS Currents Evidence on Genomic Tests)
>>
endobj
6 0 obj
<< /Type /Page
/Parent 3 0 R
/Annots [ 15 0 R 17 0 R 19 0 R 21 0 R 23 0 R 25 0 R 27 0 R 29 0 R 31 0 R 33 0 R 35 0 R 37 0 R 39 0 R 41 0 R 43 0 R 45 0 R 47 0 R 49 0 R 51 0 R 53 0 R 55 0 R 57 0 R 59 0 R 61 0 R 63 0 R 65 0 R 67 0 R 69 0 R 71 0 R 73 0 R 75 0 R 77 0 R 79 0 R 81 0 R 83 0 R 85 0 R 87 0 R 89 0 R 91 0 R 93 0 R 95 0 R 97 0 R 99 0 R 101 0 R 103 0 R 105 0 R 107 0 R 109 0 R 111 0 R 113 0 R 115 0 R 117 0 R 119 0 R 121 0 R 123 0 R 125 0 R 127 0 R 129 0 R 131 0 R 133 0 R 135 0 R 137 0 R 139 0 R 141 0 R 143 0 R 145 0 R 147 0 R 149 0 R 151 0 R 153 0 R 155 0 R 157 0 R 159 0 R 161 0 R 163 0 R ]
/Contents 7 0 R
>>
endobj
7 0 obj
<<
/Length 28749 >>
stream

q
375.000 0 0 39.000 222.000 738.000 cm /I2 Do
Q
q
15.000 659.406 577.500 78.594 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Use of the Afirma� Gene Expression Classifier for )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Preoperative Identification of Benign Thyroid Nodules with )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Indeterminate Fine Needle Aspiration Cytopathology)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 650.140 Td /F3 9.8 Tf  [(February 11, 2013)] TJ ET
BT 93.263 650.140 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 98.138 650.140 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 638.299 Td /F1 9.8 Tf  [(Syed Z. Ali)] TJ ET
0.271 0.267 0.267 rg
BT 73.391 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 78.812 638.299 Td /F1 9.8 Tf  [(Stephanie A. Fish)] TJ ET
0.271 0.267 0.267 rg
BT 155.769 642.187 Td /F1 8.7 Tf  [(1)] TJ ET
BT 160.588 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 166.009 638.299 Td /F1 9.8 Tf  [(Richard B. Lanman)] TJ ET
0.271 0.267 0.267 rg
BT 249.459 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 254.880 638.299 Td /F1 9.8 Tf  [(Gregory W. Randolph)] TJ ET
0.271 0.267 0.267 rg
BT 349.162 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 354.583 638.299 Td /F1 9.8 Tf  [(Julie Ann Sosa)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 627.127 Td /F4 9.0 Tf  [(1)] TJ ET
BT 31.254 627.127 Td /F1 9.0 Tf  [( Memorial Sloan Kettering Cancer Institute and Associate Professor of Medicine \(Endocrinology\) Weill Cornell Medical College)] TJ ET
BT 26.250 615.405 Td /F1 9.8 Tf  [(Ali SZ, Fish SA, Lanman RB, Randolph GW, Sosa JA. Use of the Afirma� Gene Expression Classifier for Preoperative )] TJ ET
BT 26.250 603.501 Td /F1 9.8 Tf  [(Identification of Benign Thyroid Nodules with Indeterminate Fine Needle Aspiration Cytopathology. PLOS Currents Evidence on )] TJ ET
BT 26.250 591.596 Td /F1 9.8 Tf  [(Genomic Tests. 2013 Feb 11 . Edition 1. doi: 10.1371/currents.eogt.e557cbb5c7e4f66568ce582a373057e7.)] TJ ET
q
15.000 25.250 577.500 563.965 re W n
0.271 0.267 0.267 rg
BT 26.250 562.493 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 542.539 Td /F1 9.8 Tf  [(Ruling out malignancy in thyroid nodules historically depended on thyroid resection and histopathological evaluation until fine )] TJ ET
BT 26.250 530.634 Td /F1 9.8 Tf  [(needle aspiration \(FNA\) biopsy was introduced into the United States in the 1970�s. Thyroid FNA biopsy identified a majority of )] TJ ET
BT 26.250 518.730 Td /F1 9.8 Tf  [(thyroid nodules as benign, obviating the need for surgery in over half of the patients. However, 15%-30% of thyroid FNAs have )] TJ ET
BT 26.250 506.825 Td /F1 9.8 Tf  [(indeterminate cytology that still requires operation, even though most of these operated nodules prove to be benign post-)] TJ ET
BT 26.250 494.920 Td /F1 9.8 Tf  [(operatively. In order to predict which cytologically indeterminate thyroid nodules are benign and to potentially avoid surgery on )] TJ ET
BT 26.250 483.015 Td /F1 9.8 Tf  [(these nodules, a recently described commercially available Gene Expression Classifier \(GEC\) test \(Afirma�, Veracyte, Inc., )] TJ ET
BT 26.250 471.111 Td /F1 9.8 Tf  [(South San Francisco, CA\) has been developed that can be run on the FNA sample. This paper reviews the published literature )] TJ ET
BT 26.250 459.206 Td /F1 9.8 Tf  [(and technology assessments/guidelines by independent parties and professional groups regarding the clinical utility as well as )] TJ ET
BT 26.250 447.301 Td /F1 9.8 Tf  [(the analytic and clinical validity of the Afirma GEC.)] TJ ET
BT 26.250 410.699 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 390.744 Td /F1 9.8 Tf  [(No outside funding was provided for this review.)] TJ ET
BT 26.250 361.642 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 341.688 Td /F1 9.8 Tf  [(Thyroid nodules are common and typically benign. However, given that 5-10% of nodules are malignant, current practice )] TJ ET
BT 26.250 329.783 Td /F1 9.8 Tf  [(guidelines recommend evaluation with ultrasound followed by fine needle aspiration \(FNA\) biopsy for most clinically significant )] TJ ET
BT 26.250 317.878 Td /F1 9.8 Tf  [(thyroid nodules.)] TJ ET
0.267 0.267 0.267 rg
BT 95.075 319.385 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 99.894 321.766 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 102.303 319.385 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 107.122 321.766 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 109.531 319.385 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 114.350 317.878 Td /F1 9.8 Tf  [( Most diagnostic FNA biopsies are read as cytopathologically benign or malignant, but 15%-30% remain )] TJ ET
BT 26.250 305.973 Td /F1 9.8 Tf  [(indeterminate.)] TJ ET
0.267 0.267 0.267 rg
BT 88.026 307.481 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 92.845 305.973 Td /F1 9.8 Tf  [( Most patients with indeterminate lesions \(defined in the Bethesda System as Atypia of Undetermined )] TJ ET
BT 26.250 294.069 Td /F1 9.8 Tf  [(Significance or Follicular Lesion of Undetermined Significance, suspicious for Follicular or H�rthle Cell Neoplasm and )] TJ ET
BT 26.250 282.164 Td /F1 9.8 Tf  [(suspicious for malignancy\) are referred for a diagnostic thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 333.482 283.671 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 338.301 282.164 Td /F1 9.8 Tf  [( Approximately three-quarters of these nodules are )] TJ ET
BT 26.250 270.259 Td /F1 9.8 Tf  [(ultimately found to be benign on final surgical pathology.)] TJ ET
0.267 0.267 0.267 rg
BT 269.044 271.766 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 273.863 274.147 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 276.273 271.766 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 250.854 Td /F1 9.8 Tf  [(In 2011, it is estimated that more than 450,000 thyroid FNAs were performed. In that same year, approximately 48,020 primary )] TJ ET
BT 26.250 238.950 Td /F1 9.8 Tf  [(thyroid malignancies were diagnosed.)] TJ ET
0.267 0.267 0.267 rg
BT 189.358 240.457 Td /F4 8.7 Tf  [(7)] TJ ET
0.271 0.267 0.267 rg
BT 194.176 238.950 Td /F1 9.8 Tf  [( In order to avoid diagnostic surgery on benign thyroid nodules with indeterminate FNA )] TJ ET
BT 26.250 227.045 Td /F1 9.8 Tf  [(cytopathology, pre-operative FNA-based genomics tests should predict a risk of malignancy comparable to the risk of )] TJ ET
BT 26.250 215.140 Td /F1 9.8 Tf  [(malignancy in a cytologically benign nodule that is resected \(�approximately 5% or less�\).)] TJ ET
0.267 0.267 0.267 rg
BT 409.347 216.647 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 414.166 215.140 Td /F1 9.8 Tf  [( At this level of risk, physicians can )] TJ ET
BT 26.250 203.235 Td /F1 9.8 Tf  [(confidently recommend clinical and sonographic monitoring )] TJ ET
BT 284.723 203.235 Td /F5 9.8 Tf  [(in lieu)] TJ ET
BT 310.190 203.235 Td /F1 9.8 Tf  [( of thyroid resection as they do for cytologically benign )] TJ ET
BT 26.250 191.331 Td /F1 9.8 Tf  [(nodules under current clinical management schemas.)] TJ ET
0.267 0.267 0.267 rg
BT 257.091 192.838 Td /F4 8.7 Tf  [(9)] TJ ET
0.271 0.267 0.267 rg
BT 261.910 191.331 Td /F1 9.8 Tf  [( Recent reviews have evaluated known gene mutation marker panels )] TJ ET
BT 26.250 179.426 Td /F1 9.8 Tf  [(associated with thyroid malignancy and the Afirma GEC towards this end.)] TJ ET
0.267 0.267 0.267 rg
BT 343.252 180.933 Td /F4 8.7 Tf  [(10)] TJ ET
0.271 0.267 0.267 rg
BT 352.889 183.314 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 355.298 180.933 Td /F4 8.7 Tf  [(11)] TJ ET
0.271 0.267 0.267 rg
BT 364.936 183.314 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 367.345 180.933 Td /F4 8.7 Tf  [(12)] TJ ET
0.271 0.267 0.267 rg
BT 376.982 179.426 Td /F1 9.8 Tf  [( A recent meta-review of a panel of somatic )] TJ ET
BT 26.250 167.521 Td /F1 9.8 Tf  [(mutation markers associated with malignancy such as BRAF, RAS, RET/PTC, and PAX8/PPARgamma found sensitivity to be )] TJ ET
BT 26.250 155.616 Td /F1 9.8 Tf  [(too low \(63.7%\) to achieve a high enough negative predictive value \(NPV\) to recommend monitoring when these mutations are )] TJ ET
BT 26.250 143.712 Td /F1 9.8 Tf  [(absent.)] TJ ET
0.267 0.267 0.267 rg
BT 58.230 145.219 Td /F4 8.7 Tf  [(13)] TJ ET
0.271 0.267 0.267 rg
BT 67.867 143.712 Td /F1 9.8 Tf  [( The Afirma GEC employs a different approach analyzing the mRNA expression of 167 genes with high enough )] TJ ET
BT 26.250 131.807 Td /F1 9.8 Tf  [(sensitivity \(92%\) in indeterminate cytology lesions to identify the signature of a benign thyroid nodule with 95% NPV: that is, )] TJ ET
BT 26.250 119.902 Td /F1 9.8 Tf  [(similar to the risk of malignancy in a resected thyroid nodule with a preoperatively benign FNA cytopathology diagnosis.)] TJ ET
0.267 0.267 0.267 rg
BT 540.504 121.409 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 550.141 123.790 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 552.551 121.409 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 83.300 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 63.345 Td /F1 9.8 Tf  [(When needle passes are made for cytologic analysis of sonographically suspicious thyroid nodules, two dedicated passes also )] TJ ET
BT 26.250 51.441 Td /F1 9.8 Tf  [(are made for Afirma GEC analysis and immediately stored in nucleic acid preservative solution. If the FNA cytopathology is )] TJ ET
BT 26.250 39.536 Td /F1 9.8 Tf  [(nondiagnostic, benign, or malignant, the sample collected for the Afirma GEC is discarded. If the FNA cytopathology is )] TJ ET
Q
q
15.000 659.406 577.500 78.594 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Use of the Afirma� Gene Expression Classifier for )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Preoperative Identification of Benign Thyroid Nodules with )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Indeterminate Fine Needle Aspiration Cytopathology)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 650.140 Td /F3 9.8 Tf  [(February 11, 2013)] TJ ET
BT 93.263 650.140 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 98.138 650.140 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 638.299 Td /F1 9.8 Tf  [(Syed Z. Ali)] TJ ET
0.271 0.267 0.267 rg
BT 73.391 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 78.812 638.299 Td /F1 9.8 Tf  [(Stephanie A. Fish)] TJ ET
0.271 0.267 0.267 rg
BT 155.769 642.187 Td /F1 8.7 Tf  [(1)] TJ ET
BT 160.588 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 166.009 638.299 Td /F1 9.8 Tf  [(Richard B. Lanman)] TJ ET
0.271 0.267 0.267 rg
BT 249.459 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 254.880 638.299 Td /F1 9.8 Tf  [(Gregory W. Randolph)] TJ ET
0.271 0.267 0.267 rg
BT 349.162 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 354.583 638.299 Td /F1 9.8 Tf  [(Julie Ann Sosa)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 627.127 Td /F4 9.0 Tf  [(1)] TJ ET
BT 31.254 627.127 Td /F1 9.0 Tf  [( Memorial Sloan Kettering Cancer Institute and Associate Professor of Medicine \(Endocrinology\) Weill Cornell Medical College)] TJ ET
BT 26.250 615.405 Td /F1 9.8 Tf  [(Ali SZ, Fish SA, Lanman RB, Randolph GW, Sosa JA. Use of the Afirma� Gene Expression Classifier for Preoperative )] TJ ET
BT 26.250 603.501 Td /F1 9.8 Tf  [(Identification of Benign Thyroid Nodules with Indeterminate Fine Needle Aspiration Cytopathology. PLOS Currents Evidence on )] TJ ET
BT 26.250 591.596 Td /F1 9.8 Tf  [(Genomic Tests. 2013 Feb 11 . Edition 1. doi: 10.1371/currents.eogt.e557cbb5c7e4f66568ce582a373057e7.)] TJ ET
q
15.000 25.250 577.500 563.965 re W n
0.271 0.267 0.267 rg
BT 26.250 562.493 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 542.539 Td /F1 9.8 Tf  [(Ruling out malignancy in thyroid nodules historically depended on thyroid resection and histopathological evaluation until fine )] TJ ET
BT 26.250 530.634 Td /F1 9.8 Tf  [(needle aspiration \(FNA\) biopsy was introduced into the United States in the 1970�s. Thyroid FNA biopsy identified a majority of )] TJ ET
BT 26.250 518.730 Td /F1 9.8 Tf  [(thyroid nodules as benign, obviating the need for surgery in over half of the patients. However, 15%-30% of thyroid FNAs have )] TJ ET
BT 26.250 506.825 Td /F1 9.8 Tf  [(indeterminate cytology that still requires operation, even though most of these operated nodules prove to be benign post-)] TJ ET
BT 26.250 494.920 Td /F1 9.8 Tf  [(operatively. In order to predict which cytologically indeterminate thyroid nodules are benign and to potentially avoid surgery on )] TJ ET
BT 26.250 483.015 Td /F1 9.8 Tf  [(these nodules, a recently described commercially available Gene Expression Classifier \(GEC\) test \(Afirma�, Veracyte, Inc., )] TJ ET
BT 26.250 471.111 Td /F1 9.8 Tf  [(South San Francisco, CA\) has been developed that can be run on the FNA sample. This paper reviews the published literature )] TJ ET
BT 26.250 459.206 Td /F1 9.8 Tf  [(and technology assessments/guidelines by independent parties and professional groups regarding the clinical utility as well as )] TJ ET
BT 26.250 447.301 Td /F1 9.8 Tf  [(the analytic and clinical validity of the Afirma GEC.)] TJ ET
BT 26.250 410.699 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 390.744 Td /F1 9.8 Tf  [(No outside funding was provided for this review.)] TJ ET
BT 26.250 361.642 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 341.688 Td /F1 9.8 Tf  [(Thyroid nodules are common and typically benign. However, given that 5-10% of nodules are malignant, current practice )] TJ ET
BT 26.250 329.783 Td /F1 9.8 Tf  [(guidelines recommend evaluation with ultrasound followed by fine needle aspiration \(FNA\) biopsy for most clinically significant )] TJ ET
BT 26.250 317.878 Td /F1 9.8 Tf  [(thyroid nodules.)] TJ ET
0.267 0.267 0.267 rg
BT 95.075 319.385 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 99.894 321.766 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 102.303 319.385 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 107.122 321.766 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 109.531 319.385 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 114.350 317.878 Td /F1 9.8 Tf  [( Most diagnostic FNA biopsies are read as cytopathologically benign or malignant, but 15%-30% remain )] TJ ET
BT 26.250 305.973 Td /F1 9.8 Tf  [(indeterminate.)] TJ ET
0.267 0.267 0.267 rg
BT 88.026 307.481 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 92.845 305.973 Td /F1 9.8 Tf  [( Most patients with indeterminate lesions \(defined in the Bethesda System as Atypia of Undetermined )] TJ ET
BT 26.250 294.069 Td /F1 9.8 Tf  [(Significance or Follicular Lesion of Undetermined Significance, suspicious for Follicular or H�rthle Cell Neoplasm and )] TJ ET
BT 26.250 282.164 Td /F1 9.8 Tf  [(suspicious for malignancy\) are referred for a diagnostic thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 333.482 283.671 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 338.301 282.164 Td /F1 9.8 Tf  [( Approximately three-quarters of these nodules are )] TJ ET
BT 26.250 270.259 Td /F1 9.8 Tf  [(ultimately found to be benign on final surgical pathology.)] TJ ET
0.267 0.267 0.267 rg
BT 269.044 271.766 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 273.863 274.147 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 276.273 271.766 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 250.854 Td /F1 9.8 Tf  [(In 2011, it is estimated that more than 450,000 thyroid FNAs were performed. In that same year, approximately 48,020 primary )] TJ ET
BT 26.250 238.950 Td /F1 9.8 Tf  [(thyroid malignancies were diagnosed.)] TJ ET
0.267 0.267 0.267 rg
BT 189.358 240.457 Td /F4 8.7 Tf  [(7)] TJ ET
0.271 0.267 0.267 rg
BT 194.176 238.950 Td /F1 9.8 Tf  [( In order to avoid diagnostic surgery on benign thyroid nodules with indeterminate FNA )] TJ ET
BT 26.250 227.045 Td /F1 9.8 Tf  [(cytopathology, pre-operative FNA-based genomics tests should predict a risk of malignancy comparable to the risk of )] TJ ET
BT 26.250 215.140 Td /F1 9.8 Tf  [(malignancy in a cytologically benign nodule that is resected \(�approximately 5% or less�\).)] TJ ET
0.267 0.267 0.267 rg
BT 409.347 216.647 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 414.166 215.140 Td /F1 9.8 Tf  [( At this level of risk, physicians can )] TJ ET
BT 26.250 203.235 Td /F1 9.8 Tf  [(confidently recommend clinical and sonographic monitoring )] TJ ET
BT 284.723 203.235 Td /F5 9.8 Tf  [(in lieu)] TJ ET
BT 310.190 203.235 Td /F1 9.8 Tf  [( of thyroid resection as they do for cytologically benign )] TJ ET
BT 26.250 191.331 Td /F1 9.8 Tf  [(nodules under current clinical management schemas.)] TJ ET
0.267 0.267 0.267 rg
BT 257.091 192.838 Td /F4 8.7 Tf  [(9)] TJ ET
0.271 0.267 0.267 rg
BT 261.910 191.331 Td /F1 9.8 Tf  [( Recent reviews have evaluated known gene mutation marker panels )] TJ ET
BT 26.250 179.426 Td /F1 9.8 Tf  [(associated with thyroid malignancy and the Afirma GEC towards this end.)] TJ ET
0.267 0.267 0.267 rg
BT 343.252 180.933 Td /F4 8.7 Tf  [(10)] TJ ET
0.271 0.267 0.267 rg
BT 352.889 183.314 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 355.298 180.933 Td /F4 8.7 Tf  [(11)] TJ ET
0.271 0.267 0.267 rg
BT 364.936 183.314 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 367.345 180.933 Td /F4 8.7 Tf  [(12)] TJ ET
0.271 0.267 0.267 rg
BT 376.982 179.426 Td /F1 9.8 Tf  [( A recent meta-review of a panel of somatic )] TJ ET
BT 26.250 167.521 Td /F1 9.8 Tf  [(mutation markers associated with malignancy such as BRAF, RAS, RET/PTC, and PAX8/PPARgamma found sensitivity to be )] TJ ET
BT 26.250 155.616 Td /F1 9.8 Tf  [(too low \(63.7%\) to achieve a high enough negative predictive value \(NPV\) to recommend monitoring when these mutations are )] TJ ET
BT 26.250 143.712 Td /F1 9.8 Tf  [(absent.)] TJ ET
0.267 0.267 0.267 rg
BT 58.230 145.219 Td /F4 8.7 Tf  [(13)] TJ ET
0.271 0.267 0.267 rg
BT 67.867 143.712 Td /F1 9.8 Tf  [( The Afirma GEC employs a different approach analyzing the mRNA expression of 167 genes with high enough )] TJ ET
BT 26.250 131.807 Td /F1 9.8 Tf  [(sensitivity \(92%\) in indeterminate cytology lesions to identify the signature of a benign thyroid nodule with 95% NPV: that is, )] TJ ET
BT 26.250 119.902 Td /F1 9.8 Tf  [(similar to the risk of malignancy in a resected thyroid nodule with a preoperatively benign FNA cytopathology diagnosis.)] TJ ET
0.267 0.267 0.267 rg
BT 540.504 121.409 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 550.141 123.790 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 552.551 121.409 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 83.300 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 63.345 Td /F1 9.8 Tf  [(When needle passes are made for cytologic analysis of sonographically suspicious thyroid nodules, two dedicated passes also )] TJ ET
BT 26.250 51.441 Td /F1 9.8 Tf  [(are made for Afirma GEC analysis and immediately stored in nucleic acid preservative solution. If the FNA cytopathology is )] TJ ET
BT 26.250 39.536 Td /F1 9.8 Tf  [(nondiagnostic, benign, or malignant, the sample collected for the Afirma GEC is discarded. If the FNA cytopathology is )] TJ ET
Q
q
15.000 659.406 577.500 78.594 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Use of the Afirma� Gene Expression Classifier for )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Preoperative Identification of Benign Thyroid Nodules with )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Indeterminate Fine Needle Aspiration Cytopathology)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 650.140 Td /F3 9.8 Tf  [(February 11, 2013)] TJ ET
BT 93.263 650.140 Td /F3 9.8 Tf  [(�)] TJ ET
0.267 0.267 0.267 rg
BT 98.138 650.140 Td /F3 9.8 Tf  [(Diagnostic)] TJ ET
BT 26.250 638.299 Td /F1 9.8 Tf  [(Syed Z. Ali)] TJ ET
0.271 0.267 0.267 rg
BT 73.391 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 78.812 638.299 Td /F1 9.8 Tf  [(Stephanie A. Fish)] TJ ET
0.271 0.267 0.267 rg
BT 155.769 642.187 Td /F1 8.7 Tf  [(1)] TJ ET
BT 160.588 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 166.009 638.299 Td /F1 9.8 Tf  [(Richard B. Lanman)] TJ ET
0.271 0.267 0.267 rg
BT 249.459 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 254.880 638.299 Td /F1 9.8 Tf  [(Gregory W. Randolph)] TJ ET
0.271 0.267 0.267 rg
BT 349.162 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 354.583 638.299 Td /F1 9.8 Tf  [(Julie Ann Sosa)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 627.127 Td /F4 9.0 Tf  [(1)] TJ ET
BT 31.254 627.127 Td /F1 9.0 Tf  [( Memorial Sloan Kettering Cancer Institute and Associate Professor of Medicine \(Endocrinology\) Weill Cornell Medical College)] TJ ET
BT 26.250 615.405 Td /F1 9.8 Tf  [(Ali SZ, Fish SA, Lanman RB, Randolph GW, Sosa JA. Use of the Afirma� Gene Expression Classifier for Preoperative )] TJ ET
BT 26.250 603.501 Td /F1 9.8 Tf  [(Identification of Benign Thyroid Nodules with Indeterminate Fine Needle Aspiration Cytopathology. PLOS Currents Evidence on )] TJ ET
BT 26.250 591.596 Td /F1 9.8 Tf  [(Genomic Tests. 2013 Feb 11 . Edition 1. doi: 10.1371/currents.eogt.e557cbb5c7e4f66568ce582a373057e7.)] TJ ET
q
15.000 25.250 577.500 563.965 re W n
0.271 0.267 0.267 rg
BT 26.250 562.493 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 542.539 Td /F1 9.8 Tf  [(Ruling out malignancy in thyroid nodules historically depended on thyroid resection and histopathological evaluation until fine )] TJ ET
BT 26.250 530.634 Td /F1 9.8 Tf  [(needle aspiration \(FNA\) biopsy was introduced into the United States in the 1970�s. Thyroid FNA biopsy identified a majority of )] TJ ET
BT 26.250 518.730 Td /F1 9.8 Tf  [(thyroid nodules as benign, obviating the need for surgery in over half of the patients. However, 15%-30% of thyroid FNAs have )] TJ ET
BT 26.250 506.825 Td /F1 9.8 Tf  [(indeterminate cytology that still requires operation, even though most of these operated nodules prove to be benign post-)] TJ ET
BT 26.250 494.920 Td /F1 9.8 Tf  [(operatively. In order to predict which cytologically indeterminate thyroid nodules are benign and to potentially avoid surgery on )] TJ ET
BT 26.250 483.015 Td /F1 9.8 Tf  [(these nodules, a recently described commercially available Gene Expression Classifier \(GEC\) test \(Afirma�, Veracyte, Inc., )] TJ ET
BT 26.250 471.111 Td /F1 9.8 Tf  [(South San Francisco, CA\) has been developed that can be run on the FNA sample. This paper reviews the published literature )] TJ ET
BT 26.250 459.206 Td /F1 9.8 Tf  [(and technology assessments/guidelines by independent parties and professional groups regarding the clinical utility as well as )] TJ ET
BT 26.250 447.301 Td /F1 9.8 Tf  [(the analytic and clinical validity of the Afirma GEC.)] TJ ET
BT 26.250 410.699 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 390.744 Td /F1 9.8 Tf  [(No outside funding was provided for this review.)] TJ ET
BT 26.250 361.642 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 341.688 Td /F1 9.8 Tf  [(Thyroid nodules are common and typically benign. However, given that 5-10% of nodules are malignant, current practice )] TJ ET
BT 26.250 329.783 Td /F1 9.8 Tf  [(guidelines recommend evaluation with ultrasound followed by fine needle aspiration \(FNA\) biopsy for most clinically significant )] TJ ET
BT 26.250 317.878 Td /F1 9.8 Tf  [(thyroid nodules.)] TJ ET
0.267 0.267 0.267 rg
BT 95.075 319.385 Td /F4 8.7 Tf  [(1)] TJ ET
0.271 0.267 0.267 rg
BT 99.894 321.766 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 102.303 319.385 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 107.122 321.766 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 109.531 319.385 Td /F4 8.7 Tf  [(3)] TJ ET
0.271 0.267 0.267 rg
BT 114.350 317.878 Td /F1 9.8 Tf  [( Most diagnostic FNA biopsies are read as cytopathologically benign or malignant, but 15%-30% remain )] TJ ET
BT 26.250 305.973 Td /F1 9.8 Tf  [(indeterminate.)] TJ ET
0.267 0.267 0.267 rg
BT 88.026 307.481 Td /F4 8.7 Tf  [(2)] TJ ET
0.271 0.267 0.267 rg
BT 92.845 305.973 Td /F1 9.8 Tf  [( Most patients with indeterminate lesions \(defined in the Bethesda System as Atypia of Undetermined )] TJ ET
BT 26.250 294.069 Td /F1 9.8 Tf  [(Significance or Follicular Lesion of Undetermined Significance, suspicious for Follicular or H�rthle Cell Neoplasm and )] TJ ET
BT 26.250 282.164 Td /F1 9.8 Tf  [(suspicious for malignancy\) are referred for a diagnostic thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 333.482 283.671 Td /F4 8.7 Tf  [(4)] TJ ET
0.271 0.267 0.267 rg
BT 338.301 282.164 Td /F1 9.8 Tf  [( Approximately three-quarters of these nodules are )] TJ ET
BT 26.250 270.259 Td /F1 9.8 Tf  [(ultimately found to be benign on final surgical pathology.)] TJ ET
0.267 0.267 0.267 rg
BT 269.044 271.766 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 273.863 274.147 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 276.273 271.766 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 250.854 Td /F1 9.8 Tf  [(In 2011, it is estimated that more than 450,000 thyroid FNAs were performed. In that same year, approximately 48,020 primary )] TJ ET
BT 26.250 238.950 Td /F1 9.8 Tf  [(thyroid malignancies were diagnosed.)] TJ ET
0.267 0.267 0.267 rg
BT 189.358 240.457 Td /F4 8.7 Tf  [(7)] TJ ET
0.271 0.267 0.267 rg
BT 194.176 238.950 Td /F1 9.8 Tf  [( In order to avoid diagnostic surgery on benign thyroid nodules with indeterminate FNA )] TJ ET
BT 26.250 227.045 Td /F1 9.8 Tf  [(cytopathology, pre-operative FNA-based genomics tests should predict a risk of malignancy comparable to the risk of )] TJ ET
BT 26.250 215.140 Td /F1 9.8 Tf  [(malignancy in a cytologically benign nodule that is resected \(�approximately 5% or less�\).)] TJ ET
0.267 0.267 0.267 rg
BT 409.347 216.647 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 414.166 215.140 Td /F1 9.8 Tf  [( At this level of risk, physicians can )] TJ ET
BT 26.250 203.235 Td /F1 9.8 Tf  [(confidently recommend clinical and sonographic monitoring )] TJ ET
BT 284.723 203.235 Td /F5 9.8 Tf  [(in lieu)] TJ ET
BT 310.190 203.235 Td /F1 9.8 Tf  [( of thyroid resection as they do for cytologically benign )] TJ ET
BT 26.250 191.331 Td /F1 9.8 Tf  [(nodules under current clinical management schemas.)] TJ ET
0.267 0.267 0.267 rg
BT 257.091 192.838 Td /F4 8.7 Tf  [(9)] TJ ET
0.271 0.267 0.267 rg
BT 261.910 191.331 Td /F1 9.8 Tf  [( Recent reviews have evaluated known gene mutation marker panels )] TJ ET
BT 26.250 179.426 Td /F1 9.8 Tf  [(associated with thyroid malignancy and the Afirma GEC towards this end.)] TJ ET
0.267 0.267 0.267 rg
BT 343.252 180.933 Td /F4 8.7 Tf  [(10)] TJ ET
0.271 0.267 0.267 rg
BT 352.889 183.314 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 355.298 180.933 Td /F4 8.7 Tf  [(11)] TJ ET
0.271 0.267 0.267 rg
BT 364.936 183.314 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 367.345 180.933 Td /F4 8.7 Tf  [(12)] TJ ET
0.271 0.267 0.267 rg
BT 376.982 179.426 Td /F1 9.8 Tf  [( A recent meta-review of a panel of somatic )] TJ ET
BT 26.250 167.521 Td /F1 9.8 Tf  [(mutation markers associated with malignancy such as BRAF, RAS, RET/PTC, and PAX8/PPARgamma found sensitivity to be )] TJ ET
BT 26.250 155.616 Td /F1 9.8 Tf  [(too low \(63.7%\) to achieve a high enough negative predictive value \(NPV\) to recommend monitoring when these mutations are )] TJ ET
BT 26.250 143.712 Td /F1 9.8 Tf  [(absent.)] TJ ET
0.267 0.267 0.267 rg
BT 58.230 145.219 Td /F4 8.7 Tf  [(13)] TJ ET
0.271 0.267 0.267 rg
BT 67.867 143.712 Td /F1 9.8 Tf  [( The Afirma GEC employs a different approach analyzing the mRNA expression of 167 genes with high enough )] TJ ET
BT 26.250 131.807 Td /F1 9.8 Tf  [(sensitivity \(92%\) in indeterminate cytology lesions to identify the signature of a benign thyroid nodule with 95% NPV: that is, )] TJ ET
BT 26.250 119.902 Td /F1 9.8 Tf  [(similar to the risk of malignancy in a resected thyroid nodule with a preoperatively benign FNA cytopathology diagnosis.)] TJ ET
0.267 0.267 0.267 rg
BT 540.504 121.409 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 550.141 123.790 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 552.551 121.409 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 83.300 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 63.345 Td /F1 9.8 Tf  [(When needle passes are made for cytologic analysis of sonographically suspicious thyroid nodules, two dedicated passes also )] TJ ET
BT 26.250 51.441 Td /F1 9.8 Tf  [(are made for Afirma GEC analysis and immediately stored in nucleic acid preservative solution. If the FNA cytopathology is )] TJ ET
BT 26.250 39.536 Td /F1 9.8 Tf  [(nondiagnostic, benign, or malignant, the sample collected for the Afirma GEC is discarded. If the FNA cytopathology is )] 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

Q
endstream
endobj
8 0 obj
<< /Type /Font
/Subtype /Type1
/Name /F1
/BaseFont /Helvetica
/Encoding /WinAnsiEncoding
>>
endobj
9 0 obj
<< /Type /Font
/Subtype /Type1
/Name /F2
/BaseFont /Times-Bold
/Encoding /WinAnsiEncoding
>>
endobj
10 0 obj
<< /Type /Font
/Subtype /Type1
/Name /F3
/BaseFont /Times-Italic
/Encoding /WinAnsiEncoding
>>
endobj
11 0 obj
<< /Type /Font
/Subtype /Type1
/Name /F4
/BaseFont /Helvetica-Bold
/Encoding /WinAnsiEncoding
>>
endobj
12 0 obj
<< /Type /Font
/Subtype /Type1
/Name /F5
/BaseFont /Helvetica-Oblique
/Encoding /WinAnsiEncoding
>>
endobj
13 0 obj
<<
/Type /XObject
/Subtype /Image
/Width 500
/Height 52
/Filter /FlateDecode
/DecodeParms << /Predictor 15 /Colors 1 /Columns 500 /BitsPerComponent 8>>
/ColorSpace /DeviceGray
/BitsPerComponent 8
/Length 144>>
stream
x���1
0���'ݲ؎�"e����{��dz��A��dz��A��dz��A��dz��A��dz��A��dz��A��dz��A��dz��A��dz��A��dz��A��dz��A��dz��A��tlM0\
endstream
endobj
14 0 obj
<<
/Type /XObject
/Subtype /Image
/Width 500
/Height 52
/SMask 13 0 R
/Filter /FlateDecode
/DecodeParms << /Predictor 15 /Colors 3 /Columns 500 /BitsPerComponent 8>>
/ColorSpace /DeviceRGB
/BitsPerComponent 8
/Length 4571>>
stream
x���y�ǝ���[��
b*�TS
��C�
p*���+�T`o����9ZI�dw�M�w����h4=\.�a��\��OW�a��xX�3�|BX�3�|BX�3�|B>R�7M�4�f�0��Ä{Y���h4UU�Qy2�0��0�.����0��~TFq�G��$��B�GQ�Q�1�0z5��b�����۷<�]2
ð�뺮� ��7M3����t:�F��3.L�S���0#c��2���bq�4�z�&��4�z�����*��fff��u����R����-��0�
��=C������,˗�!�}.�p>��W� ���}c�UU��~Q)6���a�ql��5P>8�Ln�S�����d�q_+S���x�}�L&I�P�ݮ�:���,� hv$�s��V�?� �8���4�n>�"0b;���l6��V+���^\�J�Ǯ� @���a�<��CEq�uMG�J� ���OQ�i��e��g��FQt:���m��WR�i�6MӾ�����i۶��N���F[a����֧�}�/��r�<O..MSԁ�'��$Q�(�aH��t:�)�����f,�{?W���z���z�$IBʑb�X�����S�4��W~���x<
!��Y,���p8@���(
�\��ܨ���}�߭V�,��q��,K}�GY���B1F�t]��nѺ>->���ba�����(
{wr��t��GQ4�L~�����ՆA�罼�TU�繢 A0��=�{{{��\��n��y�,��N1�NO�������/��n��������x�����q@�qU�+�i���
A@
r۶�e��x��gGV܌��
�̰
�j���!q��fo	�,��`۶��h�rA�鈞����{=��|[d�]��� %w�����	zh�u��'I��iEP��m�v���r��</�0����f�n�4�se�v��b���n��5��:��0��‚0e��2G2���V�o�UI�g}�B�f���E���a�"�_�5>*�Z��
����6�u�<۶�|�}�|>_�ah��A`I��yݑU�
��jy�7ĥ�zA}�;������������c��;s8�/�M0���ϯ�0}؄;�aE��3��U�5�BE��_]�$�e!҇Q4�a��g��8}�p���	2K�@��
��>�Ϙ��O
;
����kn�PU�jƦ��GI�g/��&k��p�\.��Y6���=���x�~�qYx� He����1�/����?�c����ݶ��2�2L���B�~.�ăI1�T�CȑFw1boiܖ��G�'ܓ$��)�(H���t�L��8���WV�=g���3�\n �|Y�����eJ
��e\ |߇h�/���~U�]�"�
½Om��Od�XD��Q�;�<�aoII�ڧ�I�Z(ï�m��\yB���S��o�h�2�S?+w�.��t:���ޮ��.��4Z���0TT6���I��nyw�l,�u�iH@K�K�|���(��4_mydŽDգBi�
.П�E����dE٧���]6�P�F��Y�F�������c���w�\���?�˻�Eqԃķ�*���	qcp.�ݨk�z0@��h�}�}50�0#\mH۶zG%��^L��2�R����+�l]|�\u��|w�
�&G[������8��%9///��)�D�zhY�����]���{��������}�\�"#����,]��|q�xB;V�M�/f��.�X۵^���%V������eY��_��$l6�$I�D����`�\".�&IoH�'N��	��(
!	�P�B��z��,����r۳,�N9x:�5��	èE�</*���Z��(2N�R�t���>��{��ܪ��w7�Xl�m���5��0��q�NLX1/���vUU��{I�
�p�^w]'��u�N�`X������{�'��������t:�s�0�W�����
�l2^EF����hKi�f����1���A�]��k�~����j:�:��0s+6�.K1�>H���|:��p�޻���v;�,K����v;�W���ӵȋ���A�-���re�)U�e�
!(�-�0��b�����Jq�#0�5�Lʲ��L�In��l�pT��9�����c��r|�Z�����;�3ӟ�.*�s���ftAY��am6�!��fc4��y.��$��c+��ܨ��z����eY��E,{�!D_n}
�A�J�����f#7A~�~}�^_������,Kc��Z,}�X+�
��-̏��.Ě�N�r�Y�M�S	F�f��f�aۦ�p�
9`x?w#t�~���f��Ǐ���iQI���U0�[�����<�|7n7�����7�"���o��uݝ�Ϫ����z\�����|eY�UUQñ݊r
�z{{[����ظ!���*#�!�rǺ���`�\��s!�x<�o��,#حw��>>>�i�����H�Ð�ƪ����XQ��~?�LP�~����nDM�_9-���\��C�� ���{�ڦ�m�gVJ�U7Q�yJ�4�Rd�ݣ�P~RB��齿]ץi��Tm�i3�L���䔰,��l6�Lpn
���0N����0\�]D��e�-#`
�H��Wכ��������d�D!�z�]���a\�_hi�M�t��o�����
>���r-eUW���@7'��S��Jy���A����tP�$I��Y�)�o�������ڣ� 4S)(I%L�%79���:�Ω���Vf�u�<��]%Ce���{�oJ��k\bL�$	5�m[^�`���S�G()��������
�4MUU��f6�}��
z����Y�
�.�p�f��>4��0���r1���|�����ⷑ$�lk*�����1-f5G3��t���ը��(
��u/K
[�@���ᶋ�2EQ ��n�1(�s��E=W�����j���Xi���k�J���>C]O�i�f��E��h�(��\��t���d�n�_�ޝ��4�[AUUx��H��^�(���vX�X��
�{���{E���
�����>�//J��v�3����,�4����+����&����s�V|߿�M��x�����B�X_-���t*oЪ�]���,=��rii���0�aP���j<��#7
j�~����q>�;�K���z����X�e��|�m�,��������F�Q�e7���r	C<[�O�O���r��l60�m�ۦi�g�x<��wb�<�!�&�:��'3�ՍI��V��v�˲L�T���[7!w]0��)Z��1mC��p��
v7�oY"PY���v��1��	]��aH��Xb�4�	��ղ��o:�"[���{&�(\n��?s�C�C��!
�J�O���3rÏ8�g��Rs���~���{9=ϫ�:�s|�Y�9j0�a|�����Oh��(t�9�Z�vד�({2\�1p�M�]Z=xe,!�(`��[F�;l�F��T��]N.'����=TIDZK(�[m��΍��b�_<tcU]l��L��|���r�6w�x@J*K��G�Vl�.��*�0��J`���[��C�͝���^��%��|���q;����m���Ϛ���M%��UZ��F`,Y,�D���*�~'�NN���
˲�,	�|>/�2��a{�e�e+$I�gP~zz����0�頎}�t���B�8�噌 h�Q�o�9ꐦ���JL&����\n�B�&����<��*��=�c�������f�Y�V��
�`4�5U���iB��뺮e}k����Ψy���c!t��i���h4���$�K��?�2o��|[r�w/�W/bB���n��;6�IBS��0��Ί�p+i��oZ9���]��\��g/��^�b���f���X��j��¤��neC���+���ԟ���?>>Zz/�g��n��E�S�`Y�RgA1�����!�zq��u����[����Y���1��G��e�ĥi��YF��+��]�fd��WFK��N'�~W/=~xu]c��p8`�3,Z�+��,#P&�(*��m[�}��b!p��-��8��[^=�r_n��c�0���ʾ��mJ��%�#��|���ew�B�94#�(��3�(G������T�k�*܁b�P���z}(��jJ���з)G]��,x���ʞ��!��*n��х �����-�Z��~B_�FIn�!l�AXZI]��{Y}`�U9R�~�!ܫz� ������	��
�ɷ�(
�G�e�����՟>��5���wO�Jn�j�����<۶%=,�c6�[x�Hqz��]AΎ�Neq�����L��A.� `�V�������֛?>t��p��P��}�P!��d�p��f��S P����C�;�0_���y������зP��yy�˕a��m�
w,��着�k�iP�������>9�0.�P�C�Y.β����G:�k�a�q���۷o$����a��r�pB����i��%Kv�a�3��[�a�����-�0��-�pg����pg����pg����pg����"�A�
endstream
endobj
15 0 obj
<< /Type /Annot
/Subtype /Link
/A 16 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 716.1516 473.9550 736.9416 ]
>>
endobj
16 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
17 0 obj
<< /Type /Annot
/Subtype /Link
/A 18 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 691.2036 554.5950 711.9936 ]
>>
endobj
18 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
19 0 obj
<< /Type /Annot
/Subtype /Link
/A 20 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 666.2556 492.1410 687.0456 ]
>>
endobj
20 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
21 0 obj
<< /Type /Annot
/Subtype /Link
/A 22 0 R
/Border [0 0 0]
/H /I
/Rect [ 98.1382 649.2621 140.9310 658.9146 ]
>>
endobj
22 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article_category/diagnostic/)
>>
endobj
23 0 obj
<< /Type /Annot
/Subtype /Link
/A 24 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 637.3973 73.3912 647.3179 ]
>>
endobj
24 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/salijhmi-edu/)
>>
endobj
25 0 obj
<< /Type /Annot
/Subtype /Link
/A 26 0 R
/Border [0 0 0]
/H /I
/Rect [ 78.8123 637.3973 155.7690 647.3179 ]
>>
endobj
26 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/fishsmskcc-org/)
>>
endobj
27 0 obj
<< /Type /Annot
/Subtype /Link
/A 28 0 R
/Border [0 0 0]
/H /I
/Rect [ 166.0087 637.3973 249.4589 647.3179 ]
>>
endobj
28 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/rlanman/)
>>
endobj
29 0 obj
<< /Type /Annot
/Subtype /Link
/A 30 0 R
/Border [0 0 0]
/H /I
/Rect [ 254.8799 637.3973 349.1624 647.3179 ]
>>
endobj
30 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/gregory_randolphmeei-harvard-edu/)
>>
endobj
31 0 obj
<< /Type /Annot
/Subtype /Link
/A 32 0 R
/Border [0 0 0]
/H /I
/Rect [ 354.5834 637.3973 419.6159 647.3179 ]
>>
endobj
32 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/julie-sosaduke-edu/)
>>
endobj
33 0 obj
<< /Type /Annot
/Subtype /Link
/A 34 0 R
/Border [0 0 0]
/H /I
/Rect [ 95.0752 318.5837 99.8939 327.4020 ]
>>
endobj
34 0 obj
<< /Type /Action
>>
endobj
35 0 obj
<< /Type /Annot
/Subtype /Link
/A 36 0 R
/Border [0 0 0]
/H /I
/Rect [ 102.3033 318.5837 107.1219 327.4020 ]
>>
endobj
36 0 obj
<< /Type /Action
>>
endobj
37 0 obj
<< /Type /Annot
/Subtype /Link
/A 38 0 R
/Border [0 0 0]
/H /I
/Rect [ 109.5313 318.5837 114.3499 327.4020 ]
>>
endobj
38 0 obj
<< /Type /Action
>>
endobj
39 0 obj
<< /Type /Annot
/Subtype /Link
/A 40 0 R
/Border [0 0 0]
/H /I
/Rect [ 88.0260 306.6789 92.8447 315.4973 ]
>>
endobj
40 0 obj
<< /Type /Action
>>
endobj
41 0 obj
<< /Type /Annot
/Subtype /Link
/A 42 0 R
/Border [0 0 0]
/H /I
/Rect [ 333.4823 282.8694 338.3009 291.6878 ]
>>
endobj
42 0 obj
<< /Type /Action
>>
endobj
43 0 obj
<< /Type /Annot
/Subtype /Link
/A 44 0 R
/Border [0 0 0]
/H /I
/Rect [ 269.0445 270.9647 273.8632 279.7830 ]
>>
endobj
44 0 obj
<< /Type /Action
>>
endobj
45 0 obj
<< /Type /Annot
/Subtype /Link
/A 46 0 R
/Border [0 0 0]
/H /I
/Rect [ 276.2725 270.9647 281.0912 279.7830 ]
>>
endobj
46 0 obj
<< /Type /Action
>>
endobj
47 0 obj
<< /Type /Annot
/Subtype /Link
/A 48 0 R
/Border [0 0 0]
/H /I
/Rect [ 189.3578 239.6552 194.1764 248.4735 ]
>>
endobj
48 0 obj
<< /Type /Action
>>
endobj
49 0 obj
<< /Type /Annot
/Subtype /Link
/A 50 0 R
/Border [0 0 0]
/H /I
/Rect [ 409.3470 215.8457 414.1657 224.6640 ]
>>
endobj
50 0 obj
<< /Type /Action
>>
endobj
51 0 obj
<< /Type /Annot
/Subtype /Link
/A 52 0 R
/Border [0 0 0]
/H /I
/Rect [ 257.0910 192.0362 261.9097 200.8545 ]
>>
endobj
52 0 obj
<< /Type /Action
>>
endobj
53 0 obj
<< /Type /Annot
/Subtype /Link
/A 54 0 R
/Border [0 0 0]
/H /I
/Rect [ 343.2518 180.1314 352.8891 188.9497 ]
>>
endobj
54 0 obj
<< /Type /Action
>>
endobj
55 0 obj
<< /Type /Annot
/Subtype /Link
/A 56 0 R
/Border [0 0 0]
/H /I
/Rect [ 355.2984 180.1314 364.9358 188.9497 ]
>>
endobj
56 0 obj
<< /Type /Action
>>
endobj
57 0 obj
<< /Type /Annot
/Subtype /Link
/A 58 0 R
/Border [0 0 0]
/H /I
/Rect [ 367.3451 180.1314 376.9824 188.9497 ]
>>
endobj
58 0 obj
<< /Type /Action
>>
endobj
59 0 obj
<< /Type /Annot
/Subtype /Link
/A 60 0 R
/Border [0 0 0]
/H /I
/Rect [ 58.2300 144.4172 67.8673 153.2355 ]
>>
endobj
60 0 obj
<< /Type /Action
>>
endobj
61 0 obj
<< /Type /Annot
/Subtype /Link
/A 62 0 R
/Border [0 0 0]
/H /I
/Rect [ 540.5040 120.6077 550.1413 129.4260 ]
>>
endobj
62 0 obj
<< /Type /Action
>>
endobj
63 0 obj
<< /Type /Annot
/Subtype /Link
/A 64 0 R
/Border [0 0 0]
/H /I
/Rect [ 552.5507 120.6077 562.1880 129.4260 ]
>>
endobj
64 0 obj
<< /Type /Action
>>
endobj
65 0 obj
<< /Type /Annot
/Subtype /Link
/A 66 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 716.1516 473.9550 736.9416 ]
>>
endobj
66 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
67 0 obj
<< /Type /Annot
/Subtype /Link
/A 68 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 691.2036 554.5950 711.9936 ]
>>
endobj
68 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
69 0 obj
<< /Type /Annot
/Subtype /Link
/A 70 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 666.2556 492.1410 687.0456 ]
>>
endobj
70 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
71 0 obj
<< /Type /Annot
/Subtype /Link
/A 72 0 R
/Border [0 0 0]
/H /I
/Rect [ 98.1382 649.2621 140.9310 658.9146 ]
>>
endobj
72 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article_category/diagnostic/)
>>
endobj
73 0 obj
<< /Type /Annot
/Subtype /Link
/A 74 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 637.3973 73.3912 647.3179 ]
>>
endobj
74 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/salijhmi-edu/)
>>
endobj
75 0 obj
<< /Type /Annot
/Subtype /Link
/A 76 0 R
/Border [0 0 0]
/H /I
/Rect [ 78.8123 637.3973 155.7690 647.3179 ]
>>
endobj
76 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/fishsmskcc-org/)
>>
endobj
77 0 obj
<< /Type /Annot
/Subtype /Link
/A 78 0 R
/Border [0 0 0]
/H /I
/Rect [ 166.0087 637.3973 249.4589 647.3179 ]
>>
endobj
78 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/rlanman/)
>>
endobj
79 0 obj
<< /Type /Annot
/Subtype /Link
/A 80 0 R
/Border [0 0 0]
/H /I
/Rect [ 254.8799 637.3973 349.1624 647.3179 ]
>>
endobj
80 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/gregory_randolphmeei-harvard-edu/)
>>
endobj
81 0 obj
<< /Type /Annot
/Subtype /Link
/A 82 0 R
/Border [0 0 0]
/H /I
/Rect [ 354.5834 637.3973 419.6159 647.3179 ]
>>
endobj
82 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/julie-sosaduke-edu/)
>>
endobj
83 0 obj
<< /Type /Annot
/Subtype /Link
/A 84 0 R
/Border [0 0 0]
/H /I
/Rect [ 95.0752 318.5837 99.8939 327.4020 ]
>>
endobj
84 0 obj
<< /Type /Action
>>
endobj
85 0 obj
<< /Type /Annot
/Subtype /Link
/A 86 0 R
/Border [0 0 0]
/H /I
/Rect [ 102.3033 318.5837 107.1219 327.4020 ]
>>
endobj
86 0 obj
<< /Type /Action
>>
endobj
87 0 obj
<< /Type /Annot
/Subtype /Link
/A 88 0 R
/Border [0 0 0]
/H /I
/Rect [ 109.5313 318.5837 114.3499 327.4020 ]
>>
endobj
88 0 obj
<< /Type /Action
>>
endobj
89 0 obj
<< /Type /Annot
/Subtype /Link
/A 90 0 R
/Border [0 0 0]
/H /I
/Rect [ 88.0260 306.6789 92.8447 315.4973 ]
>>
endobj
90 0 obj
<< /Type /Action
>>
endobj
91 0 obj
<< /Type /Annot
/Subtype /Link
/A 92 0 R
/Border [0 0 0]
/H /I
/Rect [ 333.4823 282.8694 338.3009 291.6878 ]
>>
endobj
92 0 obj
<< /Type /Action
>>
endobj
93 0 obj
<< /Type /Annot
/Subtype /Link
/A 94 0 R
/Border [0 0 0]
/H /I
/Rect [ 269.0445 270.9647 273.8632 279.7830 ]
>>
endobj
94 0 obj
<< /Type /Action
>>
endobj
95 0 obj
<< /Type /Annot
/Subtype /Link
/A 96 0 R
/Border [0 0 0]
/H /I
/Rect [ 276.2725 270.9647 281.0912 279.7830 ]
>>
endobj
96 0 obj
<< /Type /Action
>>
endobj
97 0 obj
<< /Type /Annot
/Subtype /Link
/A 98 0 R
/Border [0 0 0]
/H /I
/Rect [ 189.3578 239.6552 194.1764 248.4735 ]
>>
endobj
98 0 obj
<< /Type /Action
>>
endobj
99 0 obj
<< /Type /Annot
/Subtype /Link
/A 100 0 R
/Border [0 0 0]
/H /I
/Rect [ 409.3470 215.8457 414.1657 224.6640 ]
>>
endobj
100 0 obj
<< /Type /Action
>>
endobj
101 0 obj
<< /Type /Annot
/Subtype /Link
/A 102 0 R
/Border [0 0 0]
/H /I
/Rect [ 257.0910 192.0362 261.9097 200.8545 ]
>>
endobj
102 0 obj
<< /Type /Action
>>
endobj
103 0 obj
<< /Type /Annot
/Subtype /Link
/A 104 0 R
/Border [0 0 0]
/H /I
/Rect [ 343.2518 180.1314 352.8891 188.9497 ]
>>
endobj
104 0 obj
<< /Type /Action
>>
endobj
105 0 obj
<< /Type /Annot
/Subtype /Link
/A 106 0 R
/Border [0 0 0]
/H /I
/Rect [ 355.2984 180.1314 364.9358 188.9497 ]
>>
endobj
106 0 obj
<< /Type /Action
>>
endobj
107 0 obj
<< /Type /Annot
/Subtype /Link
/A 108 0 R
/Border [0 0 0]
/H /I
/Rect [ 367.3451 180.1314 376.9824 188.9497 ]
>>
endobj
108 0 obj
<< /Type /Action
>>
endobj
109 0 obj
<< /Type /Annot
/Subtype /Link
/A 110 0 R
/Border [0 0 0]
/H /I
/Rect [ 58.2300 144.4172 67.8673 153.2355 ]
>>
endobj
110 0 obj
<< /Type /Action
>>
endobj
111 0 obj
<< /Type /Annot
/Subtype /Link
/A 112 0 R
/Border [0 0 0]
/H /I
/Rect [ 540.5040 120.6077 550.1413 129.4260 ]
>>
endobj
112 0 obj
<< /Type /Action
>>
endobj
113 0 obj
<< /Type /Annot
/Subtype /Link
/A 114 0 R
/Border [0 0 0]
/H /I
/Rect [ 552.5507 120.6077 562.1880 129.4260 ]
>>
endobj
114 0 obj
<< /Type /Action
>>
endobj
115 0 obj
<< /Type /Annot
/Subtype /Link
/A 116 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 716.1516 473.9550 736.9416 ]
>>
endobj
116 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
117 0 obj
<< /Type /Annot
/Subtype /Link
/A 118 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 691.2036 554.5950 711.9936 ]
>>
endobj
118 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
119 0 obj
<< /Type /Annot
/Subtype /Link
/A 120 0 R
/Border [0 0 0]
/H /I
/Rect [ 15.0000 666.2556 492.1410 687.0456 ]
>>
endobj
120 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article/use-of-the-afirma-gene-expression-classifier-for-preoperative-identification-of-benign-thyroid-nodules-with-indeterminate-fine-needle-aspiration-cytopathology/)
>>
endobj
121 0 obj
<< /Type /Annot
/Subtype /Link
/A 122 0 R
/Border [0 0 0]
/H /I
/Rect [ 98.1382 649.2621 140.9310 658.9146 ]
>>
endobj
122 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/article_category/diagnostic/)
>>
endobj
123 0 obj
<< /Type /Annot
/Subtype /Link
/A 124 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 637.3973 73.3912 647.3179 ]
>>
endobj
124 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/salijhmi-edu/)
>>
endobj
125 0 obj
<< /Type /Annot
/Subtype /Link
/A 126 0 R
/Border [0 0 0]
/H /I
/Rect [ 78.8123 637.3973 155.7690 647.3179 ]
>>
endobj
126 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/fishsmskcc-org/)
>>
endobj
127 0 obj
<< /Type /Annot
/Subtype /Link
/A 128 0 R
/Border [0 0 0]
/H /I
/Rect [ 166.0087 637.3973 249.4589 647.3179 ]
>>
endobj
128 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/rlanman/)
>>
endobj
129 0 obj
<< /Type /Annot
/Subtype /Link
/A 130 0 R
/Border [0 0 0]
/H /I
/Rect [ 254.8799 637.3973 349.1624 647.3179 ]
>>
endobj
130 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/gregory_randolphmeei-harvard-edu/)
>>
endobj
131 0 obj
<< /Type /Annot
/Subtype /Link
/A 132 0 R
/Border [0 0 0]
/H /I
/Rect [ 354.5834 637.3973 419.6159 647.3179 ]
>>
endobj
132 0 obj
<< /Type /Action
/S /URI
/URI (https://currents.plos.org/genomictests/author/julie-sosaduke-edu/)
>>
endobj
133 0 obj
<< /Type /Annot
/Subtype /Link
/A 134 0 R
/Border [0 0 0]
/H /I
/Rect [ 95.0752 318.5837 99.8939 327.4020 ]
>>
endobj
134 0 obj
<< /Type /Action
>>
endobj
135 0 obj
<< /Type /Annot
/Subtype /Link
/A 136 0 R
/Border [0 0 0]
/H /I
/Rect [ 102.3033 318.5837 107.1219 327.4020 ]
>>
endobj
136 0 obj
<< /Type /Action
>>
endobj
137 0 obj
<< /Type /Annot
/Subtype /Link
/A 138 0 R
/Border [0 0 0]
/H /I
/Rect [ 109.5313 318.5837 114.3499 327.4020 ]
>>
endobj
138 0 obj
<< /Type /Action
>>
endobj
139 0 obj
<< /Type /Annot
/Subtype /Link
/A 140 0 R
/Border [0 0 0]
/H /I
/Rect [ 88.0260 306.6789 92.8447 315.4973 ]
>>
endobj
140 0 obj
<< /Type /Action
>>
endobj
141 0 obj
<< /Type /Annot
/Subtype /Link
/A 142 0 R
/Border [0 0 0]
/H /I
/Rect [ 333.4823 282.8694 338.3009 291.6878 ]
>>
endobj
142 0 obj
<< /Type /Action
>>
endobj
143 0 obj
<< /Type /Annot
/Subtype /Link
/A 144 0 R
/Border [0 0 0]
/H /I
/Rect [ 269.0445 270.9647 273.8632 279.7830 ]
>>
endobj
144 0 obj
<< /Type /Action
>>
endobj
145 0 obj
<< /Type /Annot
/Subtype /Link
/A 146 0 R
/Border [0 0 0]
/H /I
/Rect [ 276.2725 270.9647 281.0912 279.7830 ]
>>
endobj
146 0 obj
<< /Type /Action
>>
endobj
147 0 obj
<< /Type /Annot
/Subtype /Link
/A 148 0 R
/Border [0 0 0]
/H /I
/Rect [ 189.3578 239.6552 194.1764 248.4735 ]
>>
endobj
148 0 obj
<< /Type /Action
>>
endobj
149 0 obj
<< /Type /Annot
/Subtype /Link
/A 150 0 R
/Border [0 0 0]
/H /I
/Rect [ 409.3470 215.8457 414.1657 224.6640 ]
>>
endobj
150 0 obj
<< /Type /Action
>>
endobj
151 0 obj
<< /Type /Annot
/Subtype /Link
/A 152 0 R
/Border [0 0 0]
/H /I
/Rect [ 257.0910 192.0362 261.9097 200.8545 ]
>>
endobj
152 0 obj
<< /Type /Action
>>
endobj
153 0 obj
<< /Type /Annot
/Subtype /Link
/A 154 0 R
/Border [0 0 0]
/H /I
/Rect [ 343.2518 180.1314 352.8891 188.9497 ]
>>
endobj
154 0 obj
<< /Type /Action
>>
endobj
155 0 obj
<< /Type /Annot
/Subtype /Link
/A 156 0 R
/Border [0 0 0]
/H /I
/Rect [ 355.2984 180.1314 364.9358 188.9497 ]
>>
endobj
156 0 obj
<< /Type /Action
>>
endobj
157 0 obj
<< /Type /Annot
/Subtype /Link
/A 158 0 R
/Border [0 0 0]
/H /I
/Rect [ 367.3451 180.1314 376.9824 188.9497 ]
>>
endobj
158 0 obj
<< /Type /Action
>>
endobj
159 0 obj
<< /Type /Annot
/Subtype /Link
/A 160 0 R
/Border [0 0 0]
/H /I
/Rect [ 58.2300 144.4172 67.8673 153.2355 ]
>>
endobj
160 0 obj
<< /Type /Action
>>
endobj
161 0 obj
<< /Type /Annot
/Subtype /Link
/A 162 0 R
/Border [0 0 0]
/H /I
/Rect [ 540.5040 120.6077 550.1413 129.4260 ]
>>
endobj
162 0 obj
<< /Type /Action
>>
endobj
163 0 obj
<< /Type /Annot
/Subtype /Link
/A 164 0 R
/Border [0 0 0]
/H /I
/Rect [ 552.5507 120.6077 562.1880 129.4260 ]
>>
endobj
164 0 obj
<< /Type /Action
>>
endobj
165 0 obj
<< /Type /Page
/Parent 3 0 R
/Annots [ 168 0 R 170 0 R 172 0 R 174 0 R 176 0 R 178 0 R 180 0 R 182 0 R 184 0 R 186 0 R 188 0 R 190 0 R 192 0 R 194 0 R 196 0 R 198 0 R 200 0 R 202 0 R 204 0 R 206 0 R 208 0 R 210 0 R 212 0 R 214 0 R 216 0 R 218 0 R 220 0 R 222 0 R 224 0 R 226 0 R 228 0 R 230 0 R 232 0 R 234 0 R 236 0 R 238 0 R 240 0 R 242 0 R 244 0 R 246 0 R 248 0 R 250 0 R 252 0 R 254 0 R 256 0 R 258 0 R 260 0 R 262 0 R 264 0 R 266 0 R 268 0 R 270 0 R 272 0 R 274 0 R 276 0 R 278 0 R 280 0 R 282 0 R 284 0 R 286 0 R 288 0 R 290 0 R 292 0 R 294 0 R 296 0 R 298 0 R 300 0 R 302 0 R 304 0 R ]
/Contents 166 0 R
>>
endobj
166 0 obj
<<
/Length 32099 >>
stream

0.271 0.267 0.267 rg
q
15.000 32.343 577.500 744.657 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(indeterminate, the Afirma GEC sample undergoes RNA extraction and nucleic acid amplification. Processed Afirma GEC )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(samples are hybridized to a custom Afirma Thyroid microarray and analyzed with a classification algorithm using linear support )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(vector machine logic to produce either a �Benign� or �Suspicious� test result. About 10% of FNA samples have inadequate RNA )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(yield or quality and are reported by the Afirma GEC as �No Result�.)] TJ ET
0.267 0.267 0.267 rg
BT 315.065 733.269 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 695.159 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(The incidence of thyroid cancer in the U.S. has risen dramatically. In 2009, there were 37,200 new cases of thyroid cancer, )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(while in 2013, it is anticipated there will be 60,220 new cases.)] TJ ET
0.267 0.267 0.267 rg
BT 291.791 664.808 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 301.429 667.189 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 303.838 664.808 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 313.475 663.300 Td /F1 9.8 Tf  [( At the same time, there has been an increase in the )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(utilization of thyroid FNA and subsequent thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 273.900 652.903 Td /F4 8.7 Tf  [(19)] TJ ET
0.271 0.267 0.267 rg
BT 283.537 651.396 Td /F1 9.8 Tf  [( The prevalence of thyroid nodules increases with age and is more )] TJ ET
BT 26.250 639.491 Td /F1 9.8 Tf  [(common in females. Approximately 50% of women ?50 years have at least one thyroid nodule based on published ultrasound )] TJ ET
BT 26.250 627.586 Td /F1 9.8 Tf  [(and autopsy series.)] TJ ET
0.267 0.267 0.267 rg
BT 110.792 629.093 Td /F4 8.7 Tf  [(20)] TJ ET
0.271 0.267 0.267 rg
BT 120.430 627.586 Td /F1 9.8 Tf  [( Two thirds of thyroid nodules have benign FNA cytopathology and monitoring is implemented, whereas )] TJ ET
BT 26.250 615.681 Td /F1 9.8 Tf  [(those with indeterminate or malignant cytology are generally referred for surgery. Because thyroid nodules with indeterminate )] TJ ET
BT 26.250 603.777 Td /F1 9.8 Tf  [(FNA cytopathology have a 25% risk of malignancy when resected, 75% of these operations will likely be on nodules determined )] TJ ET
BT 26.250 591.872 Td /F1 9.8 Tf  [(to be benign post-operatively.)] TJ ET
0.267 0.267 0.267 rg
BT 154.150 593.379 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 158.969 595.760 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 161.379 593.379 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 166.197 591.872 Td /F1 9.8 Tf  [( Thyroid surgery is associated with potential complications, including temporary and permanent )] TJ ET
BT 26.250 579.967 Td /F1 9.8 Tf  [(hypocalcemia, recurrent laryngeal nerve injury \(with voice change, dysphagia, and potentially airway compromise if bilateral\), )] TJ ET
BT 26.250 568.062 Td /F1 9.8 Tf  [(and bleeding, with an incidence as high as 2-10%.)] TJ ET
0.267 0.267 0.267 rg
BT 243.031 569.570 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 252.669 571.951 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 255.078 569.570 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 264.716 571.951 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 267.125 569.570 Td /F4 8.7 Tf  [(23)] TJ ET
0.271 0.267 0.267 rg
BT 276.762 568.062 Td /F1 9.8 Tf  [( While there is strong evidence that high volume thyroid surgeons on )] TJ ET
BT 26.250 556.158 Td /F1 9.8 Tf  [(average have fewer complications than low volume counterparts, 50% of thyroid operations in the U.S. are still performed by )] TJ ET
BT 26.250 544.253 Td /F1 9.8 Tf  [(surgeons who perform ?5 thyroidectomies/year.)] TJ ET
0.267 0.267 0.267 rg
BT 232.160 545.760 Td /F4 8.7 Tf  [(24)] TJ ET
0.271 0.267 0.267 rg
BT 241.798 544.253 Td /F1 9.8 Tf  [( Hypothyroidism is an expected sequelae of thyroid surgery, with patients )] TJ ET
BT 26.250 532.348 Td /F1 9.8 Tf  [(requiring life-long thyroid hormone supplementation or replacement therapy.)] TJ ET
BT 26.250 495.746 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 475.791 Td /F6 9.8 Tf  [(Systematic evidence reviews.)] TJ ET
BT 163.364 475.791 Td /F1 9.8 Tf  [( Palmetto Government Benefits Administrators \(Palmetto GBA\), the CMS Medicare )] TJ ET
BT 26.250 463.887 Td /F1 9.8 Tf  [(Administrative Contractor with oversight for the Afirma GEC, has published its )] TJ ET
BT 363.824 463.887 Td /F1 9.8 Tf  [(assessment of the test as an update to its local )] TJ ET
BT 26.250 451.982 Td /F1 9.8 Tf  [(coverage article on molecular diagnostics. This review determined that the test meets criteria for analytical and clinical validity, )] TJ ET
BT 26.250 440.077 Td /F1 9.8 Tf  [(and clinical utility as a reasonable and necessary Medicare benefit, effective January 1, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 429.442 441.584 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 420.672 Td /F6 9.8 Tf  [(Recommendations by independent groups.)] TJ ET
BT 226.700 420.672 Td /F1 9.8 Tf  [( As part of the CLIA Laboratory licensure process, the analytical and clinical )] TJ ET
BT 26.250 408.768 Td /F1 9.8 Tf  [(validation data for the Afirma GEC were independently assessed by reviewers from the California Department of Public Health )] TJ ET
BT 26.250 396.863 Td /F1 9.8 Tf  [(and the New York State Department of Health.)] TJ ET
0.267 0.267 0.267 rg
BT 227.305 398.370 Td /F4 8.7 Tf  [(26)] TJ ET
0.271 0.267 0.267 rg
BT 236.942 400.751 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 239.351 398.370 Td /F4 8.7 Tf  [(27)] TJ ET
0.271 0.267 0.267 rg
BT 248.989 396.863 Td /F1 9.8 Tf  [( Both of these reviews resulted in a favorable licensure outcome.)] TJ ET
BT 26.250 377.458 Td /F6 9.8 Tf  [(Guidelines by professional groups.)] TJ ET
BT 189.338 377.458 Td /F1 9.8 Tf  [( The National Comprehensive Cancer Network \(NCCN\) thyroid carcinoma guidelines were )] TJ ET
BT 26.250 365.553 Td /F1 9.8 Tf  [(updated in December, 2012 to state �Molecular diagnostics may be useful to allow reclassification of follicular lesions \(follicular )] TJ ET
BT 26.250 353.649 Td /F1 9.8 Tf  [(neoplasm or follicular lesion of undetermined significance\) as more likely to be benign or more likely to be malignant�If )] TJ ET
BT 26.250 341.744 Td /F1 9.8 Tf  [(molecular testing predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology )] TJ ET
BT 26.250 329.839 Td /F1 9.8 Tf  [(\(approximately 5% or less\), consider observation.� The NCCN guidelines for abnormal gene/gene expression profile testing are )] TJ ET
BT 26.250 317.934 Td /F1 9.8 Tf  [(associated with Level of Evidence 2A \(lower level evidence, uniform NCCN consensus that the intervention is appropriate\).)] TJ ET
0.267 0.267 0.267 rg
BT 555.129 319.442 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 559.948 321.823 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 562.357 319.442 Td /F4 8.7 Tf  [(28)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 281.332 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 261.378 Td /F6 9.8 Tf  [(Analytical Validity)] TJ ET
BT 109.700 261.378 Td /F4 9.8 Tf  [(: test accuracy, reliability in measuring differences in expression of relevant genes \(analytic )] TJ ET
BT 26.250 249.473 Td /F4 9.8 Tf  [(sensitivity and specificity\), and robustness.)] TJ ET
BT 26.250 230.068 Td /F1 9.8 Tf  [(� Building on an earlier study by Chudova et al.)] TJ ET
0.267 0.267 0.267 rg
BT 228.553 231.575 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 238.190 230.068 Td /F1 9.8 Tf  [(, a large collaborative study by Walsh et al. reviewed over 30 sub-studies on )] TJ ET
BT 26.250 218.163 Td /F1 9.8 Tf  [(the Afirma GEC, finding high analytic sensitivity and specificity after dilution of thyroid neoplasm FNA samples with adjacent )] TJ ET
BT 26.250 206.259 Td /F1 9.8 Tf  [(normal tissue or benign neoplasms \(such as nodular hyperplasia and lymphocytic thyroiditis\), as well as dilution with blood and )] TJ ET
BT 26.250 194.354 Td /F1 9.8 Tf  [(genomic DNA, respectively.)] TJ ET
0.267 0.267 0.267 rg
BT 145.990 195.861 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 155.627 198.242 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 158.036 195.861 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 174.949 Td /F1 9.8 Tf  [(� High reproducibility was found in studies of interlaboratory concordance \(R)] TJ ET
BT 353.704 178.837 Td /F1 8.7 Tf  [(2)] TJ ET
BT 358.522 174.949 Td /F1 9.8 Tf  [( 0.98\), as well as intra-assay, inter-assay, and )] TJ ET
BT 26.250 163.044 Td /F1 9.8 Tf  [(intra-nodule concordance \(R)] TJ ET
BT 149.256 166.933 Td /F1 8.7 Tf  [(2)] TJ ET
BT 154.075 163.044 Td /F1 9.8 Tf  [( 0.99, 0.98, and 0.95, respectively\).)] TJ ET
0.267 0.267 0.267 rg
BT 306.370 164.552 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 143.640 Td /F1 9.8 Tf  [(� The assay was robust to a wide range of temperature, storage and stressed shipping conditions and was reproducible across )] TJ ET
BT 26.250 131.735 Td /F1 9.8 Tf  [(different operators, runs, and reagent lots with routine use of control reagents/samples for in-process Quality Control monitoring.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 121.337 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 101.748 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 101.748 Td /F4 9.8 Tf  [(: test accuracy in correctly determining which indeterminate cytology FNA biopsies are benign )] TJ ET
BT 26.250 89.843 Td /F4 9.8 Tf  [(compared to expert surgical histopathology.)] TJ ET
BT 26.250 70.439 Td /F1 9.8 Tf  [(� Two prospective multicenter studies evaluated the negative predictive value \(NPV\) for the Afirma GEC, which is the key )] TJ ET
BT 26.250 58.534 Td /F1 9.8 Tf  [(diagnostic performance metric used to make a decision to monitor patients)] TJ ET
BT 347.591 58.534 Td /F5 9.8 Tf  [( in lieu)] TJ ET
BT 375.768 58.534 Td /F1 9.8 Tf  [( of referral for diagnostic thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 550.790 60.041 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 560.428 62.422 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 562.837 60.041 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 46.629 Td /F1 9.8 Tf  [(Both studies utilized diagnosis of the surgical pathology specimen by a central panel of blinded academic endocrine )] TJ ET
Q
q
15.000 32.343 577.500 744.657 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(indeterminate, the Afirma GEC sample undergoes RNA extraction and nucleic acid amplification. Processed Afirma GEC )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(samples are hybridized to a custom Afirma Thyroid microarray and analyzed with a classification algorithm using linear support )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(vector machine logic to produce either a �Benign� or �Suspicious� test result. About 10% of FNA samples have inadequate RNA )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(yield or quality and are reported by the Afirma GEC as �No Result�.)] TJ ET
0.267 0.267 0.267 rg
BT 315.065 733.269 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 695.159 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(The incidence of thyroid cancer in the U.S. has risen dramatically. In 2009, there were 37,200 new cases of thyroid cancer, )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(while in 2013, it is anticipated there will be 60,220 new cases.)] TJ ET
0.267 0.267 0.267 rg
BT 291.791 664.808 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 301.429 667.189 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 303.838 664.808 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 313.475 663.300 Td /F1 9.8 Tf  [( At the same time, there has been an increase in the )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(utilization of thyroid FNA and subsequent thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 273.900 652.903 Td /F4 8.7 Tf  [(19)] TJ ET
0.271 0.267 0.267 rg
BT 283.537 651.396 Td /F1 9.8 Tf  [( The prevalence of thyroid nodules increases with age and is more )] TJ ET
BT 26.250 639.491 Td /F1 9.8 Tf  [(common in females. Approximately 50% of women ?50 years have at least one thyroid nodule based on published ultrasound )] TJ ET
BT 26.250 627.586 Td /F1 9.8 Tf  [(and autopsy series.)] TJ ET
0.267 0.267 0.267 rg
BT 110.792 629.093 Td /F4 8.7 Tf  [(20)] TJ ET
0.271 0.267 0.267 rg
BT 120.430 627.586 Td /F1 9.8 Tf  [( Two thirds of thyroid nodules have benign FNA cytopathology and monitoring is implemented, whereas )] TJ ET
BT 26.250 615.681 Td /F1 9.8 Tf  [(those with indeterminate or malignant cytology are generally referred for surgery. Because thyroid nodules with indeterminate )] TJ ET
BT 26.250 603.777 Td /F1 9.8 Tf  [(FNA cytopathology have a 25% risk of malignancy when resected, 75% of these operations will likely be on nodules determined )] TJ ET
BT 26.250 591.872 Td /F1 9.8 Tf  [(to be benign post-operatively.)] TJ ET
0.267 0.267 0.267 rg
BT 154.150 593.379 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 158.969 595.760 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 161.379 593.379 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 166.197 591.872 Td /F1 9.8 Tf  [( Thyroid surgery is associated with potential complications, including temporary and permanent )] TJ ET
BT 26.250 579.967 Td /F1 9.8 Tf  [(hypocalcemia, recurrent laryngeal nerve injury \(with voice change, dysphagia, and potentially airway compromise if bilateral\), )] TJ ET
BT 26.250 568.062 Td /F1 9.8 Tf  [(and bleeding, with an incidence as high as 2-10%.)] TJ ET
0.267 0.267 0.267 rg
BT 243.031 569.570 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 252.669 571.951 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 255.078 569.570 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 264.716 571.951 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 267.125 569.570 Td /F4 8.7 Tf  [(23)] TJ ET
0.271 0.267 0.267 rg
BT 276.762 568.062 Td /F1 9.8 Tf  [( While there is strong evidence that high volume thyroid surgeons on )] TJ ET
BT 26.250 556.158 Td /F1 9.8 Tf  [(average have fewer complications than low volume counterparts, 50% of thyroid operations in the U.S. are still performed by )] TJ ET
BT 26.250 544.253 Td /F1 9.8 Tf  [(surgeons who perform ?5 thyroidectomies/year.)] TJ ET
0.267 0.267 0.267 rg
BT 232.160 545.760 Td /F4 8.7 Tf  [(24)] TJ ET
0.271 0.267 0.267 rg
BT 241.798 544.253 Td /F1 9.8 Tf  [( Hypothyroidism is an expected sequelae of thyroid surgery, with patients )] TJ ET
BT 26.250 532.348 Td /F1 9.8 Tf  [(requiring life-long thyroid hormone supplementation or replacement therapy.)] TJ ET
BT 26.250 495.746 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 475.791 Td /F6 9.8 Tf  [(Systematic evidence reviews.)] TJ ET
BT 163.364 475.791 Td /F1 9.8 Tf  [( Palmetto Government Benefits Administrators \(Palmetto GBA\), the CMS Medicare )] TJ ET
BT 26.250 463.887 Td /F1 9.8 Tf  [(Administrative Contractor with oversight for the Afirma GEC, has published its )] TJ ET
BT 363.824 463.887 Td /F1 9.8 Tf  [(assessment of the test as an update to its local )] TJ ET
BT 26.250 451.982 Td /F1 9.8 Tf  [(coverage article on molecular diagnostics. This review determined that the test meets criteria for analytical and clinical validity, )] TJ ET
BT 26.250 440.077 Td /F1 9.8 Tf  [(and clinical utility as a reasonable and necessary Medicare benefit, effective January 1, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 429.442 441.584 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 420.672 Td /F6 9.8 Tf  [(Recommendations by independent groups.)] TJ ET
BT 226.700 420.672 Td /F1 9.8 Tf  [( As part of the CLIA Laboratory licensure process, the analytical and clinical )] TJ ET
BT 26.250 408.768 Td /F1 9.8 Tf  [(validation data for the Afirma GEC were independently assessed by reviewers from the California Department of Public Health )] TJ ET
BT 26.250 396.863 Td /F1 9.8 Tf  [(and the New York State Department of Health.)] TJ ET
0.267 0.267 0.267 rg
BT 227.305 398.370 Td /F4 8.7 Tf  [(26)] TJ ET
0.271 0.267 0.267 rg
BT 236.942 400.751 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 239.351 398.370 Td /F4 8.7 Tf  [(27)] TJ ET
0.271 0.267 0.267 rg
BT 248.989 396.863 Td /F1 9.8 Tf  [( Both of these reviews resulted in a favorable licensure outcome.)] TJ ET
BT 26.250 377.458 Td /F6 9.8 Tf  [(Guidelines by professional groups.)] TJ ET
BT 189.338 377.458 Td /F1 9.8 Tf  [( The National Comprehensive Cancer Network \(NCCN\) thyroid carcinoma guidelines were )] TJ ET
BT 26.250 365.553 Td /F1 9.8 Tf  [(updated in December, 2012 to state �Molecular diagnostics may be useful to allow reclassification of follicular lesions \(follicular )] TJ ET
BT 26.250 353.649 Td /F1 9.8 Tf  [(neoplasm or follicular lesion of undetermined significance\) as more likely to be benign or more likely to be malignant�If )] TJ ET
BT 26.250 341.744 Td /F1 9.8 Tf  [(molecular testing predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology )] TJ ET
BT 26.250 329.839 Td /F1 9.8 Tf  [(\(approximately 5% or less\), consider observation.� The NCCN guidelines for abnormal gene/gene expression profile testing are )] TJ ET
BT 26.250 317.934 Td /F1 9.8 Tf  [(associated with Level of Evidence 2A \(lower level evidence, uniform NCCN consensus that the intervention is appropriate\).)] TJ ET
0.267 0.267 0.267 rg
BT 555.129 319.442 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 559.948 321.823 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 562.357 319.442 Td /F4 8.7 Tf  [(28)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 281.332 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 261.378 Td /F6 9.8 Tf  [(Analytical Validity)] TJ ET
BT 109.700 261.378 Td /F4 9.8 Tf  [(: test accuracy, reliability in measuring differences in expression of relevant genes \(analytic )] TJ ET
BT 26.250 249.473 Td /F4 9.8 Tf  [(sensitivity and specificity\), and robustness.)] TJ ET
BT 26.250 230.068 Td /F1 9.8 Tf  [(� Building on an earlier study by Chudova et al.)] TJ ET
0.267 0.267 0.267 rg
BT 228.553 231.575 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 238.190 230.068 Td /F1 9.8 Tf  [(, a large collaborative study by Walsh et al. reviewed over 30 sub-studies on )] TJ ET
BT 26.250 218.163 Td /F1 9.8 Tf  [(the Afirma GEC, finding high analytic sensitivity and specificity after dilution of thyroid neoplasm FNA samples with adjacent )] TJ ET
BT 26.250 206.259 Td /F1 9.8 Tf  [(normal tissue or benign neoplasms \(such as nodular hyperplasia and lymphocytic thyroiditis\), as well as dilution with blood and )] TJ ET
BT 26.250 194.354 Td /F1 9.8 Tf  [(genomic DNA, respectively.)] TJ ET
0.267 0.267 0.267 rg
BT 145.990 195.861 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 155.627 198.242 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 158.036 195.861 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 174.949 Td /F1 9.8 Tf  [(� High reproducibility was found in studies of interlaboratory concordance \(R)] TJ ET
BT 353.704 178.837 Td /F1 8.7 Tf  [(2)] TJ ET
BT 358.522 174.949 Td /F1 9.8 Tf  [( 0.98\), as well as intra-assay, inter-assay, and )] TJ ET
BT 26.250 163.044 Td /F1 9.8 Tf  [(intra-nodule concordance \(R)] TJ ET
BT 149.256 166.933 Td /F1 8.7 Tf  [(2)] TJ ET
BT 154.075 163.044 Td /F1 9.8 Tf  [( 0.99, 0.98, and 0.95, respectively\).)] TJ ET
0.267 0.267 0.267 rg
BT 306.370 164.552 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 143.640 Td /F1 9.8 Tf  [(� The assay was robust to a wide range of temperature, storage and stressed shipping conditions and was reproducible across )] TJ ET
BT 26.250 131.735 Td /F1 9.8 Tf  [(different operators, runs, and reagent lots with routine use of control reagents/samples for in-process Quality Control monitoring.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 121.337 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 101.748 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 101.748 Td /F4 9.8 Tf  [(: test accuracy in correctly determining which indeterminate cytology FNA biopsies are benign )] TJ ET
BT 26.250 89.843 Td /F4 9.8 Tf  [(compared to expert surgical histopathology.)] TJ ET
BT 26.250 70.439 Td /F1 9.8 Tf  [(� Two prospective multicenter studies evaluated the negative predictive value \(NPV\) for the Afirma GEC, which is the key )] TJ ET
BT 26.250 58.534 Td /F1 9.8 Tf  [(diagnostic performance metric used to make a decision to monitor patients)] TJ ET
BT 347.591 58.534 Td /F5 9.8 Tf  [( in lieu)] TJ ET
BT 375.768 58.534 Td /F1 9.8 Tf  [( of referral for diagnostic thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 550.790 60.041 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 560.428 62.422 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 562.837 60.041 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 46.629 Td /F1 9.8 Tf  [(Both studies utilized diagnosis of the surgical pathology specimen by a central panel of blinded academic endocrine )] TJ ET
Q
q
15.000 32.343 577.500 744.657 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(indeterminate, the Afirma GEC sample undergoes RNA extraction and nucleic acid amplification. Processed Afirma GEC )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(samples are hybridized to a custom Afirma Thyroid microarray and analyzed with a classification algorithm using linear support )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(vector machine logic to produce either a �Benign� or �Suspicious� test result. About 10% of FNA samples have inadequate RNA )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(yield or quality and are reported by the Afirma GEC as �No Result�.)] TJ ET
0.267 0.267 0.267 rg
BT 315.065 733.269 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 695.159 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(The incidence of thyroid cancer in the U.S. has risen dramatically. In 2009, there were 37,200 new cases of thyroid cancer, )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(while in 2013, it is anticipated there will be 60,220 new cases.)] TJ ET
0.267 0.267 0.267 rg
BT 291.791 664.808 Td /F4 8.7 Tf  [(17)] TJ ET
0.271 0.267 0.267 rg
BT 301.429 667.189 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 303.838 664.808 Td /F4 8.7 Tf  [(18)] TJ ET
0.271 0.267 0.267 rg
BT 313.475 663.300 Td /F1 9.8 Tf  [( At the same time, there has been an increase in the )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(utilization of thyroid FNA and subsequent thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 273.900 652.903 Td /F4 8.7 Tf  [(19)] TJ ET
0.271 0.267 0.267 rg
BT 283.537 651.396 Td /F1 9.8 Tf  [( The prevalence of thyroid nodules increases with age and is more )] TJ ET
BT 26.250 639.491 Td /F1 9.8 Tf  [(common in females. Approximately 50% of women ?50 years have at least one thyroid nodule based on published ultrasound )] TJ ET
BT 26.250 627.586 Td /F1 9.8 Tf  [(and autopsy series.)] TJ ET
0.267 0.267 0.267 rg
BT 110.792 629.093 Td /F4 8.7 Tf  [(20)] TJ ET
0.271 0.267 0.267 rg
BT 120.430 627.586 Td /F1 9.8 Tf  [( Two thirds of thyroid nodules have benign FNA cytopathology and monitoring is implemented, whereas )] TJ ET
BT 26.250 615.681 Td /F1 9.8 Tf  [(those with indeterminate or malignant cytology are generally referred for surgery. Because thyroid nodules with indeterminate )] TJ ET
BT 26.250 603.777 Td /F1 9.8 Tf  [(FNA cytopathology have a 25% risk of malignancy when resected, 75% of these operations will likely be on nodules determined )] TJ ET
BT 26.250 591.872 Td /F1 9.8 Tf  [(to be benign post-operatively.)] TJ ET
0.267 0.267 0.267 rg
BT 154.150 593.379 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 158.969 595.760 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 161.379 593.379 Td /F4 8.7 Tf  [(6)] TJ ET
0.271 0.267 0.267 rg
BT 166.197 591.872 Td /F1 9.8 Tf  [( Thyroid surgery is associated with potential complications, including temporary and permanent )] TJ ET
BT 26.250 579.967 Td /F1 9.8 Tf  [(hypocalcemia, recurrent laryngeal nerve injury \(with voice change, dysphagia, and potentially airway compromise if bilateral\), )] TJ ET
BT 26.250 568.062 Td /F1 9.8 Tf  [(and bleeding, with an incidence as high as 2-10%.)] TJ ET
0.267 0.267 0.267 rg
BT 243.031 569.570 Td /F4 8.7 Tf  [(21)] TJ ET
0.271 0.267 0.267 rg
BT 252.669 571.951 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 255.078 569.570 Td /F4 8.7 Tf  [(22)] TJ ET
0.271 0.267 0.267 rg
BT 264.716 571.951 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 267.125 569.570 Td /F4 8.7 Tf  [(23)] TJ ET
0.271 0.267 0.267 rg
BT 276.762 568.062 Td /F1 9.8 Tf  [( While there is strong evidence that high volume thyroid surgeons on )] TJ ET
BT 26.250 556.158 Td /F1 9.8 Tf  [(average have fewer complications than low volume counterparts, 50% of thyroid operations in the U.S. are still performed by )] TJ ET
BT 26.250 544.253 Td /F1 9.8 Tf  [(surgeons who perform ?5 thyroidectomies/year.)] TJ ET
0.267 0.267 0.267 rg
BT 232.160 545.760 Td /F4 8.7 Tf  [(24)] TJ ET
0.271 0.267 0.267 rg
BT 241.798 544.253 Td /F1 9.8 Tf  [( Hypothyroidism is an expected sequelae of thyroid surgery, with patients )] TJ ET
BT 26.250 532.348 Td /F1 9.8 Tf  [(requiring life-long thyroid hormone supplementation or replacement therapy.)] TJ ET
BT 26.250 495.746 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 475.791 Td /F6 9.8 Tf  [(Systematic evidence reviews.)] TJ ET
BT 163.364 475.791 Td /F1 9.8 Tf  [( Palmetto Government Benefits Administrators \(Palmetto GBA\), the CMS Medicare )] TJ ET
BT 26.250 463.887 Td /F1 9.8 Tf  [(Administrative Contractor with oversight for the Afirma GEC, has published its )] TJ ET
BT 363.824 463.887 Td /F1 9.8 Tf  [(assessment of the test as an update to its local )] TJ ET
BT 26.250 451.982 Td /F1 9.8 Tf  [(coverage article on molecular diagnostics. This review determined that the test meets criteria for analytical and clinical validity, )] TJ ET
BT 26.250 440.077 Td /F1 9.8 Tf  [(and clinical utility as a reasonable and necessary Medicare benefit, effective January 1, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 429.442 441.584 Td /F4 8.7 Tf  [(25)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 420.672 Td /F6 9.8 Tf  [(Recommendations by independent groups.)] TJ ET
BT 226.700 420.672 Td /F1 9.8 Tf  [( As part of the CLIA Laboratory licensure process, the analytical and clinical )] TJ ET
BT 26.250 408.768 Td /F1 9.8 Tf  [(validation data for the Afirma GEC were independently assessed by reviewers from the California Department of Public Health )] TJ ET
BT 26.250 396.863 Td /F1 9.8 Tf  [(and the New York State Department of Health.)] TJ ET
0.267 0.267 0.267 rg
BT 227.305 398.370 Td /F4 8.7 Tf  [(26)] TJ ET
0.271 0.267 0.267 rg
BT 236.942 400.751 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 239.351 398.370 Td /F4 8.7 Tf  [(27)] TJ ET
0.271 0.267 0.267 rg
BT 248.989 396.863 Td /F1 9.8 Tf  [( Both of these reviews resulted in a favorable licensure outcome.)] TJ ET
BT 26.250 377.458 Td /F6 9.8 Tf  [(Guidelines by professional groups.)] TJ ET
BT 189.338 377.458 Td /F1 9.8 Tf  [( The National Comprehensive Cancer Network \(NCCN\) thyroid carcinoma guidelines were )] TJ ET
BT 26.250 365.553 Td /F1 9.8 Tf  [(updated in December, 2012 to state �Molecular diagnostics may be useful to allow reclassification of follicular lesions \(follicular )] TJ ET
BT 26.250 353.649 Td /F1 9.8 Tf  [(neoplasm or follicular lesion of undetermined significance\) as more likely to be benign or more likely to be malignant�If )] TJ ET
BT 26.250 341.744 Td /F1 9.8 Tf  [(molecular testing predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology )] TJ ET
BT 26.250 329.839 Td /F1 9.8 Tf  [(\(approximately 5% or less\), consider observation.� The NCCN guidelines for abnormal gene/gene expression profile testing are )] TJ ET
BT 26.250 317.934 Td /F1 9.8 Tf  [(associated with Level of Evidence 2A \(lower level evidence, uniform NCCN consensus that the intervention is appropriate\).)] TJ ET
0.267 0.267 0.267 rg
BT 555.129 319.442 Td /F4 8.7 Tf  [(8)] TJ ET
0.271 0.267 0.267 rg
BT 559.948 321.823 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 562.357 319.442 Td /F4 8.7 Tf  [(28)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 281.332 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 261.378 Td /F6 9.8 Tf  [(Analytical Validity)] TJ ET
BT 109.700 261.378 Td /F4 9.8 Tf  [(: test accuracy, reliability in measuring differences in expression of relevant genes \(analytic )] TJ ET
BT 26.250 249.473 Td /F4 9.8 Tf  [(sensitivity and specificity\), and robustness.)] TJ ET
BT 26.250 230.068 Td /F1 9.8 Tf  [(� Building on an earlier study by Chudova et al.)] TJ ET
0.267 0.267 0.267 rg
BT 228.553 231.575 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 238.190 230.068 Td /F1 9.8 Tf  [(, a large collaborative study by Walsh et al. reviewed over 30 sub-studies on )] TJ ET
BT 26.250 218.163 Td /F1 9.8 Tf  [(the Afirma GEC, finding high analytic sensitivity and specificity after dilution of thyroid neoplasm FNA samples with adjacent )] TJ ET
BT 26.250 206.259 Td /F1 9.8 Tf  [(normal tissue or benign neoplasms \(such as nodular hyperplasia and lymphocytic thyroiditis\), as well as dilution with blood and )] TJ ET
BT 26.250 194.354 Td /F1 9.8 Tf  [(genomic DNA, respectively.)] TJ ET
0.267 0.267 0.267 rg
BT 145.990 195.861 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 155.627 198.242 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 158.036 195.861 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 174.949 Td /F1 9.8 Tf  [(� High reproducibility was found in studies of interlaboratory concordance \(R)] TJ ET
BT 353.704 178.837 Td /F1 8.7 Tf  [(2)] TJ ET
BT 358.522 174.949 Td /F1 9.8 Tf  [( 0.98\), as well as intra-assay, inter-assay, and )] TJ ET
BT 26.250 163.044 Td /F1 9.8 Tf  [(intra-nodule concordance \(R)] TJ ET
BT 149.256 166.933 Td /F1 8.7 Tf  [(2)] TJ ET
BT 154.075 163.044 Td /F1 9.8 Tf  [( 0.99, 0.98, and 0.95, respectively\).)] TJ ET
0.267 0.267 0.267 rg
BT 306.370 164.552 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 143.640 Td /F1 9.8 Tf  [(� The assay was robust to a wide range of temperature, storage and stressed shipping conditions and was reproducible across )] TJ ET
BT 26.250 131.735 Td /F1 9.8 Tf  [(different operators, runs, and reagent lots with routine use of control reagents/samples for in-process Quality Control monitoring.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 121.337 Td /F4 8.7 Tf  [(29)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 101.748 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 101.748 Td /F4 9.8 Tf  [(: test accuracy in correctly determining which indeterminate cytology FNA biopsies are benign )] TJ ET
BT 26.250 89.843 Td /F4 9.8 Tf  [(compared to expert surgical histopathology.)] TJ ET
BT 26.250 70.439 Td /F1 9.8 Tf  [(� Two prospective multicenter studies evaluated the negative predictive value \(NPV\) for the Afirma GEC, which is the key )] TJ ET
BT 26.250 58.534 Td /F1 9.8 Tf  [(diagnostic performance metric used to make a decision to monitor patients)] TJ ET
BT 347.591 58.534 Td /F5 9.8 Tf  [( in lieu)] TJ ET
BT 375.768 58.534 Td /F1 9.8 Tf  [( of referral for diagnostic thyroid surgery.)] TJ ET
0.267 0.267 0.267 rg
BT 550.790 60.041 Td /F4 8.7 Tf  [(14)] TJ ET
0.271 0.267 0.267 rg
BT 560.428 62.422 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 562.837 60.041 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 46.629 Td /F1 9.8 Tf  [(Both studies utilized diagnosis of the surgical pathology specimen by a central panel of blinded academic endocrine )] 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

Q
endstream
endobj
167 0 obj
<< /Type /Font
/Subtype /Type1
/Name /F6
/BaseFont /Helvetica-BoldOblique
/Encoding /WinAnsiEncoding
>>
endobj
168 0 obj
<< /Type /Annot
/Subtype /Link
/A 169 0 R
/Border [0 0 0]
/H /I
/Rect [ 315.0645 732.4674 324.7018 741.2858 ]
>>
endobj
169 0 obj
<< /Type /Action
>>
endobj
170 0 obj
<< /Type /Annot
/Subtype /Link
/A 171 0 R
/Border [0 0 0]
/H /I
/Rect [ 291.7912 664.0059 301.4286 672.8243 ]
>>
endobj
171 0 obj
<< /Type /Action
>>
endobj
172 0 obj
<< /Type /Annot
/Subtype /Link
/A 173 0 R
/Border [0 0 0]
/H /I
/Rect [ 303.8379 664.0059 313.4753 672.8243 ]
>>
endobj
173 0 obj
<< /Type /Action
>>
endobj
174 0 obj
<< /Type /Annot
/Subtype /Link
/A 175 0 R
/Border [0 0 0]
/H /I
/Rect [ 273.9000 652.1012 283.5373 660.9195 ]
>>
endobj
175 0 obj
<< /Type /Action
>>
endobj
176 0 obj
<< /Type /Annot
/Subtype /Link
/A 177 0 R
/Border [0 0 0]
/H /I
/Rect [ 110.7922 628.2917 120.4296 637.1100 ]
>>
endobj
177 0 obj
<< /Type /Action
>>
endobj
178 0 obj
<< /Type /Annot
/Subtype /Link
/A 179 0 R
/Border [0 0 0]
/H /I
/Rect [ 154.1505 592.5774 158.9692 601.3957 ]
>>
endobj
179 0 obj
<< /Type /Action
>>
endobj
180 0 obj
<< /Type /Annot
/Subtype /Link
/A 181 0 R
/Border [0 0 0]
/H /I
/Rect [ 161.3785 592.5774 166.1972 601.3957 ]
>>
endobj
181 0 obj
<< /Type /Action
>>
endobj
182 0 obj
<< /Type /Annot
/Subtype /Link
/A 183 0 R
/Border [0 0 0]
/H /I
/Rect [ 243.0315 568.7679 252.6688 577.5862 ]
>>
endobj
183 0 obj
<< /Type /Action
>>
endobj
184 0 obj
<< /Type /Annot
/Subtype /Link
/A 185 0 R
/Border [0 0 0]
/H /I
/Rect [ 255.0782 568.7679 264.7155 577.5862 ]
>>
endobj
185 0 obj
<< /Type /Action
>>
endobj
186 0 obj
<< /Type /Annot
/Subtype /Link
/A 187 0 R
/Border [0 0 0]
/H /I
/Rect [ 267.1248 568.7679 276.7622 577.5862 ]
>>
endobj
187 0 obj
<< /Type /Action
>>
endobj
188 0 obj
<< /Type /Annot
/Subtype /Link
/A 189 0 R
/Border [0 0 0]
/H /I
/Rect [ 232.1602 544.9584 241.7976 553.7767 ]
>>
endobj
189 0 obj
<< /Type /Action
>>
endobj
190 0 obj
<< /Type /Annot
/Subtype /Link
/A 191 0 R
/Border [0 0 0]
/H /I
/Rect [ 429.4418 440.7827 439.0791 449.6010 ]
>>
endobj
191 0 obj
<< /Type /Action
>>
endobj
192 0 obj
<< /Type /Annot
/Subtype /Link
/A 193 0 R
/Border [0 0 0]
/H /I
/Rect [ 227.3048 397.5684 236.9421 406.3868 ]
>>
endobj
193 0 obj
<< /Type /Action
>>
endobj
194 0 obj
<< /Type /Annot
/Subtype /Link
/A 195 0 R
/Border [0 0 0]
/H /I
/Rect [ 239.3514 397.5684 248.9888 406.3868 ]
>>
endobj
195 0 obj
<< /Type /Action
>>
endobj
196 0 obj
<< /Type /Annot
/Subtype /Link
/A 197 0 R
/Border [0 0 0]
/H /I
/Rect [ 555.1290 318.6399 559.9477 327.4583 ]
>>
endobj
197 0 obj
<< /Type /Action
>>
endobj
198 0 obj
<< /Type /Annot
/Subtype /Link
/A 199 0 R
/Border [0 0 0]
/H /I
/Rect [ 562.3570 318.6399 571.9943 327.4583 ]
>>
endobj
199 0 obj
<< /Type /Action
>>
endobj
200 0 obj
<< /Type /Annot
/Subtype /Link
/A 201 0 R
/Border [0 0 0]
/H /I
/Rect [ 228.5528 230.7737 238.1901 239.5920 ]
>>
endobj
201 0 obj
<< /Type /Action
>>
endobj
202 0 obj
<< /Type /Annot
/Subtype /Link
/A 203 0 R
/Border [0 0 0]
/H /I
/Rect [ 145.9898 195.0594 155.6271 203.8777 ]
>>
endobj
203 0 obj
<< /Type /Action
>>
endobj
204 0 obj
<< /Type /Annot
/Subtype /Link
/A 205 0 R
/Border [0 0 0]
/H /I
/Rect [ 158.0364 195.0594 167.6738 203.8777 ]
>>
endobj
205 0 obj
<< /Type /Action
>>
endobj
206 0 obj
<< /Type /Annot
/Subtype /Link
/A 207 0 R
/Border [0 0 0]
/H /I
/Rect [ 306.3697 163.7499 316.0070 172.5682 ]
>>
endobj
207 0 obj
<< /Type /Action
>>
endobj
208 0 obj
<< /Type /Annot
/Subtype /Link
/A 209 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 120.5357 35.8873 129.3540 ]
>>
endobj
209 0 obj
<< /Type /Action
>>
endobj
210 0 obj
<< /Type /Annot
/Subtype /Link
/A 211 0 R
/Border [0 0 0]
/H /I
/Rect [ 550.7903 59.2394 560.4276 68.0577 ]
>>
endobj
211 0 obj
<< /Type /Action
>>
endobj
212 0 obj
<< /Type /Annot
/Subtype /Link
/A 213 0 R
/Border [0 0 0]
/H /I
/Rect [ 562.8369 59.2394 572.4743 68.0577 ]
>>
endobj
213 0 obj
<< /Type /Action
>>
endobj
214 0 obj
<< /Type /Annot
/Subtype /Link
/A 215 0 R
/Border [0 0 0]
/H /I
/Rect [ 315.0645 732.4674 324.7018 741.2858 ]
>>
endobj
215 0 obj
<< /Type /Action
>>
endobj
216 0 obj
<< /Type /Annot
/Subtype /Link
/A 217 0 R
/Border [0 0 0]
/H /I
/Rect [ 291.7912 664.0059 301.4286 672.8243 ]
>>
endobj
217 0 obj
<< /Type /Action
>>
endobj
218 0 obj
<< /Type /Annot
/Subtype /Link
/A 219 0 R
/Border [0 0 0]
/H /I
/Rect [ 303.8379 664.0059 313.4753 672.8243 ]
>>
endobj
219 0 obj
<< /Type /Action
>>
endobj
220 0 obj
<< /Type /Annot
/Subtype /Link
/A 221 0 R
/Border [0 0 0]
/H /I
/Rect [ 273.9000 652.1012 283.5373 660.9195 ]
>>
endobj
221 0 obj
<< /Type /Action
>>
endobj
222 0 obj
<< /Type /Annot
/Subtype /Link
/A 223 0 R
/Border [0 0 0]
/H /I
/Rect [ 110.7922 628.2917 120.4296 637.1100 ]
>>
endobj
223 0 obj
<< /Type /Action
>>
endobj
224 0 obj
<< /Type /Annot
/Subtype /Link
/A 225 0 R
/Border [0 0 0]
/H /I
/Rect [ 154.1505 592.5774 158.9692 601.3957 ]
>>
endobj
225 0 obj
<< /Type /Action
>>
endobj
226 0 obj
<< /Type /Annot
/Subtype /Link
/A 227 0 R
/Border [0 0 0]
/H /I
/Rect [ 161.3785 592.5774 166.1972 601.3957 ]
>>
endobj
227 0 obj
<< /Type /Action
>>
endobj
228 0 obj
<< /Type /Annot
/Subtype /Link
/A 229 0 R
/Border [0 0 0]
/H /I
/Rect [ 243.0315 568.7679 252.6688 577.5862 ]
>>
endobj
229 0 obj
<< /Type /Action
>>
endobj
230 0 obj
<< /Type /Annot
/Subtype /Link
/A 231 0 R
/Border [0 0 0]
/H /I
/Rect [ 255.0782 568.7679 264.7155 577.5862 ]
>>
endobj
231 0 obj
<< /Type /Action
>>
endobj
232 0 obj
<< /Type /Annot
/Subtype /Link
/A 233 0 R
/Border [0 0 0]
/H /I
/Rect [ 267.1248 568.7679 276.7622 577.5862 ]
>>
endobj
233 0 obj
<< /Type /Action
>>
endobj
234 0 obj
<< /Type /Annot
/Subtype /Link
/A 235 0 R
/Border [0 0 0]
/H /I
/Rect [ 232.1602 544.9584 241.7976 553.7767 ]
>>
endobj
235 0 obj
<< /Type /Action
>>
endobj
236 0 obj
<< /Type /Annot
/Subtype /Link
/A 237 0 R
/Border [0 0 0]
/H /I
/Rect [ 429.4418 440.7827 439.0791 449.6010 ]
>>
endobj
237 0 obj
<< /Type /Action
>>
endobj
238 0 obj
<< /Type /Annot
/Subtype /Link
/A 239 0 R
/Border [0 0 0]
/H /I
/Rect [ 227.3048 397.5684 236.9421 406.3868 ]
>>
endobj
239 0 obj
<< /Type /Action
>>
endobj
240 0 obj
<< /Type /Annot
/Subtype /Link
/A 241 0 R
/Border [0 0 0]
/H /I
/Rect [ 239.3514 397.5684 248.9888 406.3868 ]
>>
endobj
241 0 obj
<< /Type /Action
>>
endobj
242 0 obj
<< /Type /Annot
/Subtype /Link
/A 243 0 R
/Border [0 0 0]
/H /I
/Rect [ 555.1290 318.6399 559.9477 327.4583 ]
>>
endobj
243 0 obj
<< /Type /Action
>>
endobj
244 0 obj
<< /Type /Annot
/Subtype /Link
/A 245 0 R
/Border [0 0 0]
/H /I
/Rect [ 562.3570 318.6399 571.9943 327.4583 ]
>>
endobj
245 0 obj
<< /Type /Action
>>
endobj
246 0 obj
<< /Type /Annot
/Subtype /Link
/A 247 0 R
/Border [0 0 0]
/H /I
/Rect [ 228.5528 230.7737 238.1901 239.5920 ]
>>
endobj
247 0 obj
<< /Type /Action
>>
endobj
248 0 obj
<< /Type /Annot
/Subtype /Link
/A 249 0 R
/Border [0 0 0]
/H /I
/Rect [ 145.9898 195.0594 155.6271 203.8777 ]
>>
endobj
249 0 obj
<< /Type /Action
>>
endobj
250 0 obj
<< /Type /Annot
/Subtype /Link
/A 251 0 R
/Border [0 0 0]
/H /I
/Rect [ 158.0364 195.0594 167.6738 203.8777 ]
>>
endobj
251 0 obj
<< /Type /Action
>>
endobj
252 0 obj
<< /Type /Annot
/Subtype /Link
/A 253 0 R
/Border [0 0 0]
/H /I
/Rect [ 306.3697 163.7499 316.0070 172.5682 ]
>>
endobj
253 0 obj
<< /Type /Action
>>
endobj
254 0 obj
<< /Type /Annot
/Subtype /Link
/A 255 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 120.5357 35.8873 129.3540 ]
>>
endobj
255 0 obj
<< /Type /Action
>>
endobj
256 0 obj
<< /Type /Annot
/Subtype /Link
/A 257 0 R
/Border [0 0 0]
/H /I
/Rect [ 550.7903 59.2394 560.4276 68.0577 ]
>>
endobj
257 0 obj
<< /Type /Action
>>
endobj
258 0 obj
<< /Type /Annot
/Subtype /Link
/A 259 0 R
/Border [0 0 0]
/H /I
/Rect [ 562.8369 59.2394 572.4743 68.0577 ]
>>
endobj
259 0 obj
<< /Type /Action
>>
endobj
260 0 obj
<< /Type /Annot
/Subtype /Link
/A 261 0 R
/Border [0 0 0]
/H /I
/Rect [ 315.0645 732.4674 324.7018 741.2858 ]
>>
endobj
261 0 obj
<< /Type /Action
>>
endobj
262 0 obj
<< /Type /Annot
/Subtype /Link
/A 263 0 R
/Border [0 0 0]
/H /I
/Rect [ 291.7912 664.0059 301.4286 672.8243 ]
>>
endobj
263 0 obj
<< /Type /Action
>>
endobj
264 0 obj
<< /Type /Annot
/Subtype /Link
/A 265 0 R
/Border [0 0 0]
/H /I
/Rect [ 303.8379 664.0059 313.4753 672.8243 ]
>>
endobj
265 0 obj
<< /Type /Action
>>
endobj
266 0 obj
<< /Type /Annot
/Subtype /Link
/A 267 0 R
/Border [0 0 0]
/H /I
/Rect [ 273.9000 652.1012 283.5373 660.9195 ]
>>
endobj
267 0 obj
<< /Type /Action
>>
endobj
268 0 obj
<< /Type /Annot
/Subtype /Link
/A 269 0 R
/Border [0 0 0]
/H /I
/Rect [ 110.7922 628.2917 120.4296 637.1100 ]
>>
endobj
269 0 obj
<< /Type /Action
>>
endobj
270 0 obj
<< /Type /Annot
/Subtype /Link
/A 271 0 R
/Border [0 0 0]
/H /I
/Rect [ 154.1505 592.5774 158.9692 601.3957 ]
>>
endobj
271 0 obj
<< /Type /Action
>>
endobj
272 0 obj
<< /Type /Annot
/Subtype /Link
/A 273 0 R
/Border [0 0 0]
/H /I
/Rect [ 161.3785 592.5774 166.1972 601.3957 ]
>>
endobj
273 0 obj
<< /Type /Action
>>
endobj
274 0 obj
<< /Type /Annot
/Subtype /Link
/A 275 0 R
/Border [0 0 0]
/H /I
/Rect [ 243.0315 568.7679 252.6688 577.5862 ]
>>
endobj
275 0 obj
<< /Type /Action
>>
endobj
276 0 obj
<< /Type /Annot
/Subtype /Link
/A 277 0 R
/Border [0 0 0]
/H /I
/Rect [ 255.0782 568.7679 264.7155 577.5862 ]
>>
endobj
277 0 obj
<< /Type /Action
>>
endobj
278 0 obj
<< /Type /Annot
/Subtype /Link
/A 279 0 R
/Border [0 0 0]
/H /I
/Rect [ 267.1248 568.7679 276.7622 577.5862 ]
>>
endobj
279 0 obj
<< /Type /Action
>>
endobj
280 0 obj
<< /Type /Annot
/Subtype /Link
/A 281 0 R
/Border [0 0 0]
/H /I
/Rect [ 232.1602 544.9584 241.7976 553.7767 ]
>>
endobj
281 0 obj
<< /Type /Action
>>
endobj
282 0 obj
<< /Type /Annot
/Subtype /Link
/A 283 0 R
/Border [0 0 0]
/H /I
/Rect [ 429.4418 440.7827 439.0791 449.6010 ]
>>
endobj
283 0 obj
<< /Type /Action
>>
endobj
284 0 obj
<< /Type /Annot
/Subtype /Link
/A 285 0 R
/Border [0 0 0]
/H /I
/Rect [ 227.3048 397.5684 236.9421 406.3868 ]
>>
endobj
285 0 obj
<< /Type /Action
>>
endobj
286 0 obj
<< /Type /Annot
/Subtype /Link
/A 287 0 R
/Border [0 0 0]
/H /I
/Rect [ 239.3514 397.5684 248.9888 406.3868 ]
>>
endobj
287 0 obj
<< /Type /Action
>>
endobj
288 0 obj
<< /Type /Annot
/Subtype /Link
/A 289 0 R
/Border [0 0 0]
/H /I
/Rect [ 555.1290 318.6399 559.9477 327.4583 ]
>>
endobj
289 0 obj
<< /Type /Action
>>
endobj
290 0 obj
<< /Type /Annot
/Subtype /Link
/A 291 0 R
/Border [0 0 0]
/H /I
/Rect [ 562.3570 318.6399 571.9943 327.4583 ]
>>
endobj
291 0 obj
<< /Type /Action
>>
endobj
292 0 obj
<< /Type /Annot
/Subtype /Link
/A 293 0 R
/Border [0 0 0]
/H /I
/Rect [ 228.5528 230.7737 238.1901 239.5920 ]
>>
endobj
293 0 obj
<< /Type /Action
>>
endobj
294 0 obj
<< /Type /Annot
/Subtype /Link
/A 295 0 R
/Border [0 0 0]
/H /I
/Rect [ 145.9898 195.0594 155.6271 203.8777 ]
>>
endobj
295 0 obj
<< /Type /Action
>>
endobj
296 0 obj
<< /Type /Annot
/Subtype /Link
/A 297 0 R
/Border [0 0 0]
/H /I
/Rect [ 158.0364 195.0594 167.6738 203.8777 ]
>>
endobj
297 0 obj
<< /Type /Action
>>
endobj
298 0 obj
<< /Type /Annot
/Subtype /Link
/A 299 0 R
/Border [0 0 0]
/H /I
/Rect [ 306.3697 163.7499 316.0070 172.5682 ]
>>
endobj
299 0 obj
<< /Type /Action
>>
endobj
300 0 obj
<< /Type /Annot
/Subtype /Link
/A 301 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 120.5357 35.8873 129.3540 ]
>>
endobj
301 0 obj
<< /Type /Action
>>
endobj
302 0 obj
<< /Type /Annot
/Subtype /Link
/A 303 0 R
/Border [0 0 0]
/H /I
/Rect [ 550.7903 59.2394 560.4276 68.0577 ]
>>
endobj
303 0 obj
<< /Type /Action
>>
endobj
304 0 obj
<< /Type /Annot
/Subtype /Link
/A 305 0 R
/Border [0 0 0]
/H /I
/Rect [ 562.8369 59.2394 572.4743 68.0577 ]
>>
endobj
305 0 obj
<< /Type /Action
>>
endobj
306 0 obj
<< /Type /Page
/Parent 3 0 R
/Annots [ 308 0 R 310 0 R 312 0 R 314 0 R 316 0 R 318 0 R 320 0 R 322 0 R 324 0 R 326 0 R 328 0 R 330 0 R 332 0 R 334 0 R 336 0 R 338 0 R 340 0 R 342 0 R 344 0 R 346 0 R 348 0 R 350 0 R 352 0 R 354 0 R 356 0 R 358 0 R 360 0 R 362 0 R 364 0 R 366 0 R 368 0 R 370 0 R 372 0 R 374 0 R 376 0 R 378 0 R 380 0 R 382 0 R 384 0 R 386 0 R 388 0 R 390 0 R 392 0 R 394 0 R 396 0 R ]
/Contents 307 0 R
>>
endobj
307 0 obj
<<
/Length 28391 >>
stream

0.271 0.267 0.267 rg
q
15.000 26.616 577.500 750.384 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(histopathologists as the reference standard for clinical validation. Approximately one quarter of study sites were academic and )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(three quarters were community-based \(total sites n=49\).)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(� In both studies, NPV was >94% for cytologically indeterminate thyroid FNAs with atypia/follicular lesions of undetermined )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(significance and follicular/H�rthle cell neoplasm diagnoses, but lower when the cytology was suspicious for malignancy. Overall, )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(the NPV for the Afirma GEC was similar to the NPV for a resected thyroid nodule with benign cytopathology.)] TJ ET
0.267 0.267 0.267 rg
BT 492.281 713.864 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 497.099 716.245 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 499.509 713.864 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 692.952 Td /F1 9.8 Tf  [(� In the second, larger study)] TJ ET
0.267 0.267 0.267 rg
BT 147.267 694.460 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 156.904 692.952 Td /F1 9.8 Tf  [(, although the NPV was 95% for all indeterminate cytology nodules \(at the 24% risk of malignancy )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(expected in clinical practice\), the NPV was 85% for FNAs with a cytopathology diagnosis suspicious for malignancy. Sensitivity )] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(was 92% for indeterminate nodules overall. Clinical specificity for indeterminate nodules rose from 0% for cytopathology alone )] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(to 52% with the Afirma GEC, meaning that half of the benign nodules with indeterminate cytopathology could be identified with )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(this pre-operative test.)] TJ ET
BT 26.250 625.929 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 625.929 Td /F4 9.8 Tf  [(: net benefit of test in improving health outcomes by allowing recommendation for monitoring instead of )] TJ ET
BT 26.250 614.024 Td /F4 9.8 Tf  [(a diagnostic surgery on benign thyroid nodules.)] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(� Duick et al. was a retrospective analysis based on chart review of 368 patients \(395 indeterminate thyroid nodules\) cared for )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(by 51 physicians at 21 practice locations in 11 states. When compared to historical controls, the relative rate of operation on )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(cytologically indeterminate nodules fell 90%, from 74% historically to 7.6% with Afirma GEC benign results \(p < 0.001\).)] TJ ET
0.267 0.267 0.267 rg
BT 536.965 572.317 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 546.602 570.810 Td /F1 9.8 Tf  [( The )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(comparisons between historical controls and operative rates based on the binomial test achieved more than 99% power in )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(detecting a less than 25% change.)] TJ ET
0.267 0.267 0.267 rg
BT 175.298 548.507 Td /F4 8.7 Tf  [(31)] TJ ET
0.271 0.267 0.267 rg
BT 184.936 547.000 Td /F1 9.8 Tf  [( With Afirma GEC benign results, in 92.4% of the cases, physicians recommended watchful )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(waiting )] TJ ET
BT 59.303 535.095 Td /F5 9.8 Tf  [(in lieu)] TJ ET
BT 84.769 535.095 Td /F1 9.8 Tf  [( of a diagnostic thyroid resection. The residual rate of surgery was similar to the historic 9% resection rate on )] TJ ET
BT 26.250 523.191 Td /F1 9.8 Tf  [(cytologically benign thyroid nodules and may relate to other clinical parameters and issues of patient and physician preference, )] TJ ET
BT 26.250 511.286 Td /F1 9.8 Tf  [(including issues related to nodule size.)] TJ ET
0.267 0.267 0.267 rg
BT 193.160 512.793 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 491.881 Td /F1 9.8 Tf  [(� These results were consistent with a previously conducted web- and mail-based opinion survey of 84 physician practices, with )] TJ ET
BT 26.250 479.976 Td /F1 9.8 Tf  [(a mean of 89% of physicians reporting that they recommended watchful waiting for patients with cytologically indeterminate )] TJ ET
BT 26.250 468.072 Td /F1 9.8 Tf  [(FNAs but benign Afirma GEC results.)] TJ ET
0.267 0.267 0.267 rg
BT 187.720 469.579 Td /F4 8.7 Tf  [(32)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 448.667 Td /F6 9.8 Tf  [(Limitations.)] TJ ET
BT 80.967 448.667 Td /F1 9.8 Tf  [( In the clinical validity studies, thyroid FNAs with indeterminate cytology diagnoses that were cytologically )] TJ ET
BT 26.250 436.762 Td /F1 9.8 Tf  [(suspicious for malignancy did not have sufficiently low NPV to generally recommend monitoring.)] TJ ET
0.267 0.267 0.267 rg
BT 440.235 438.269 Td /F4 8.7 Tf  [(10)] TJ ET
0.271 0.267 0.267 rg
BT 449.872 436.762 Td /F1 9.8 Tf  [( Secondly, the Duick et al )] TJ ET
BT 26.250 424.857 Td /F1 9.8 Tf  [(clinical utility study used historical rather than contemporary controls.)] TJ ET
0.267 0.267 0.267 rg
BT 323.186 426.365 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 332.824 424.857 Td /F1 9.8 Tf  [( Although historical controls were used, these were )] TJ ET
BT 26.250 412.953 Td /F1 9.8 Tf  [(appropriately validated based on a meta-review of 11 recent thyroid pathology studies where thyroid nodule evaluation was )] TJ ET
BT 26.250 401.048 Td /F1 9.8 Tf  [(similar to current community practice.)] TJ ET
0.267 0.267 0.267 rg
BT 187.700 402.555 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 364.445 Td /F4 12.0 Tf  [(Conclusions)] TJ ET
BT 26.250 344.491 Td /F1 9.8 Tf  [(The clinical validity studies reviewed would fall into the Level 1 category in the Evaluation of Genomic Applications in Practice )] TJ ET
BT 26.250 332.586 Td /F1 9.8 Tf  [(and Prevention \(EGAPP\) hierarchy of data sources and study designs, based on two prospective, multicenter, double blinded )] TJ ET
BT 26.250 320.682 Td /F1 9.8 Tf  [(cohort studies.)] TJ ET
0.267 0.267 0.267 rg
BT 89.654 322.189 Td /F4 8.7 Tf  [(33)] TJ ET
0.271 0.267 0.267 rg
BT 99.292 320.682 Td /F1 9.8 Tf  [( A validated clinical decision rule was based on classification concordance of Afirma GEC benign results with )] TJ ET
BT 26.250 308.777 Td /F1 9.8 Tf  [(blinded expert surgical pathology benign diagnosis. )] TJ ET
0.267 0.267 0.267 rg
BT 250.071 310.284 Td /F4 8.7 Tf  [(11)] TJ ET
0.271 0.267 0.267 rg
BT 259.708 308.777 Td /F1 9.8 Tf  [( Sensitivity in most indeterminate FNAs was high enough \(92%\) to )] TJ ET
BT 26.250 296.872 Td /F1 9.8 Tf  [(achieve a NPV of 94-95%, which is comparable to a thyroid nodule that is benign on cytopathology but undergoes surgical )] TJ ET
BT 26.250 284.967 Td /F1 9.8 Tf  [(resection \(93-94%\).)] TJ ET
0.267 0.267 0.267 rg
BT 111.319 286.475 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 116.137 288.856 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 118.547 286.475 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 128.184 284.967 Td /F1 9.8 Tf  [( However, the Afirma GEC NPV for FNAs where the cytopathology was suspicious for malignancy was )] TJ ET
BT 26.250 273.063 Td /F1 9.8 Tf  [(only 85%. While this lowers the residual risk of malignancy from 62% to 15%, surgical consultation still should be planned in )] TJ ET
BT 26.250 261.158 Td /F1 9.8 Tf  [(these patients. The test utilized interlaboratory comparisons in a large collaborative study, an EGAPP criterion for Level 1 )] TJ ET
BT 26.250 249.253 Td /F1 9.8 Tf  [(hierarchy of analytic validity study design.)] TJ ET
0.267 0.267 0.267 rg
BT 205.611 250.760 Td /F4 8.7 Tf  [(34)] TJ ET
0.271 0.267 0.267 rg
BT 215.248 249.253 Td /F1 9.8 Tf  [( Improvement in the net health outcome is based on avoidance of surgery in )] TJ ET
BT 26.250 237.348 Td /F1 9.8 Tf  [(patients with indeterminate thyroid FNA cytology that would have been found to be benign on surgical pathology. Clinical utility )] TJ ET
BT 26.250 225.444 Td /F1 9.8 Tf  [(of the Afirma GEC was evaluated in clinical practice, outside of the investigational setting, in an opinion survey and a controlled )] TJ ET
BT 26.250 213.539 Td /F1 9.8 Tf  [(study consistent with EGAPP Level 3 criteria for clinical utility study design. The Afirma GEC potentially can improve the net )] TJ ET
BT 26.250 201.634 Td /F1 9.8 Tf  [(health outcome by providing an alternative to diagnostic thyroid surgery, and therein the risk of downstream complications of )] TJ ET
BT 26.250 189.729 Td /F1 9.8 Tf  [(surgery, in patients with benign thyroid nodules but indeterminate FNA cytopathology. In summary, the studies reviewed here )] TJ ET
BT 26.250 177.825 Td /F1 9.8 Tf  [(regarding clinical and analytic validity, and clinical utility support recommendation for offering patients the alternative of using )] TJ ET
BT 26.250 165.920 Td /F1 9.8 Tf  [(the Afirma GEC to monitor patients in lieu of thyroid resection when applied in the specific case of thyroid FNAs where there is )] TJ ET
BT 26.250 154.015 Td /F1 9.8 Tf  [(indeterminate cytopathology: atypia/follicular lesion of undetermined significance, and follicular/H�rthle cell neoplasm.)] TJ ET
BT 26.250 117.413 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 97.458 Td /F1 9.8 Tf  [(Dr. Lanman is an employee of Veracyte, Inc. The other co-authors have no conflict of interest.)] TJ ET
Q
q
15.000 26.616 577.500 750.384 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(histopathologists as the reference standard for clinical validation. Approximately one quarter of study sites were academic and )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(three quarters were community-based \(total sites n=49\).)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(� In both studies, NPV was >94% for cytologically indeterminate thyroid FNAs with atypia/follicular lesions of undetermined )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(significance and follicular/H�rthle cell neoplasm diagnoses, but lower when the cytology was suspicious for malignancy. Overall, )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(the NPV for the Afirma GEC was similar to the NPV for a resected thyroid nodule with benign cytopathology.)] TJ ET
0.267 0.267 0.267 rg
BT 492.281 713.864 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 497.099 716.245 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 499.509 713.864 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 692.952 Td /F1 9.8 Tf  [(� In the second, larger study)] TJ ET
0.267 0.267 0.267 rg
BT 147.267 694.460 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 156.904 692.952 Td /F1 9.8 Tf  [(, although the NPV was 95% for all indeterminate cytology nodules \(at the 24% risk of malignancy )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(expected in clinical practice\), the NPV was 85% for FNAs with a cytopathology diagnosis suspicious for malignancy. Sensitivity )] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(was 92% for indeterminate nodules overall. Clinical specificity for indeterminate nodules rose from 0% for cytopathology alone )] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(to 52% with the Afirma GEC, meaning that half of the benign nodules with indeterminate cytopathology could be identified with )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(this pre-operative test.)] TJ ET
BT 26.250 625.929 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 625.929 Td /F4 9.8 Tf  [(: net benefit of test in improving health outcomes by allowing recommendation for monitoring instead of )] TJ ET
BT 26.250 614.024 Td /F4 9.8 Tf  [(a diagnostic surgery on benign thyroid nodules.)] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(� Duick et al. was a retrospective analysis based on chart review of 368 patients \(395 indeterminate thyroid nodules\) cared for )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(by 51 physicians at 21 practice locations in 11 states. When compared to historical controls, the relative rate of operation on )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(cytologically indeterminate nodules fell 90%, from 74% historically to 7.6% with Afirma GEC benign results \(p < 0.001\).)] TJ ET
0.267 0.267 0.267 rg
BT 536.965 572.317 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 546.602 570.810 Td /F1 9.8 Tf  [( The )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(comparisons between historical controls and operative rates based on the binomial test achieved more than 99% power in )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(detecting a less than 25% change.)] TJ ET
0.267 0.267 0.267 rg
BT 175.298 548.507 Td /F4 8.7 Tf  [(31)] TJ ET
0.271 0.267 0.267 rg
BT 184.936 547.000 Td /F1 9.8 Tf  [( With Afirma GEC benign results, in 92.4% of the cases, physicians recommended watchful )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(waiting )] TJ ET
BT 59.303 535.095 Td /F5 9.8 Tf  [(in lieu)] TJ ET
BT 84.769 535.095 Td /F1 9.8 Tf  [( of a diagnostic thyroid resection. The residual rate of surgery was similar to the historic 9% resection rate on )] TJ ET
BT 26.250 523.191 Td /F1 9.8 Tf  [(cytologically benign thyroid nodules and may relate to other clinical parameters and issues of patient and physician preference, )] TJ ET
BT 26.250 511.286 Td /F1 9.8 Tf  [(including issues related to nodule size.)] TJ ET
0.267 0.267 0.267 rg
BT 193.160 512.793 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 491.881 Td /F1 9.8 Tf  [(� These results were consistent with a previously conducted web- and mail-based opinion survey of 84 physician practices, with )] TJ ET
BT 26.250 479.976 Td /F1 9.8 Tf  [(a mean of 89% of physicians reporting that they recommended watchful waiting for patients with cytologically indeterminate )] TJ ET
BT 26.250 468.072 Td /F1 9.8 Tf  [(FNAs but benign Afirma GEC results.)] TJ ET
0.267 0.267 0.267 rg
BT 187.720 469.579 Td /F4 8.7 Tf  [(32)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 448.667 Td /F6 9.8 Tf  [(Limitations.)] TJ ET
BT 80.967 448.667 Td /F1 9.8 Tf  [( In the clinical validity studies, thyroid FNAs with indeterminate cytology diagnoses that were cytologically )] TJ ET
BT 26.250 436.762 Td /F1 9.8 Tf  [(suspicious for malignancy did not have sufficiently low NPV to generally recommend monitoring.)] TJ ET
0.267 0.267 0.267 rg
BT 440.235 438.269 Td /F4 8.7 Tf  [(10)] TJ ET
0.271 0.267 0.267 rg
BT 449.872 436.762 Td /F1 9.8 Tf  [( Secondly, the Duick et al )] TJ ET
BT 26.250 424.857 Td /F1 9.8 Tf  [(clinical utility study used historical rather than contemporary controls.)] TJ ET
0.267 0.267 0.267 rg
BT 323.186 426.365 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 332.824 424.857 Td /F1 9.8 Tf  [( Although historical controls were used, these were )] TJ ET
BT 26.250 412.953 Td /F1 9.8 Tf  [(appropriately validated based on a meta-review of 11 recent thyroid pathology studies where thyroid nodule evaluation was )] TJ ET
BT 26.250 401.048 Td /F1 9.8 Tf  [(similar to current community practice.)] TJ ET
0.267 0.267 0.267 rg
BT 187.700 402.555 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 364.445 Td /F4 12.0 Tf  [(Conclusions)] TJ ET
BT 26.250 344.491 Td /F1 9.8 Tf  [(The clinical validity studies reviewed would fall into the Level 1 category in the Evaluation of Genomic Applications in Practice )] TJ ET
BT 26.250 332.586 Td /F1 9.8 Tf  [(and Prevention \(EGAPP\) hierarchy of data sources and study designs, based on two prospective, multicenter, double blinded )] TJ ET
BT 26.250 320.682 Td /F1 9.8 Tf  [(cohort studies.)] TJ ET
0.267 0.267 0.267 rg
BT 89.654 322.189 Td /F4 8.7 Tf  [(33)] TJ ET
0.271 0.267 0.267 rg
BT 99.292 320.682 Td /F1 9.8 Tf  [( A validated clinical decision rule was based on classification concordance of Afirma GEC benign results with )] TJ ET
BT 26.250 308.777 Td /F1 9.8 Tf  [(blinded expert surgical pathology benign diagnosis. )] TJ ET
0.267 0.267 0.267 rg
BT 250.071 310.284 Td /F4 8.7 Tf  [(11)] TJ ET
0.271 0.267 0.267 rg
BT 259.708 308.777 Td /F1 9.8 Tf  [( Sensitivity in most indeterminate FNAs was high enough \(92%\) to )] TJ ET
BT 26.250 296.872 Td /F1 9.8 Tf  [(achieve a NPV of 94-95%, which is comparable to a thyroid nodule that is benign on cytopathology but undergoes surgical )] TJ ET
BT 26.250 284.967 Td /F1 9.8 Tf  [(resection \(93-94%\).)] TJ ET
0.267 0.267 0.267 rg
BT 111.319 286.475 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 116.137 288.856 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 118.547 286.475 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 128.184 284.967 Td /F1 9.8 Tf  [( However, the Afirma GEC NPV for FNAs where the cytopathology was suspicious for malignancy was )] TJ ET
BT 26.250 273.063 Td /F1 9.8 Tf  [(only 85%. While this lowers the residual risk of malignancy from 62% to 15%, surgical consultation still should be planned in )] TJ ET
BT 26.250 261.158 Td /F1 9.8 Tf  [(these patients. The test utilized interlaboratory comparisons in a large collaborative study, an EGAPP criterion for Level 1 )] TJ ET
BT 26.250 249.253 Td /F1 9.8 Tf  [(hierarchy of analytic validity study design.)] TJ ET
0.267 0.267 0.267 rg
BT 205.611 250.760 Td /F4 8.7 Tf  [(34)] TJ ET
0.271 0.267 0.267 rg
BT 215.248 249.253 Td /F1 9.8 Tf  [( Improvement in the net health outcome is based on avoidance of surgery in )] TJ ET
BT 26.250 237.348 Td /F1 9.8 Tf  [(patients with indeterminate thyroid FNA cytology that would have been found to be benign on surgical pathology. Clinical utility )] TJ ET
BT 26.250 225.444 Td /F1 9.8 Tf  [(of the Afirma GEC was evaluated in clinical practice, outside of the investigational setting, in an opinion survey and a controlled )] TJ ET
BT 26.250 213.539 Td /F1 9.8 Tf  [(study consistent with EGAPP Level 3 criteria for clinical utility study design. The Afirma GEC potentially can improve the net )] TJ ET
BT 26.250 201.634 Td /F1 9.8 Tf  [(health outcome by providing an alternative to diagnostic thyroid surgery, and therein the risk of downstream complications of )] TJ ET
BT 26.250 189.729 Td /F1 9.8 Tf  [(surgery, in patients with benign thyroid nodules but indeterminate FNA cytopathology. In summary, the studies reviewed here )] TJ ET
BT 26.250 177.825 Td /F1 9.8 Tf  [(regarding clinical and analytic validity, and clinical utility support recommendation for offering patients the alternative of using )] TJ ET
BT 26.250 165.920 Td /F1 9.8 Tf  [(the Afirma GEC to monitor patients in lieu of thyroid resection when applied in the specific case of thyroid FNAs where there is )] TJ ET
BT 26.250 154.015 Td /F1 9.8 Tf  [(indeterminate cytopathology: atypia/follicular lesion of undetermined significance, and follicular/H�rthle cell neoplasm.)] TJ ET
BT 26.250 117.413 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 97.458 Td /F1 9.8 Tf  [(Dr. Lanman is an employee of Veracyte, Inc. The other co-authors have no conflict of interest.)] TJ ET
Q
q
15.000 26.616 577.500 750.384 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(histopathologists as the reference standard for clinical validation. Approximately one quarter of study sites were academic and )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(three quarters were community-based \(total sites n=49\).)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(� In both studies, NPV was >94% for cytologically indeterminate thyroid FNAs with atypia/follicular lesions of undetermined )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(significance and follicular/H�rthle cell neoplasm diagnoses, but lower when the cytology was suspicious for malignancy. Overall, )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(the NPV for the Afirma GEC was similar to the NPV for a resected thyroid nodule with benign cytopathology.)] TJ ET
0.267 0.267 0.267 rg
BT 492.281 713.864 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 497.099 716.245 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 499.509 713.864 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 692.952 Td /F1 9.8 Tf  [(� In the second, larger study)] TJ ET
0.267 0.267 0.267 rg
BT 147.267 694.460 Td /F4 8.7 Tf  [(15)] TJ ET
0.271 0.267 0.267 rg
BT 156.904 692.952 Td /F1 9.8 Tf  [(, although the NPV was 95% for all indeterminate cytology nodules \(at the 24% risk of malignancy )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(expected in clinical practice\), the NPV was 85% for FNAs with a cytopathology diagnosis suspicious for malignancy. Sensitivity )] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(was 92% for indeterminate nodules overall. Clinical specificity for indeterminate nodules rose from 0% for cytopathology alone )] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(to 52% with the Afirma GEC, meaning that half of the benign nodules with indeterminate cytopathology could be identified with )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(this pre-operative test.)] TJ ET
BT 26.250 625.929 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 625.929 Td /F4 9.8 Tf  [(: net benefit of test in improving health outcomes by allowing recommendation for monitoring instead of )] TJ ET
BT 26.250 614.024 Td /F4 9.8 Tf  [(a diagnostic surgery on benign thyroid nodules.)] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(� Duick et al. was a retrospective analysis based on chart review of 368 patients \(395 indeterminate thyroid nodules\) cared for )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(by 51 physicians at 21 practice locations in 11 states. When compared to historical controls, the relative rate of operation on )] TJ ET
BT 26.250 570.810 Td /F1 9.8 Tf  [(cytologically indeterminate nodules fell 90%, from 74% historically to 7.6% with Afirma GEC benign results \(p < 0.001\).)] TJ ET
0.267 0.267 0.267 rg
BT 536.965 572.317 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 546.602 570.810 Td /F1 9.8 Tf  [( The )] TJ ET
BT 26.250 558.905 Td /F1 9.8 Tf  [(comparisons between historical controls and operative rates based on the binomial test achieved more than 99% power in )] TJ ET
BT 26.250 547.000 Td /F1 9.8 Tf  [(detecting a less than 25% change.)] TJ ET
0.267 0.267 0.267 rg
BT 175.298 548.507 Td /F4 8.7 Tf  [(31)] TJ ET
0.271 0.267 0.267 rg
BT 184.936 547.000 Td /F1 9.8 Tf  [( With Afirma GEC benign results, in 92.4% of the cases, physicians recommended watchful )] TJ ET
BT 26.250 535.095 Td /F1 9.8 Tf  [(waiting )] TJ ET
BT 59.303 535.095 Td /F5 9.8 Tf  [(in lieu)] TJ ET
BT 84.769 535.095 Td /F1 9.8 Tf  [( of a diagnostic thyroid resection. The residual rate of surgery was similar to the historic 9% resection rate on )] TJ ET
BT 26.250 523.191 Td /F1 9.8 Tf  [(cytologically benign thyroid nodules and may relate to other clinical parameters and issues of patient and physician preference, )] TJ ET
BT 26.250 511.286 Td /F1 9.8 Tf  [(including issues related to nodule size.)] TJ ET
0.267 0.267 0.267 rg
BT 193.160 512.793 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 491.881 Td /F1 9.8 Tf  [(� These results were consistent with a previously conducted web- and mail-based opinion survey of 84 physician practices, with )] TJ ET
BT 26.250 479.976 Td /F1 9.8 Tf  [(a mean of 89% of physicians reporting that they recommended watchful waiting for patients with cytologically indeterminate )] TJ ET
BT 26.250 468.072 Td /F1 9.8 Tf  [(FNAs but benign Afirma GEC results.)] TJ ET
0.267 0.267 0.267 rg
BT 187.720 469.579 Td /F4 8.7 Tf  [(32)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 448.667 Td /F6 9.8 Tf  [(Limitations.)] TJ ET
BT 80.967 448.667 Td /F1 9.8 Tf  [( In the clinical validity studies, thyroid FNAs with indeterminate cytology diagnoses that were cytologically )] TJ ET
BT 26.250 436.762 Td /F1 9.8 Tf  [(suspicious for malignancy did not have sufficiently low NPV to generally recommend monitoring.)] TJ ET
0.267 0.267 0.267 rg
BT 440.235 438.269 Td /F4 8.7 Tf  [(10)] TJ ET
0.271 0.267 0.267 rg
BT 449.872 436.762 Td /F1 9.8 Tf  [( Secondly, the Duick et al )] TJ ET
BT 26.250 424.857 Td /F1 9.8 Tf  [(clinical utility study used historical rather than contemporary controls.)] TJ ET
0.267 0.267 0.267 rg
BT 323.186 426.365 Td /F4 8.7 Tf  [(16)] TJ ET
0.271 0.267 0.267 rg
BT 332.824 424.857 Td /F1 9.8 Tf  [( Although historical controls were used, these were )] TJ ET
BT 26.250 412.953 Td /F1 9.8 Tf  [(appropriately validated based on a meta-review of 11 recent thyroid pathology studies where thyroid nodule evaluation was )] TJ ET
BT 26.250 401.048 Td /F1 9.8 Tf  [(similar to current community practice.)] TJ ET
0.267 0.267 0.267 rg
BT 187.700 402.555 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 364.445 Td /F4 12.0 Tf  [(Conclusions)] TJ ET
BT 26.250 344.491 Td /F1 9.8 Tf  [(The clinical validity studies reviewed would fall into the Level 1 category in the Evaluation of Genomic Applications in Practice )] TJ ET
BT 26.250 332.586 Td /F1 9.8 Tf  [(and Prevention \(EGAPP\) hierarchy of data sources and study designs, based on two prospective, multicenter, double blinded )] TJ ET
BT 26.250 320.682 Td /F1 9.8 Tf  [(cohort studies.)] TJ ET
0.267 0.267 0.267 rg
BT 89.654 322.189 Td /F4 8.7 Tf  [(33)] TJ ET
0.271 0.267 0.267 rg
BT 99.292 320.682 Td /F1 9.8 Tf  [( A validated clinical decision rule was based on classification concordance of Afirma GEC benign results with )] TJ ET
BT 26.250 308.777 Td /F1 9.8 Tf  [(blinded expert surgical pathology benign diagnosis. )] TJ ET
0.267 0.267 0.267 rg
BT 250.071 310.284 Td /F4 8.7 Tf  [(11)] TJ ET
0.271 0.267 0.267 rg
BT 259.708 308.777 Td /F1 9.8 Tf  [( Sensitivity in most indeterminate FNAs was high enough \(92%\) to )] TJ ET
BT 26.250 296.872 Td /F1 9.8 Tf  [(achieve a NPV of 94-95%, which is comparable to a thyroid nodule that is benign on cytopathology but undergoes surgical )] TJ ET
BT 26.250 284.967 Td /F1 9.8 Tf  [(resection \(93-94%\).)] TJ ET
0.267 0.267 0.267 rg
BT 111.319 286.475 Td /F4 8.7 Tf  [(5)] TJ ET
0.271 0.267 0.267 rg
BT 116.137 288.856 Td /F1 8.7 Tf  [(,)] TJ ET
0.267 0.267 0.267 rg
BT 118.547 286.475 Td /F4 8.7 Tf  [(30)] TJ ET
0.271 0.267 0.267 rg
BT 128.184 284.967 Td /F1 9.8 Tf  [( However, the Afirma GEC NPV for FNAs where the cytopathology was suspicious for malignancy was )] TJ ET
BT 26.250 273.063 Td /F1 9.8 Tf  [(only 85%. While this lowers the residual risk of malignancy from 62% to 15%, surgical consultation still should be planned in )] TJ ET
BT 26.250 261.158 Td /F1 9.8 Tf  [(these patients. The test utilized interlaboratory comparisons in a large collaborative study, an EGAPP criterion for Level 1 )] TJ ET
BT 26.250 249.253 Td /F1 9.8 Tf  [(hierarchy of analytic validity study design.)] TJ ET
0.267 0.267 0.267 rg
BT 205.611 250.760 Td /F4 8.7 Tf  [(34)] TJ ET
0.271 0.267 0.267 rg
BT 215.248 249.253 Td /F1 9.8 Tf  [( Improvement in the net health outcome is based on avoidance of surgery in )] TJ ET
BT 26.250 237.348 Td /F1 9.8 Tf  [(patients with indeterminate thyroid FNA cytology that would have been found to be benign on surgical pathology. Clinical utility )] TJ ET
BT 26.250 225.444 Td /F1 9.8 Tf  [(of the Afirma GEC was evaluated in clinical practice, outside of the investigational setting, in an opinion survey and a controlled )] TJ ET
BT 26.250 213.539 Td /F1 9.8 Tf  [(study consistent with EGAPP Level 3 criteria for clinical utility study design. The Afirma GEC potentially can improve the net )] TJ ET
BT 26.250 201.634 Td /F1 9.8 Tf  [(health outcome by providing an alternative to diagnostic thyroid surgery, and therein the risk of downstream complications of )] TJ ET
BT 26.250 189.729 Td /F1 9.8 Tf  [(surgery, in patients with benign thyroid nodules but indeterminate FNA cytopathology. In summary, the studies reviewed here )] TJ ET
BT 26.250 177.825 Td /F1 9.8 Tf  [(regarding clinical and analytic validity, and clinical utility support recommendation for offering patients the alternative of using )] TJ ET
BT 26.250 165.920 Td /F1 9.8 Tf  [(the Afirma GEC to monitor patients in lieu of thyroid resection when applied in the specific case of thyroid FNAs where there is )] TJ ET
BT 26.250 154.015 Td /F1 9.8 Tf  [(indeterminate cytopathology: atypia/follicular lesion of undetermined significance, and follicular/H�rthle cell neoplasm.)] TJ ET
BT 26.250 117.413 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 97.458 Td /F1 9.8 Tf  [(Dr. Lanman is an employee of Veracyte, Inc. The other co-authors have no conflict of interest.)] 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

Q
endstream
endobj
308 0 obj
<< /Type /Annot
/Subtype /Link
/A 309 0 R
/Border [0 0 0]
/H /I
/Rect [ 492.2805 713.0627 497.0992 721.8810 ]
>>
endobj
309 0 obj
<< /Type /Action
>>
endobj
310 0 obj
<< /Type /Annot
/Subtype /Link
/A 311 0 R
/Border [0 0 0]
/H /I
/Rect [ 499.5085 713.0627 509.1458 721.8810 ]
>>
endobj
311 0 obj
<< /Type /Action
>>
endobj
312 0 obj
<< /Type /Annot
/Subtype /Link
/A 313 0 R
/Border [0 0 0]
/H /I
/Rect [ 147.2670 693.6579 156.9043 702.4762 ]
>>
endobj
313 0 obj
<< /Type /Action
>>
endobj
314 0 obj
<< /Type /Annot
/Subtype /Link
/A 315 0 R
/Border [0 0 0]
/H /I
/Rect [ 536.9647 571.5152 546.6021 580.3335 ]
>>
endobj
315 0 obj
<< /Type /Action
>>
endobj
316 0 obj
<< /Type /Annot
/Subtype /Link
/A 317 0 R
/Border [0 0 0]
/H /I
/Rect [ 175.2982 547.7057 184.9356 556.5240 ]
>>
endobj
317 0 obj
<< /Type /Action
>>
endobj
318 0 obj
<< /Type /Annot
/Subtype /Link
/A 319 0 R
/Border [0 0 0]
/H /I
/Rect [ 193.1602 511.9914 197.9789 520.8097 ]
>>
endobj
319 0 obj
<< /Type /Action
>>
endobj
320 0 obj
<< /Type /Annot
/Subtype /Link
/A 321 0 R
/Border [0 0 0]
/H /I
/Rect [ 187.7198 468.7772 197.3571 477.5955 ]
>>
endobj
321 0 obj
<< /Type /Action
>>
endobj
322 0 obj
<< /Type /Annot
/Subtype /Link
/A 323 0 R
/Border [0 0 0]
/H /I
/Rect [ 440.2350 437.4677 449.8723 446.2860 ]
>>
endobj
323 0 obj
<< /Type /Action
>>
endobj
324 0 obj
<< /Type /Annot
/Subtype /Link
/A 325 0 R
/Border [0 0 0]
/H /I
/Rect [ 323.1862 425.5629 332.8236 434.3813 ]
>>
endobj
325 0 obj
<< /Type /Action
>>
endobj
326 0 obj
<< /Type /Annot
/Subtype /Link
/A 327 0 R
/Border [0 0 0]
/H /I
/Rect [ 187.7003 401.7534 192.5189 410.5718 ]
>>
endobj
327 0 obj
<< /Type /Action
>>
endobj
328 0 obj
<< /Type /Annot
/Subtype /Link
/A 329 0 R
/Border [0 0 0]
/H /I
/Rect [ 89.6542 321.3872 99.2916 330.2055 ]
>>
endobj
329 0 obj
<< /Type /Action
>>
endobj
330 0 obj
<< /Type /Annot
/Subtype /Link
/A 331 0 R
/Border [0 0 0]
/H /I
/Rect [ 250.0710 309.4824 259.7083 318.3007 ]
>>
endobj
331 0 obj
<< /Type /Action
>>
endobj
332 0 obj
<< /Type /Annot
/Subtype /Link
/A 333 0 R
/Border [0 0 0]
/H /I
/Rect [ 111.3187 285.6729 116.1374 294.4913 ]
>>
endobj
333 0 obj
<< /Type /Action
>>
endobj
334 0 obj
<< /Type /Annot
/Subtype /Link
/A 335 0 R
/Border [0 0 0]
/H /I
/Rect [ 118.5468 285.6729 128.1841 294.4913 ]
>>
endobj
335 0 obj
<< /Type /Action
>>
endobj
336 0 obj
<< /Type /Annot
/Subtype /Link
/A 337 0 R
/Border [0 0 0]
/H /I
/Rect [ 205.6110 249.9587 215.2483 258.7770 ]
>>
endobj
337 0 obj
<< /Type /Action
>>
endobj
338 0 obj
<< /Type /Annot
/Subtype /Link
/A 339 0 R
/Border [0 0 0]
/H /I
/Rect [ 492.2805 713.0627 497.0992 721.8810 ]
>>
endobj
339 0 obj
<< /Type /Action
>>
endobj
340 0 obj
<< /Type /Annot
/Subtype /Link
/A 341 0 R
/Border [0 0 0]
/H /I
/Rect [ 499.5085 713.0627 509.1458 721.8810 ]
>>
endobj
341 0 obj
<< /Type /Action
>>
endobj
342 0 obj
<< /Type /Annot
/Subtype /Link
/A 343 0 R
/Border [0 0 0]
/H /I
/Rect [ 147.2670 693.6579 156.9043 702.4762 ]
>>
endobj
343 0 obj
<< /Type /Action
>>
endobj
344 0 obj
<< /Type /Annot
/Subtype /Link
/A 345 0 R
/Border [0 0 0]
/H /I
/Rect [ 536.9647 571.5152 546.6021 580.3335 ]
>>
endobj
345 0 obj
<< /Type /Action
>>
endobj
346 0 obj
<< /Type /Annot
/Subtype /Link
/A 347 0 R
/Border [0 0 0]
/H /I
/Rect [ 175.2982 547.7057 184.9356 556.5240 ]
>>
endobj
347 0 obj
<< /Type /Action
>>
endobj
348 0 obj
<< /Type /Annot
/Subtype /Link
/A 349 0 R
/Border [0 0 0]
/H /I
/Rect [ 193.1602 511.9914 197.9789 520.8097 ]
>>
endobj
349 0 obj
<< /Type /Action
>>
endobj
350 0 obj
<< /Type /Annot
/Subtype /Link
/A 351 0 R
/Border [0 0 0]
/H /I
/Rect [ 187.7198 468.7772 197.3571 477.5955 ]
>>
endobj
351 0 obj
<< /Type /Action
>>
endobj
352 0 obj
<< /Type /Annot
/Subtype /Link
/A 353 0 R
/Border [0 0 0]
/H /I
/Rect [ 440.2350 437.4677 449.8723 446.2860 ]
>>
endobj
353 0 obj
<< /Type /Action
>>
endobj
354 0 obj
<< /Type /Annot
/Subtype /Link
/A 355 0 R
/Border [0 0 0]
/H /I
/Rect [ 323.1862 425.5629 332.8236 434.3813 ]
>>
endobj
355 0 obj
<< /Type /Action
>>
endobj
356 0 obj
<< /Type /Annot
/Subtype /Link
/A 357 0 R
/Border [0 0 0]
/H /I
/Rect [ 187.7003 401.7534 192.5189 410.5718 ]
>>
endobj
357 0 obj
<< /Type /Action
>>
endobj
358 0 obj
<< /Type /Annot
/Subtype /Link
/A 359 0 R
/Border [0 0 0]
/H /I
/Rect [ 89.6542 321.3872 99.2916 330.2055 ]
>>
endobj
359 0 obj
<< /Type /Action
>>
endobj
360 0 obj
<< /Type /Annot
/Subtype /Link
/A 361 0 R
/Border [0 0 0]
/H /I
/Rect [ 250.0710 309.4824 259.7083 318.3007 ]
>>
endobj
361 0 obj
<< /Type /Action
>>
endobj
362 0 obj
<< /Type /Annot
/Subtype /Link
/A 363 0 R
/Border [0 0 0]
/H /I
/Rect [ 111.3187 285.6729 116.1374 294.4913 ]
>>
endobj
363 0 obj
<< /Type /Action
>>
endobj
364 0 obj
<< /Type /Annot
/Subtype /Link
/A 365 0 R
/Border [0 0 0]
/H /I
/Rect [ 118.5468 285.6729 128.1841 294.4913 ]
>>
endobj
365 0 obj
<< /Type /Action
>>
endobj
366 0 obj
<< /Type /Annot
/Subtype /Link
/A 367 0 R
/Border [0 0 0]
/H /I
/Rect [ 205.6110 249.9587 215.2483 258.7770 ]
>>
endobj
367 0 obj
<< /Type /Action
>>
endobj
368 0 obj
<< /Type /Annot
/Subtype /Link
/A 369 0 R
/Border [0 0 0]
/H /I
/Rect [ 492.2805 713.0627 497.0992 721.8810 ]
>>
endobj
369 0 obj
<< /Type /Action
>>
endobj
370 0 obj
<< /Type /Annot
/Subtype /Link
/A 371 0 R
/Border [0 0 0]
/H /I
/Rect [ 499.5085 713.0627 509.1458 721.8810 ]
>>
endobj
371 0 obj
<< /Type /Action
>>
endobj
372 0 obj
<< /Type /Annot
/Subtype /Link
/A 373 0 R
/Border [0 0 0]
/H /I
/Rect [ 147.2670 693.6579 156.9043 702.4762 ]
>>
endobj
373 0 obj
<< /Type /Action
>>
endobj
374 0 obj
<< /Type /Annot
/Subtype /Link
/A 375 0 R
/Border [0 0 0]
/H /I
/Rect [ 536.9647 571.5152 546.6021 580.3335 ]
>>
endobj
375 0 obj
<< /Type /Action
>>
endobj
376 0 obj
<< /Type /Annot
/Subtype /Link
/A 377 0 R
/Border [0 0 0]
/H /I
/Rect [ 175.2982 547.7057 184.9356 556.5240 ]
>>
endobj
377 0 obj
<< /Type /Action
>>
endobj
378 0 obj
<< /Type /Annot
/Subtype /Link
/A 379 0 R
/Border [0 0 0]
/H /I
/Rect [ 193.1602 511.9914 197.9789 520.8097 ]
>>
endobj
379 0 obj
<< /Type /Action
>>
endobj
380 0 obj
<< /Type /Annot
/Subtype /Link
/A 381 0 R
/Border [0 0 0]
/H /I
/Rect [ 187.7198 468.7772 197.3571 477.5955 ]
>>
endobj
381 0 obj
<< /Type /Action
>>
endobj
382 0 obj
<< /Type /Annot
/Subtype /Link
/A 383 0 R
/Border [0 0 0]
/H /I
/Rect [ 440.2350 437.4677 449.8723 446.2860 ]
>>
endobj
383 0 obj
<< /Type /Action
>>
endobj
384 0 obj
<< /Type /Annot
/Subtype /Link
/A 385 0 R
/Border [0 0 0]
/H /I
/Rect [ 323.1862 425.5629 332.8236 434.3813 ]
>>
endobj
385 0 obj
<< /Type /Action
>>
endobj
386 0 obj
<< /Type /Annot
/Subtype /Link
/A 387 0 R
/Border [0 0 0]
/H /I
/Rect [ 187.7003 401.7534 192.5189 410.5718 ]
>>
endobj
387 0 obj
<< /Type /Action
>>
endobj
388 0 obj
<< /Type /Annot
/Subtype /Link
/A 389 0 R
/Border [0 0 0]
/H /I
/Rect [ 89.6542 321.3872 99.2916 330.2055 ]
>>
endobj
389 0 obj
<< /Type /Action
>>
endobj
390 0 obj
<< /Type /Annot
/Subtype /Link
/A 391 0 R
/Border [0 0 0]
/H /I
/Rect [ 250.0710 309.4824 259.7083 318.3007 ]
>>
endobj
391 0 obj
<< /Type /Action
>>
endobj
392 0 obj
<< /Type /Annot
/Subtype /Link
/A 393 0 R
/Border [0 0 0]
/H /I
/Rect [ 111.3187 285.6729 116.1374 294.4913 ]
>>
endobj
393 0 obj
<< /Type /Action
>>
endobj
394 0 obj
<< /Type /Annot
/Subtype /Link
/A 395 0 R
/Border [0 0 0]
/H /I
/Rect [ 118.5468 285.6729 128.1841 294.4913 ]
>>
endobj
395 0 obj
<< /Type /Action
>>
endobj
396 0 obj
<< /Type /Annot
/Subtype /Link
/A 397 0 R
/Border [0 0 0]
/H /I
/Rect [ 205.6110 249.9587 215.2483 258.7770 ]
>>
endobj
397 0 obj
<< /Type /Action
>>
endobj
398 0 obj
<< /Type /Page
/Parent 3 0 R
/Annots [ 400 0 R 402 0 R 404 0 R ]
/Contents 399 0 R
>>
endobj
399 0 obj
<<
/Length 21668 >>
stream

0.271 0.267 0.267 rg
q
15.000 43.756 577.500 733.244 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Acknowledgements)] TJ ET
BT 26.250 730.324 Td /F1 9.8 Tf  [(The co-authors wish to thank the Office of Public Health Genomics for inviting us to submit this brief technical review paper, )] TJ ET
BT 560.550 730.324 Td /F1 9.8 Tf  [(and )] TJ ET
BT 26.250 718.419 Td /F1 9.8 Tf  [(for the helpful comments of the editor and independent reviewers.)] TJ ET
BT 26.250 689.317 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 661.863 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 661.863 Td /F1 9.8 Tf  [(Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Heged�s L, Vitti P. American Association of Clinical Endocrinologists, )] TJ ET
BT 26.250 649.958 Td /F1 9.8 Tf  [(Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis )] TJ ET
BT 26.250 638.053 Td /F1 9.8 Tf  [(and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest. 2010;33\(5 Suppl\):51-6. )] TJ ET
BT 26.250 626.148 Td /F1 9.8 Tf  [(PubMed PMID:20543551.)] TJ ET
BT 26.250 606.744 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 606.744 Td /F1 9.8 Tf  [(Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, )] TJ ET
BT 26.250 594.839 Td /F1 9.8 Tf  [(Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid )] TJ ET
BT 26.250 582.934 Td /F1 9.8 Tf  [(nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19\(11\):1167-214. PubMed PMID:19860577.)] TJ ET
BT 26.250 563.529 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 563.529 Td /F1 9.8 Tf  [(Tuttle RM, Ball DW, Byrd D, Dilawari RA, Doherty GM, Duh QY, Ehya H, Farrar WB, Haddad RI, Kandeel F, Kloos RT, Kopp )] TJ ET
BT 26.250 551.625 Td /F1 9.8 Tf  [(P, Lamonica DM, Loree TR, Lydiatt WM, McCaffrey JC, Olson JA Jr, Parks L, Ridge JA, Shah JP, Sherman SI, Sturgeon C, )] TJ ET
BT 26.250 539.720 Td /F1 9.8 Tf  [(Waguespack SG, Wang TN, Wirth LJ. Thyroid carcinoma. J Natl Compr Canc Netw. 2010 Nov;8\(11\):1228-74. PubMed )] TJ ET
BT 26.250 527.815 Td /F1 9.8 Tf  [(PMID:21081783.)] TJ ET
BT 26.250 508.410 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 508.410 Td /F1 9.8 Tf  [(Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2009 Nov;19\(11\):1159-65. PubMed )] TJ ET
BT 26.250 496.506 Td /F1 9.8 Tf  [(PMID:19888858.)] TJ ET
BT 26.250 477.101 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 477.101 Td /F1 9.8 Tf  [(Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, Zeiger MA, Westra WH, Wang Y, Khanafshar E, )] TJ ET
BT 26.250 465.196 Td /F1 9.8 Tf  [(Fellegara G, Rosai J, Livolsi V, Lanman RB. A large multicenter correlation study of thyroid nodule cytopathology and )] TJ ET
BT 26.250 453.291 Td /F1 9.8 Tf  [(histopathology. Thyroid. 2011 Mar;21\(3\):243-51. PubMed PMID:21190442.)] TJ ET
BT 26.250 433.887 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 433.887 Td /F1 9.8 Tf  [(Bryson PC, Shores CG, Hart C, Thorne L, Patel MR, Richey L, Farag A, Zanation AM. Immunohistochemical distinction of )] TJ ET
BT 26.250 421.982 Td /F1 9.8 Tf  [(follicular thyroid adenomas and follicular carcinomas. Arch Otolaryngol Head Neck Surg. 2008 Jun;134\(6\):581-6. PubMed )] TJ ET
BT 26.250 410.077 Td /F1 9.8 Tf  [(PMID:18559722.)] TJ ET
BT 26.250 390.672 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 390.672 Td /F1 9.8 Tf  [(Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities )] TJ ET
BT 26.250 378.768 Td /F1 9.8 Tf  [(on premature cancer deaths. CA Cancer J Clin. 2011 Jul-Aug;61\(4\):212-36. PubMed PMID:21685461.)] TJ ET
BT 26.250 359.363 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 359.363 Td /F1 9.8 Tf  [(NCCN Clinical Practice Guidelines Thyroid Carcinoma Version 1.2013. December 21, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 350.877 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 332.327 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 332.327 Td /F1 9.8 Tf  [(Li H, Robinson KA, Anton B, Saldanha IJ, Ladenson PW. Cost-effectiveness of a novel molecular test for cytologically )] TJ ET
BT 26.250 320.422 Td /F1 9.8 Tf  [(indeterminate thyroid nodules. J Clin Endocrinol Metab. 2011 Nov;96\(11\):E1719-26. PubMed PMID:21865367.)] TJ ET
BT 26.250 301.017 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 301.017 Td /F1 9.8 Tf  [(Jameson JL. Minimizing unnecessary surgery for thyroid nodules. N Engl J Med. 2012 Aug 23;367\(8\):765-7. PubMed )] TJ ET
BT 26.250 289.113 Td /F1 9.8 Tf  [(PMID:22731671.)] TJ ET
BT 26.250 269.708 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 269.708 Td /F1 9.8 Tf  [(Kim MI, Alexander EK. Diagnostic use of molecular markers in the evaluation of thyroid nodules. Endocr Pract. 2012 Sep-)] TJ ET
BT 26.250 257.803 Td /F1 9.8 Tf  [(Oct;18\(5\):796-802. PubMed PMID:22982803.)] TJ ET
BT 26.250 238.398 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 238.398 Td /F1 9.8 Tf  [(Melillo RM, Santoro M. Molecular biomarkers in thyroid FNA samples. J Clin Endocrinol Metab. 2012 Dec;97\(12\):4370-3. )] TJ ET
BT 26.250 226.494 Td /F1 9.8 Tf  [(PubMed PMID:23223485.)] TJ ET
BT 26.250 207.089 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 207.089 Td /F1 9.8 Tf  [(Ferraz C, Eszlinger M, Paschke R. Current state and future perspective of molecular diagnosis of fine-needle aspiration )] TJ ET
BT 26.250 195.184 Td /F1 9.8 Tf  [(biopsy of thyroid nodules. J Clin Endocrinol Metab. 2011 Jul;96\(7\):2016-26. PubMed PMID:21593119.)] TJ ET
BT 26.250 175.779 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 175.779 Td /F1 9.8 Tf  [(Chudova D, Wilde JI, Wang ET, Wang H, Rabbee N, Egidio CM, Reynolds J, Tom E, Pagan M, Rigl CT, Friedman L, Wang )] TJ ET
BT 26.250 163.875 Td /F1 9.8 Tf  [(CC, Lanman RB, Zeiger M, Kebebew E, Rosai J, Fellegara G, LiVolsi VA, Kennedy GC. Molecular classification of thyroid )] TJ ET
BT 26.250 151.970 Td /F1 9.8 Tf  [(nodules using high-dimensionality genomic data. J Clin Endocrinol Metab. 2010 Dec;95\(12\):5296-304. PubMed )] TJ ET
BT 26.250 140.065 Td /F1 9.8 Tf  [(PMID:20826580.)] TJ ET
BT 26.250 120.660 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 120.660 Td /F1 9.8 Tf  [(Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, )] TJ ET
BT 26.250 108.756 Td /F1 9.8 Tf  [(Raab SS, Rosai J, Steward DL, Walsh PS, Wilde JI, Zeiger MA, Lanman RB, Haugen BR. Preoperative diagnosis of benign )] TJ ET
BT 26.250 96.851 Td /F1 9.8 Tf  [(thyroid nodules with indeterminate cytology. N Engl J Med. 2012 Aug 23;367\(8\):705-15. PubMed PMID:22731672.)] TJ ET
BT 26.250 77.446 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 77.446 Td /F1 9.8 Tf  [(Duick DS, Klopper JP, Diggans JC, Friedman L, Kennedy GC, Lanman RB, McIver B. The impact of benign gene )] TJ ET
BT 26.250 65.541 Td /F1 9.8 Tf  [(expression classifier test results on the endocrinologist-patient decision to operate on patients with thyroid nodules with )] TJ ET
BT 26.250 53.637 Td /F1 9.8 Tf  [(indeterminate fine-needle aspiration cytopathology. Thyroid. 2012 Oct;22\(10\):996-1001. PubMed PMID:22873825.)] TJ ET
Q
q
15.000 43.756 577.500 733.244 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Acknowledgements)] TJ ET
BT 26.250 730.324 Td /F1 9.8 Tf  [(The co-authors wish to thank the Office of Public Health Genomics for inviting us to submit this brief technical review paper, )] TJ ET
BT 560.550 730.324 Td /F1 9.8 Tf  [(and )] TJ ET
BT 26.250 718.419 Td /F1 9.8 Tf  [(for the helpful comments of the editor and independent reviewers.)] TJ ET
BT 26.250 689.317 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 661.863 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 661.863 Td /F1 9.8 Tf  [(Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Heged�s L, Vitti P. American Association of Clinical Endocrinologists, )] TJ ET
BT 26.250 649.958 Td /F1 9.8 Tf  [(Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis )] TJ ET
BT 26.250 638.053 Td /F1 9.8 Tf  [(and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest. 2010;33\(5 Suppl\):51-6. )] TJ ET
BT 26.250 626.148 Td /F1 9.8 Tf  [(PubMed PMID:20543551.)] TJ ET
BT 26.250 606.744 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 606.744 Td /F1 9.8 Tf  [(Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, )] TJ ET
BT 26.250 594.839 Td /F1 9.8 Tf  [(Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid )] TJ ET
BT 26.250 582.934 Td /F1 9.8 Tf  [(nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19\(11\):1167-214. PubMed PMID:19860577.)] TJ ET
BT 26.250 563.529 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 563.529 Td /F1 9.8 Tf  [(Tuttle RM, Ball DW, Byrd D, Dilawari RA, Doherty GM, Duh QY, Ehya H, Farrar WB, Haddad RI, Kandeel F, Kloos RT, Kopp )] TJ ET
BT 26.250 551.625 Td /F1 9.8 Tf  [(P, Lamonica DM, Loree TR, Lydiatt WM, McCaffrey JC, Olson JA Jr, Parks L, Ridge JA, Shah JP, Sherman SI, Sturgeon C, )] TJ ET
BT 26.250 539.720 Td /F1 9.8 Tf  [(Waguespack SG, Wang TN, Wirth LJ. Thyroid carcinoma. J Natl Compr Canc Netw. 2010 Nov;8\(11\):1228-74. PubMed )] TJ ET
BT 26.250 527.815 Td /F1 9.8 Tf  [(PMID:21081783.)] TJ ET
BT 26.250 508.410 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 508.410 Td /F1 9.8 Tf  [(Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2009 Nov;19\(11\):1159-65. PubMed )] TJ ET
BT 26.250 496.506 Td /F1 9.8 Tf  [(PMID:19888858.)] TJ ET
BT 26.250 477.101 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 477.101 Td /F1 9.8 Tf  [(Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, Zeiger MA, Westra WH, Wang Y, Khanafshar E, )] TJ ET
BT 26.250 465.196 Td /F1 9.8 Tf  [(Fellegara G, Rosai J, Livolsi V, Lanman RB. A large multicenter correlation study of thyroid nodule cytopathology and )] TJ ET
BT 26.250 453.291 Td /F1 9.8 Tf  [(histopathology. Thyroid. 2011 Mar;21\(3\):243-51. PubMed PMID:21190442.)] TJ ET
BT 26.250 433.887 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 433.887 Td /F1 9.8 Tf  [(Bryson PC, Shores CG, Hart C, Thorne L, Patel MR, Richey L, Farag A, Zanation AM. Immunohistochemical distinction of )] TJ ET
BT 26.250 421.982 Td /F1 9.8 Tf  [(follicular thyroid adenomas and follicular carcinomas. Arch Otolaryngol Head Neck Surg. 2008 Jun;134\(6\):581-6. PubMed )] TJ ET
BT 26.250 410.077 Td /F1 9.8 Tf  [(PMID:18559722.)] TJ ET
BT 26.250 390.672 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 390.672 Td /F1 9.8 Tf  [(Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities )] TJ ET
BT 26.250 378.768 Td /F1 9.8 Tf  [(on premature cancer deaths. CA Cancer J Clin. 2011 Jul-Aug;61\(4\):212-36. PubMed PMID:21685461.)] TJ ET
BT 26.250 359.363 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 359.363 Td /F1 9.8 Tf  [(NCCN Clinical Practice Guidelines Thyroid Carcinoma Version 1.2013. December 21, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 350.877 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 332.327 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 332.327 Td /F1 9.8 Tf  [(Li H, Robinson KA, Anton B, Saldanha IJ, Ladenson PW. Cost-effectiveness of a novel molecular test for cytologically )] TJ ET
BT 26.250 320.422 Td /F1 9.8 Tf  [(indeterminate thyroid nodules. J Clin Endocrinol Metab. 2011 Nov;96\(11\):E1719-26. PubMed PMID:21865367.)] TJ ET
BT 26.250 301.017 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 301.017 Td /F1 9.8 Tf  [(Jameson JL. Minimizing unnecessary surgery for thyroid nodules. N Engl J Med. 2012 Aug 23;367\(8\):765-7. PubMed )] TJ ET
BT 26.250 289.113 Td /F1 9.8 Tf  [(PMID:22731671.)] TJ ET
BT 26.250 269.708 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 269.708 Td /F1 9.8 Tf  [(Kim MI, Alexander EK. Diagnostic use of molecular markers in the evaluation of thyroid nodules. Endocr Pract. 2012 Sep-)] TJ ET
BT 26.250 257.803 Td /F1 9.8 Tf  [(Oct;18\(5\):796-802. PubMed PMID:22982803.)] TJ ET
BT 26.250 238.398 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 238.398 Td /F1 9.8 Tf  [(Melillo RM, Santoro M. Molecular biomarkers in thyroid FNA samples. J Clin Endocrinol Metab. 2012 Dec;97\(12\):4370-3. )] TJ ET
BT 26.250 226.494 Td /F1 9.8 Tf  [(PubMed PMID:23223485.)] TJ ET
BT 26.250 207.089 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 207.089 Td /F1 9.8 Tf  [(Ferraz C, Eszlinger M, Paschke R. Current state and future perspective of molecular diagnosis of fine-needle aspiration )] TJ ET
BT 26.250 195.184 Td /F1 9.8 Tf  [(biopsy of thyroid nodules. J Clin Endocrinol Metab. 2011 Jul;96\(7\):2016-26. PubMed PMID:21593119.)] TJ ET
BT 26.250 175.779 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 175.779 Td /F1 9.8 Tf  [(Chudova D, Wilde JI, Wang ET, Wang H, Rabbee N, Egidio CM, Reynolds J, Tom E, Pagan M, Rigl CT, Friedman L, Wang )] TJ ET
BT 26.250 163.875 Td /F1 9.8 Tf  [(CC, Lanman RB, Zeiger M, Kebebew E, Rosai J, Fellegara G, LiVolsi VA, Kennedy GC. Molecular classification of thyroid )] TJ ET
BT 26.250 151.970 Td /F1 9.8 Tf  [(nodules using high-dimensionality genomic data. J Clin Endocrinol Metab. 2010 Dec;95\(12\):5296-304. PubMed )] TJ ET
BT 26.250 140.065 Td /F1 9.8 Tf  [(PMID:20826580.)] TJ ET
BT 26.250 120.660 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 120.660 Td /F1 9.8 Tf  [(Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, )] TJ ET
BT 26.250 108.756 Td /F1 9.8 Tf  [(Raab SS, Rosai J, Steward DL, Walsh PS, Wilde JI, Zeiger MA, Lanman RB, Haugen BR. Preoperative diagnosis of benign )] TJ ET
BT 26.250 96.851 Td /F1 9.8 Tf  [(thyroid nodules with indeterminate cytology. N Engl J Med. 2012 Aug 23;367\(8\):705-15. PubMed PMID:22731672.)] TJ ET
BT 26.250 77.446 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 77.446 Td /F1 9.8 Tf  [(Duick DS, Klopper JP, Diggans JC, Friedman L, Kennedy GC, Lanman RB, McIver B. The impact of benign gene )] TJ ET
BT 26.250 65.541 Td /F1 9.8 Tf  [(expression classifier test results on the endocrinologist-patient decision to operate on patients with thyroid nodules with )] TJ ET
BT 26.250 53.637 Td /F1 9.8 Tf  [(indeterminate fine-needle aspiration cytopathology. Thyroid. 2012 Oct;22\(10\):996-1001. PubMed PMID:22873825.)] TJ ET
Q
q
15.000 43.756 577.500 733.244 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Acknowledgements)] TJ ET
BT 26.250 730.324 Td /F1 9.8 Tf  [(The co-authors wish to thank the Office of Public Health Genomics for inviting us to submit this brief technical review paper, )] TJ ET
BT 560.550 730.324 Td /F1 9.8 Tf  [(and )] TJ ET
BT 26.250 718.419 Td /F1 9.8 Tf  [(for the helpful comments of the editor and independent reviewers.)] TJ ET
BT 26.250 689.317 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 661.863 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 661.863 Td /F1 9.8 Tf  [(Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Heged�s L, Vitti P. American Association of Clinical Endocrinologists, )] TJ ET
BT 26.250 649.958 Td /F1 9.8 Tf  [(Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis )] TJ ET
BT 26.250 638.053 Td /F1 9.8 Tf  [(and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest. 2010;33\(5 Suppl\):51-6. )] TJ ET
BT 26.250 626.148 Td /F1 9.8 Tf  [(PubMed PMID:20543551.)] TJ ET
BT 26.250 606.744 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 606.744 Td /F1 9.8 Tf  [(Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, )] TJ ET
BT 26.250 594.839 Td /F1 9.8 Tf  [(Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid )] TJ ET
BT 26.250 582.934 Td /F1 9.8 Tf  [(nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19\(11\):1167-214. PubMed PMID:19860577.)] TJ ET
BT 26.250 563.529 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 563.529 Td /F1 9.8 Tf  [(Tuttle RM, Ball DW, Byrd D, Dilawari RA, Doherty GM, Duh QY, Ehya H, Farrar WB, Haddad RI, Kandeel F, Kloos RT, Kopp )] TJ ET
BT 26.250 551.625 Td /F1 9.8 Tf  [(P, Lamonica DM, Loree TR, Lydiatt WM, McCaffrey JC, Olson JA Jr, Parks L, Ridge JA, Shah JP, Sherman SI, Sturgeon C, )] TJ ET
BT 26.250 539.720 Td /F1 9.8 Tf  [(Waguespack SG, Wang TN, Wirth LJ. Thyroid carcinoma. J Natl Compr Canc Netw. 2010 Nov;8\(11\):1228-74. PubMed )] TJ ET
BT 26.250 527.815 Td /F1 9.8 Tf  [(PMID:21081783.)] TJ ET
BT 26.250 508.410 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 508.410 Td /F1 9.8 Tf  [(Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2009 Nov;19\(11\):1159-65. PubMed )] TJ ET
BT 26.250 496.506 Td /F1 9.8 Tf  [(PMID:19888858.)] TJ ET
BT 26.250 477.101 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 477.101 Td /F1 9.8 Tf  [(Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, Zeiger MA, Westra WH, Wang Y, Khanafshar E, )] TJ ET
BT 26.250 465.196 Td /F1 9.8 Tf  [(Fellegara G, Rosai J, Livolsi V, Lanman RB. A large multicenter correlation study of thyroid nodule cytopathology and )] TJ ET
BT 26.250 453.291 Td /F1 9.8 Tf  [(histopathology. Thyroid. 2011 Mar;21\(3\):243-51. PubMed PMID:21190442.)] TJ ET
BT 26.250 433.887 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 433.887 Td /F1 9.8 Tf  [(Bryson PC, Shores CG, Hart C, Thorne L, Patel MR, Richey L, Farag A, Zanation AM. Immunohistochemical distinction of )] TJ ET
BT 26.250 421.982 Td /F1 9.8 Tf  [(follicular thyroid adenomas and follicular carcinomas. Arch Otolaryngol Head Neck Surg. 2008 Jun;134\(6\):581-6. PubMed )] TJ ET
BT 26.250 410.077 Td /F1 9.8 Tf  [(PMID:18559722.)] TJ ET
BT 26.250 390.672 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 390.672 Td /F1 9.8 Tf  [(Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities )] TJ ET
BT 26.250 378.768 Td /F1 9.8 Tf  [(on premature cancer deaths. CA Cancer J Clin. 2011 Jul-Aug;61\(4\):212-36. PubMed PMID:21685461.)] TJ ET
BT 26.250 359.363 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 359.363 Td /F1 9.8 Tf  [(NCCN Clinical Practice Guidelines Thyroid Carcinoma Version 1.2013. December 21, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 350.877 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 332.327 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 332.327 Td /F1 9.8 Tf  [(Li H, Robinson KA, Anton B, Saldanha IJ, Ladenson PW. Cost-effectiveness of a novel molecular test for cytologically )] TJ ET
BT 26.250 320.422 Td /F1 9.8 Tf  [(indeterminate thyroid nodules. J Clin Endocrinol Metab. 2011 Nov;96\(11\):E1719-26. PubMed PMID:21865367.)] TJ ET
BT 26.250 301.017 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 301.017 Td /F1 9.8 Tf  [(Jameson JL. Minimizing unnecessary surgery for thyroid nodules. N Engl J Med. 2012 Aug 23;367\(8\):765-7. PubMed )] TJ ET
BT 26.250 289.113 Td /F1 9.8 Tf  [(PMID:22731671.)] TJ ET
BT 26.250 269.708 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 269.708 Td /F1 9.8 Tf  [(Kim MI, Alexander EK. Diagnostic use of molecular markers in the evaluation of thyroid nodules. Endocr Pract. 2012 Sep-)] TJ ET
BT 26.250 257.803 Td /F1 9.8 Tf  [(Oct;18\(5\):796-802. PubMed PMID:22982803.)] TJ ET
BT 26.250 238.398 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 238.398 Td /F1 9.8 Tf  [(Melillo RM, Santoro M. Molecular biomarkers in thyroid FNA samples. J Clin Endocrinol Metab. 2012 Dec;97\(12\):4370-3. )] TJ ET
BT 26.250 226.494 Td /F1 9.8 Tf  [(PubMed PMID:23223485.)] TJ ET
BT 26.250 207.089 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 207.089 Td /F1 9.8 Tf  [(Ferraz C, Eszlinger M, Paschke R. Current state and future perspective of molecular diagnosis of fine-needle aspiration )] TJ ET
BT 26.250 195.184 Td /F1 9.8 Tf  [(biopsy of thyroid nodules. J Clin Endocrinol Metab. 2011 Jul;96\(7\):2016-26. PubMed PMID:21593119.)] TJ ET
BT 26.250 175.779 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 175.779 Td /F1 9.8 Tf  [(Chudova D, Wilde JI, Wang ET, Wang H, Rabbee N, Egidio CM, Reynolds J, Tom E, Pagan M, Rigl CT, Friedman L, Wang )] TJ ET
BT 26.250 163.875 Td /F1 9.8 Tf  [(CC, Lanman RB, Zeiger M, Kebebew E, Rosai J, Fellegara G, LiVolsi VA, Kennedy GC. Molecular classification of thyroid )] TJ ET
BT 26.250 151.970 Td /F1 9.8 Tf  [(nodules using high-dimensionality genomic data. J Clin Endocrinol Metab. 2010 Dec;95\(12\):5296-304. PubMed )] TJ ET
BT 26.250 140.065 Td /F1 9.8 Tf  [(PMID:20826580.)] TJ ET
BT 26.250 120.660 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 120.660 Td /F1 9.8 Tf  [(Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, )] TJ ET
BT 26.250 108.756 Td /F1 9.8 Tf  [(Raab SS, Rosai J, Steward DL, Walsh PS, Wilde JI, Zeiger MA, Lanman RB, Haugen BR. Preoperative diagnosis of benign )] TJ ET
BT 26.250 96.851 Td /F1 9.8 Tf  [(thyroid nodules with indeterminate cytology. N Engl J Med. 2012 Aug 23;367\(8\):705-15. PubMed PMID:22731672.)] TJ ET
BT 26.250 77.446 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 77.446 Td /F1 9.8 Tf  [(Duick DS, Klopper JP, Diggans JC, Friedman L, Kennedy GC, Lanman RB, McIver B. The impact of benign gene )] TJ ET
BT 26.250 65.541 Td /F1 9.8 Tf  [(expression classifier test results on the endocrinologist-patient decision to operate on patients with thyroid nodules with )] TJ ET
BT 26.250 53.637 Td /F1 9.8 Tf  [(indeterminate fine-needle aspiration cytopathology. Thyroid. 2012 Oct;22\(10\):996-1001. PubMed PMID:22873825.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(4)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
endstream
endobj
400 0 obj
<< /Type /Annot
/Subtype /Link
/A 401 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 350.1832 91.2600 357.8145 ]
>>
endobj
401 0 obj
<< /Type /Action
/S /URI
/URI (https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf)
>>
endobj
402 0 obj
<< /Type /Annot
/Subtype /Link
/A 403 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 350.1832 91.2600 357.8145 ]
>>
endobj
403 0 obj
<< /Type /Action
/S /URI
/URI (https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf)
>>
endobj
404 0 obj
<< /Type /Annot
/Subtype /Link
/A 405 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 350.1832 91.2600 357.8145 ]
>>
endobj
405 0 obj
<< /Type /Action
/S /URI
/URI (https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf)
>>
endobj
406 0 obj
<< /Type /Page
/Parent 3 0 R
/Annots [ 408 0 R 410 0 R 412 0 R 414 0 R 416 0 R 418 0 R 420 0 R 422 0 R 424 0 R ]
/Contents 407 0 R
>>
endobj
407 0 obj
<<
/Length 17447 >>
stream

0.271 0.267 0.267 rg
q
15.000 187.440 577.500 589.560 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59\(4\):225-49. )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(PubMed PMID:19474385.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan;63\(1\):11-30. PubMed )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(PMID:23335087.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(10;295\(18\):2164-7. PubMed PMID:16684987.)] TJ ET
BT 26.250 666.048 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 666.048 Td /F1 9.8 Tf  [(Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med. 1993 Feb 25;328\(8\):553-9. PubMed PMID:8426623.)] TJ ET
BT 26.250 646.643 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 646.643 Td /F1 9.8 Tf  [(Randolph GW \(ed\). Surgery of the Thyroid and Parathyroid Glands. 2nd edition Philadelphia, PA: Elsevier Saunders, 2012.)] TJ ET
BT 26.250 627.238 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 627.238 Td /F1 9.8 Tf  [(Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R. The importance of surgeon experience for clinical )] TJ ET
BT 26.250 615.333 Td /F1 9.8 Tf  [(and economic outcomes from thyroidectomy. Ann Surg. 1998 Sep;228\(3\):320-30. PubMed PMID:9742915.)] TJ ET
BT 26.250 595.929 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 595.929 Td /F1 9.8 Tf  [(Bergenfelz A, Jansson S, Kristoffersson A, M�rtensson H, Reihn�r E, Wallin G, Lausen I. Complications to thyroid surgery: )] TJ ET
BT 26.250 584.024 Td /F1 9.8 Tf  [(results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg. 2008 )] TJ ET
BT 26.250 572.119 Td /F1 9.8 Tf  [(Sep;393\(5\):667-73. PubMed PMID:18633639.)] TJ ET
BT 26.250 552.714 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 552.714 Td /F1 9.8 Tf  [(Saunders BD, Wainess RM, Dimick JB, Doherty GM, Upchurch GR, Gauger PG. Who performs endocrine operations in the )] TJ ET
BT 26.250 540.810 Td /F1 9.8 Tf  [(United States? Surgery. 2003 Dec;134\(6\):924-31; discussion 931. PubMed PMID:14668724.)] TJ ET
BT 26.250 521.405 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 521.405 Td /F1 9.8 Tf  [(Palmetto GBA. Local Coverage Article for MolDx: AFIRMA� Assay by Veracyte Update \(Article ID Number A51697\). )] TJ ET
BT 26.250 509.500 Td /F1 9.8 Tf  [(January 1, 2012. )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 501.014 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 482.464 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 482.464 Td /F1 9.8 Tf  [(Statley D. CLIA Examiner I Report. September 29, 2010.)] TJ ET
BT 26.250 463.059 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 463.059 Td /F1 9.8 Tf  [(Klees RF. Assay Validation Review. July 27, 2012.)] TJ ET
BT 26.250 443.655 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 443.655 Td /F1 9.8 Tf  [(NCCN Biomarkers Compendium. Accessed December 21, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 435.169 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 416.619 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 416.619 Td /F1 9.8 Tf  [(Walsh PS, Wilde JI, Tom EY, Reynolds JD, Chen DC, Chudova DI, Pagan M, Pankratz DG, Wong M, Veitch J, Friedman L, )] TJ ET
BT 26.250 404.714 Td /F1 9.8 Tf  [(Monroe R, Steward DL, Lupo MA, Lanman RB, Kennedy GC. Analytical performance verification of a molecular diagnostic for )] TJ ET
BT 26.250 392.809 Td /F1 9.8 Tf  [(cytology-indeterminate thyroid nodules. J Clin Endocrinol Metab. 2012 Dec;97\(12\):E2297-306. PubMed PMID:23087323.)] TJ ET
BT 26.250 373.404 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 373.404 Td /F1 9.8 Tf  [(Lewis CM, Chang KP, Pitman M, Faquin WC, Randolph GW. Thyroid fine-needle aspiration biopsy: variability in reporting. )] TJ ET
BT 26.250 361.500 Td /F1 9.8 Tf  [(Thyroid. 2009 Jul;19\(7\):717-23. PubMed PMID:19485775.)] TJ ET
BT 26.250 342.095 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 342.095 Td /F1 9.8 Tf  [(Agresti A, Coull BA. Approximate Is Better than �Exact� for Interval Estimation of Binomial Proportions. Amer Statistician )] TJ ET
BT 26.250 330.190 Td /F1 9.8 Tf  [(1998 May;52\(2\):119-126.)] TJ ET
BT 26.250 310.785 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 310.785 Td /F1 9.8 Tf  [(Monroe R, Zalles C, Traweek T, O�Reilly K, Romanowsky J, Brunt K, Kennedy GC, Lanman RB 2011 Clinical practice )] TJ ET
BT 26.250 298.881 Td /F1 9.8 Tf  [(impact of a novel mRNA�based gene expression classifier in thyroid nodules with indeterminate fine needle aspiration )] TJ ET
BT 26.250 286.976 Td /F1 9.8 Tf  [(cytopathology. Thyroid 21:A-101 \(Poster 244; abstract\).)] TJ ET
BT 26.250 267.571 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 267.571 Td /F1 9.8 Tf  [(Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, Berg AO. The )] TJ ET
BT 26.250 255.666 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention \(EGAPP\) Initiative: methods of the EGAPP Working Group. )] TJ ET
BT 26.250 243.762 Td /F1 9.8 Tf  [(Genet Med. 2009 Jan;11\(1\):3-14. PubMed PMID:18813139.)] TJ ET
BT 26.250 224.357 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 224.357 Td /F1 9.8 Tf  [(National Office of Public Health Genomics, CDC. ACCE model system for collecting, analyzing and disseminating )] TJ ET
BT 26.250 212.452 Td /F1 9.8 Tf  [(information on genetic tests. Accessed November 4, 2012. )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 203.966 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
Q
q
15.000 187.440 577.500 589.560 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59\(4\):225-49. )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(PubMed PMID:19474385.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan;63\(1\):11-30. PubMed )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(PMID:23335087.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(10;295\(18\):2164-7. PubMed PMID:16684987.)] TJ ET
BT 26.250 666.048 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 666.048 Td /F1 9.8 Tf  [(Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med. 1993 Feb 25;328\(8\):553-9. PubMed PMID:8426623.)] TJ ET
BT 26.250 646.643 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 646.643 Td /F1 9.8 Tf  [(Randolph GW \(ed\). Surgery of the Thyroid and Parathyroid Glands. 2nd edition Philadelphia, PA: Elsevier Saunders, 2012.)] TJ ET
BT 26.250 627.238 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 627.238 Td /F1 9.8 Tf  [(Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R. The importance of surgeon experience for clinical )] TJ ET
BT 26.250 615.333 Td /F1 9.8 Tf  [(and economic outcomes from thyroidectomy. Ann Surg. 1998 Sep;228\(3\):320-30. PubMed PMID:9742915.)] TJ ET
BT 26.250 595.929 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 595.929 Td /F1 9.8 Tf  [(Bergenfelz A, Jansson S, Kristoffersson A, M�rtensson H, Reihn�r E, Wallin G, Lausen I. Complications to thyroid surgery: )] TJ ET
BT 26.250 584.024 Td /F1 9.8 Tf  [(results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg. 2008 )] TJ ET
BT 26.250 572.119 Td /F1 9.8 Tf  [(Sep;393\(5\):667-73. PubMed PMID:18633639.)] TJ ET
BT 26.250 552.714 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 552.714 Td /F1 9.8 Tf  [(Saunders BD, Wainess RM, Dimick JB, Doherty GM, Upchurch GR, Gauger PG. Who performs endocrine operations in the )] TJ ET
BT 26.250 540.810 Td /F1 9.8 Tf  [(United States? Surgery. 2003 Dec;134\(6\):924-31; discussion 931. PubMed PMID:14668724.)] TJ ET
BT 26.250 521.405 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 521.405 Td /F1 9.8 Tf  [(Palmetto GBA. Local Coverage Article for MolDx: AFIRMA� Assay by Veracyte Update \(Article ID Number A51697\). )] TJ ET
BT 26.250 509.500 Td /F1 9.8 Tf  [(January 1, 2012. )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 501.014 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 482.464 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 482.464 Td /F1 9.8 Tf  [(Statley D. CLIA Examiner I Report. September 29, 2010.)] TJ ET
BT 26.250 463.059 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 463.059 Td /F1 9.8 Tf  [(Klees RF. Assay Validation Review. July 27, 2012.)] TJ ET
BT 26.250 443.655 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 443.655 Td /F1 9.8 Tf  [(NCCN Biomarkers Compendium. Accessed December 21, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 435.169 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 416.619 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 416.619 Td /F1 9.8 Tf  [(Walsh PS, Wilde JI, Tom EY, Reynolds JD, Chen DC, Chudova DI, Pagan M, Pankratz DG, Wong M, Veitch J, Friedman L, )] TJ ET
BT 26.250 404.714 Td /F1 9.8 Tf  [(Monroe R, Steward DL, Lupo MA, Lanman RB, Kennedy GC. Analytical performance verification of a molecular diagnostic for )] TJ ET
BT 26.250 392.809 Td /F1 9.8 Tf  [(cytology-indeterminate thyroid nodules. J Clin Endocrinol Metab. 2012 Dec;97\(12\):E2297-306. PubMed PMID:23087323.)] TJ ET
BT 26.250 373.404 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 373.404 Td /F1 9.8 Tf  [(Lewis CM, Chang KP, Pitman M, Faquin WC, Randolph GW. Thyroid fine-needle aspiration biopsy: variability in reporting. )] TJ ET
BT 26.250 361.500 Td /F1 9.8 Tf  [(Thyroid. 2009 Jul;19\(7\):717-23. PubMed PMID:19485775.)] TJ ET
BT 26.250 342.095 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 342.095 Td /F1 9.8 Tf  [(Agresti A, Coull BA. Approximate Is Better than �Exact� for Interval Estimation of Binomial Proportions. Amer Statistician )] TJ ET
BT 26.250 330.190 Td /F1 9.8 Tf  [(1998 May;52\(2\):119-126.)] TJ ET
BT 26.250 310.785 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 310.785 Td /F1 9.8 Tf  [(Monroe R, Zalles C, Traweek T, O�Reilly K, Romanowsky J, Brunt K, Kennedy GC, Lanman RB 2011 Clinical practice )] TJ ET
BT 26.250 298.881 Td /F1 9.8 Tf  [(impact of a novel mRNA�based gene expression classifier in thyroid nodules with indeterminate fine needle aspiration )] TJ ET
BT 26.250 286.976 Td /F1 9.8 Tf  [(cytopathology. Thyroid 21:A-101 \(Poster 244; abstract\).)] TJ ET
BT 26.250 267.571 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 267.571 Td /F1 9.8 Tf  [(Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, Berg AO. The )] TJ ET
BT 26.250 255.666 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention \(EGAPP\) Initiative: methods of the EGAPP Working Group. )] TJ ET
BT 26.250 243.762 Td /F1 9.8 Tf  [(Genet Med. 2009 Jan;11\(1\):3-14. PubMed PMID:18813139.)] TJ ET
BT 26.250 224.357 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 224.357 Td /F1 9.8 Tf  [(National Office of Public Health Genomics, CDC. ACCE model system for collecting, analyzing and disseminating )] TJ ET
BT 26.250 212.452 Td /F1 9.8 Tf  [(information on genetic tests. Accessed November 4, 2012. )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 203.966 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
Q
q
15.000 187.440 577.500 589.560 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 759.976 Td /F1 9.8 Tf  [(Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59\(4\):225-49. )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(PubMed PMID:19474385.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 728.667 Td /F1 9.8 Tf  [(Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan;63\(1\):11-30. PubMed )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(PMID:23335087.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(10;295\(18\):2164-7. PubMed PMID:16684987.)] TJ ET
BT 26.250 666.048 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 666.048 Td /F1 9.8 Tf  [(Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med. 1993 Feb 25;328\(8\):553-9. PubMed PMID:8426623.)] TJ ET
BT 26.250 646.643 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 646.643 Td /F1 9.8 Tf  [(Randolph GW \(ed\). Surgery of the Thyroid and Parathyroid Glands. 2nd edition Philadelphia, PA: Elsevier Saunders, 2012.)] TJ ET
BT 26.250 627.238 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 627.238 Td /F1 9.8 Tf  [(Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R. The importance of surgeon experience for clinical )] TJ ET
BT 26.250 615.333 Td /F1 9.8 Tf  [(and economic outcomes from thyroidectomy. Ann Surg. 1998 Sep;228\(3\):320-30. PubMed PMID:9742915.)] TJ ET
BT 26.250 595.929 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 595.929 Td /F1 9.8 Tf  [(Bergenfelz A, Jansson S, Kristoffersson A, M�rtensson H, Reihn�r E, Wallin G, Lausen I. Complications to thyroid surgery: )] TJ ET
BT 26.250 584.024 Td /F1 9.8 Tf  [(results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg. 2008 )] TJ ET
BT 26.250 572.119 Td /F1 9.8 Tf  [(Sep;393\(5\):667-73. PubMed PMID:18633639.)] TJ ET
BT 26.250 552.714 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 552.714 Td /F1 9.8 Tf  [(Saunders BD, Wainess RM, Dimick JB, Doherty GM, Upchurch GR, Gauger PG. Who performs endocrine operations in the )] TJ ET
BT 26.250 540.810 Td /F1 9.8 Tf  [(United States? Surgery. 2003 Dec;134\(6\):924-31; discussion 931. PubMed PMID:14668724.)] TJ ET
BT 26.250 521.405 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 521.405 Td /F1 9.8 Tf  [(Palmetto GBA. Local Coverage Article for MolDx: AFIRMA� Assay by Veracyte Update \(Article ID Number A51697\). )] TJ ET
BT 26.250 509.500 Td /F1 9.8 Tf  [(January 1, 2012. )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 501.014 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 482.464 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 482.464 Td /F1 9.8 Tf  [(Statley D. CLIA Examiner I Report. September 29, 2010.)] TJ ET
BT 26.250 463.059 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 463.059 Td /F1 9.8 Tf  [(Klees RF. Assay Validation Review. July 27, 2012.)] TJ ET
BT 26.250 443.655 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 443.655 Td /F1 9.8 Tf  [(NCCN Biomarkers Compendium. Accessed December 21, 2012.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 435.169 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 416.619 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 416.619 Td /F1 9.8 Tf  [(Walsh PS, Wilde JI, Tom EY, Reynolds JD, Chen DC, Chudova DI, Pagan M, Pankratz DG, Wong M, Veitch J, Friedman L, )] TJ ET
BT 26.250 404.714 Td /F1 9.8 Tf  [(Monroe R, Steward DL, Lupo MA, Lanman RB, Kennedy GC. Analytical performance verification of a molecular diagnostic for )] TJ ET
BT 26.250 392.809 Td /F1 9.8 Tf  [(cytology-indeterminate thyroid nodules. J Clin Endocrinol Metab. 2012 Dec;97\(12\):E2297-306. PubMed PMID:23087323.)] TJ ET
BT 26.250 373.404 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 373.404 Td /F1 9.8 Tf  [(Lewis CM, Chang KP, Pitman M, Faquin WC, Randolph GW. Thyroid fine-needle aspiration biopsy: variability in reporting. )] TJ ET
BT 26.250 361.500 Td /F1 9.8 Tf  [(Thyroid. 2009 Jul;19\(7\):717-23. PubMed PMID:19485775.)] TJ ET
BT 26.250 342.095 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 342.095 Td /F1 9.8 Tf  [(Agresti A, Coull BA. Approximate Is Better than �Exact� for Interval Estimation of Binomial Proportions. Amer Statistician )] TJ ET
BT 26.250 330.190 Td /F1 9.8 Tf  [(1998 May;52\(2\):119-126.)] TJ ET
BT 26.250 310.785 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 310.785 Td /F1 9.8 Tf  [(Monroe R, Zalles C, Traweek T, O�Reilly K, Romanowsky J, Brunt K, Kennedy GC, Lanman RB 2011 Clinical practice )] TJ ET
BT 26.250 298.881 Td /F1 9.8 Tf  [(impact of a novel mRNA�based gene expression classifier in thyroid nodules with indeterminate fine needle aspiration )] TJ ET
BT 26.250 286.976 Td /F1 9.8 Tf  [(cytopathology. Thyroid 21:A-101 \(Poster 244; abstract\).)] TJ ET
BT 26.250 267.571 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 267.571 Td /F1 9.8 Tf  [(Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, Berg AO. The )] TJ ET
BT 26.250 255.666 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention \(EGAPP\) Initiative: methods of the EGAPP Working Group. )] TJ ET
BT 26.250 243.762 Td /F1 9.8 Tf  [(Genet Med. 2009 Jan;11\(1\):3-14. PubMed PMID:18813139.)] TJ ET
BT 26.250 224.357 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 224.357 Td /F1 9.8 Tf  [(National Office of Public Health Genomics, CDC. ACCE model system for collecting, analyzing and disseminating )] TJ ET
BT 26.250 212.452 Td /F1 9.8 Tf  [(information on genetic tests. Accessed November 4, 2012. )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 203.966 Td /F1 7.5 Tf  [(REFERENCE LINK)] 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

Q
endstream
endobj
408 0 obj
<< /Type /Annot
/Subtype /Link
/A 409 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 500.3205 91.2600 507.9517 ]
>>
endobj
409 0 obj
<< /Type /Action
/S /URI
/URI (https://www.palmettogba.com/palmetto/providers.nsf/DocsCat/Providers~Jurisdiction 11 Part B~Browse by Topic~Lab~8Q7MRU7038?open&navmenu=BrowsebyTopic||||)
>>
endobj
410 0 obj
<< /Type /Annot
/Subtype /Link
/A 411 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 434.4750 91.2600 442.1062 ]
>>
endobj
411 0 obj
<< /Type /Action
/S /URI
/URI (https://www.nccn.org/professionals/biomarkers/default.asp )
>>
endobj
412 0 obj
<< /Type /Annot
/Subtype /Link
/A 413 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 203.2725 91.2600 210.9037 ]
>>
endobj
413 0 obj
<< /Type /Action
/S /URI
/URI (https://www.cdc.gov/genomics/gtesting/ACCE/index.htm)
>>
endobj
414 0 obj
<< /Type /Annot
/Subtype /Link
/A 415 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 500.3205 91.2600 507.9517 ]
>>
endobj
415 0 obj
<< /Type /Action
/S /URI
/URI (https://www.palmettogba.com/palmetto/providers.nsf/DocsCat/Providers~Jurisdiction 11 Part B~Browse by Topic~Lab~8Q7MRU7038?open&navmenu=BrowsebyTopic||||)
>>
endobj
416 0 obj
<< /Type /Annot
/Subtype /Link
/A 417 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 434.4750 91.2600 442.1062 ]
>>
endobj
417 0 obj
<< /Type /Action
/S /URI
/URI (https://www.nccn.org/professionals/biomarkers/default.asp )
>>
endobj
418 0 obj
<< /Type /Annot
/Subtype /Link
/A 419 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 203.2725 91.2600 210.9037 ]
>>
endobj
419 0 obj
<< /Type /Action
/S /URI
/URI (https://www.cdc.gov/genomics/gtesting/ACCE/index.htm)
>>
endobj
420 0 obj
<< /Type /Annot
/Subtype /Link
/A 421 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 500.3205 91.2600 507.9517 ]
>>
endobj
421 0 obj
<< /Type /Action
/S /URI
/URI (https://www.palmettogba.com/palmetto/providers.nsf/DocsCat/Providers~Jurisdiction 11 Part B~Browse by Topic~Lab~8Q7MRU7038?open&navmenu=BrowsebyTopic||||)
>>
endobj
422 0 obj
<< /Type /Annot
/Subtype /Link
/A 423 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 434.4750 91.2600 442.1062 ]
>>
endobj
423 0 obj
<< /Type /Action
/S /URI
/URI (https://www.nccn.org/professionals/biomarkers/default.asp )
>>
endobj
424 0 obj
<< /Type /Annot
/Subtype /Link
/A 425 0 R
/Border [0 0 0]
/H /I
/Rect [ 26.2500 203.2725 91.2600 210.9037 ]
>>
endobj
425 0 obj
<< /Type /Action
/S /URI
/URI (https://www.cdc.gov/genomics/gtesting/ACCE/index.htm)
>>
endobj
xref
0 426
0000000000 65535 f 
0000000008 00000 n 
0000000073 00000 n 
0000000119 00000 n 
0000000398 00000 n 
0000000435 00000 n 
0000000760 00000 n 
0000001392 00000 n 
0000030194 00000 n 
0000030301 00000 n 
0000030409 00000 n 
0000030520 00000 n 
0000030633 00000 n 
0000030749 00000 n 
0000031137 00000 n 
0000035966 00000 n 
0000036093 00000 n 
0000036350 00000 n 
0000036477 00000 n 
0000036734 00000 n 
0000036861 00000 n 
0000037118 00000 n 
0000037245 00000 n 
0000037363 00000 n 
0000037489 00000 n 
0000037599 00000 n 
0000037726 00000 n 
0000037838 00000 n 
0000037966 00000 n 
0000038071 00000 n 
0000038199 00000 n 
0000038329 00000 n 
0000038457 00000 n 
0000038573 00000 n 
0000038699 00000 n 
0000038735 00000 n 
0000038863 00000 n 
0000038899 00000 n 
0000039027 00000 n 
0000039063 00000 n 
0000039189 00000 n 
0000039225 00000 n 
0000039353 00000 n 
0000039389 00000 n 
0000039517 00000 n 
0000039553 00000 n 
0000039681 00000 n 
0000039717 00000 n 
0000039845 00000 n 
0000039881 00000 n 
0000040009 00000 n 
0000040045 00000 n 
0000040173 00000 n 
0000040209 00000 n 
0000040337 00000 n 
0000040373 00000 n 
0000040501 00000 n 
0000040537 00000 n 
0000040665 00000 n 
0000040701 00000 n 
0000040827 00000 n 
0000040863 00000 n 
0000040991 00000 n 
0000041027 00000 n 
0000041155 00000 n 
0000041191 00000 n 
0000041318 00000 n 
0000041575 00000 n 
0000041702 00000 n 
0000041959 00000 n 
0000042086 00000 n 
0000042343 00000 n 
0000042470 00000 n 
0000042588 00000 n 
0000042714 00000 n 
0000042824 00000 n 
0000042951 00000 n 
0000043063 00000 n 
0000043191 00000 n 
0000043296 00000 n 
0000043424 00000 n 
0000043554 00000 n 
0000043682 00000 n 
0000043798 00000 n 
0000043924 00000 n 
0000043960 00000 n 
0000044088 00000 n 
0000044124 00000 n 
0000044252 00000 n 
0000044288 00000 n 
0000044414 00000 n 
0000044450 00000 n 
0000044578 00000 n 
0000044614 00000 n 
0000044742 00000 n 
0000044778 00000 n 
0000044906 00000 n 
0000044942 00000 n 
0000045070 00000 n 
0000045106 00000 n 
0000045235 00000 n 
0000045272 00000 n 
0000045402 00000 n 
0000045439 00000 n 
0000045569 00000 n 
0000045606 00000 n 
0000045736 00000 n 
0000045773 00000 n 
0000045903 00000 n 
0000045940 00000 n 
0000046068 00000 n 
0000046105 00000 n 
0000046235 00000 n 
0000046272 00000 n 
0000046402 00000 n 
0000046439 00000 n 
0000046568 00000 n 
0000046826 00000 n 
0000046955 00000 n 
0000047213 00000 n 
0000047342 00000 n 
0000047600 00000 n 
0000047729 00000 n 
0000047848 00000 n 
0000047976 00000 n 
0000048087 00000 n 
0000048216 00000 n 
0000048329 00000 n 
0000048459 00000 n 
0000048565 00000 n 
0000048695 00000 n 
0000048826 00000 n 
0000048956 00000 n 
0000049073 00000 n 
0000049201 00000 n 
0000049238 00000 n 
0000049368 00000 n 
0000049405 00000 n 
0000049535 00000 n 
0000049572 00000 n 
0000049700 00000 n 
0000049737 00000 n 
0000049867 00000 n 
0000049904 00000 n 
0000050034 00000 n 
0000050071 00000 n 
0000050201 00000 n 
0000050238 00000 n 
0000050368 00000 n 
0000050405 00000 n 
0000050535 00000 n 
0000050572 00000 n 
0000050702 00000 n 
0000050739 00000 n 
0000050869 00000 n 
0000050906 00000 n 
0000051036 00000 n 
0000051073 00000 n 
0000051203 00000 n 
0000051240 00000 n 
0000051368 00000 n 
0000051405 00000 n 
0000051535 00000 n 
0000051572 00000 n 
0000051702 00000 n 
0000051739 00000 n 
0000052370 00000 n 
0000084524 00000 n 
0000084645 00000 n 
0000084775 00000 n 
0000084812 00000 n 
0000084942 00000 n 
0000084979 00000 n 
0000085109 00000 n 
0000085146 00000 n 
0000085276 00000 n 
0000085313 00000 n 
0000085443 00000 n 
0000085480 00000 n 
0000085610 00000 n 
0000085647 00000 n 
0000085777 00000 n 
0000085814 00000 n 
0000085944 00000 n 
0000085981 00000 n 
0000086111 00000 n 
0000086148 00000 n 
0000086278 00000 n 
0000086315 00000 n 
0000086445 00000 n 
0000086482 00000 n 
0000086612 00000 n 
0000086649 00000 n 
0000086779 00000 n 
0000086816 00000 n 
0000086946 00000 n 
0000086983 00000 n 
0000087113 00000 n 
0000087150 00000 n 
0000087280 00000 n 
0000087317 00000 n 
0000087447 00000 n 
0000087484 00000 n 
0000087614 00000 n 
0000087651 00000 n 
0000087781 00000 n 
0000087818 00000 n 
0000087948 00000 n 
0000087985 00000 n 
0000088113 00000 n 
0000088150 00000 n 
0000088278 00000 n 
0000088315 00000 n 
0000088443 00000 n 
0000088480 00000 n 
0000088610 00000 n 
0000088647 00000 n 
0000088777 00000 n 
0000088814 00000 n 
0000088944 00000 n 
0000088981 00000 n 
0000089111 00000 n 
0000089148 00000 n 
0000089278 00000 n 
0000089315 00000 n 
0000089445 00000 n 
0000089482 00000 n 
0000089612 00000 n 
0000089649 00000 n 
0000089779 00000 n 
0000089816 00000 n 
0000089946 00000 n 
0000089983 00000 n 
0000090113 00000 n 
0000090150 00000 n 
0000090280 00000 n 
0000090317 00000 n 
0000090447 00000 n 
0000090484 00000 n 
0000090614 00000 n 
0000090651 00000 n 
0000090781 00000 n 
0000090818 00000 n 
0000090948 00000 n 
0000090985 00000 n 
0000091115 00000 n 
0000091152 00000 n 
0000091282 00000 n 
0000091319 00000 n 
0000091449 00000 n 
0000091486 00000 n 
0000091616 00000 n 
0000091653 00000 n 
0000091783 00000 n 
0000091820 00000 n 
0000091948 00000 n 
0000091985 00000 n 
0000092113 00000 n 
0000092150 00000 n 
0000092278 00000 n 
0000092315 00000 n 
0000092445 00000 n 
0000092482 00000 n 
0000092612 00000 n 
0000092649 00000 n 
0000092779 00000 n 
0000092816 00000 n 
0000092946 00000 n 
0000092983 00000 n 
0000093113 00000 n 
0000093150 00000 n 
0000093280 00000 n 
0000093317 00000 n 
0000093447 00000 n 
0000093484 00000 n 
0000093614 00000 n 
0000093651 00000 n 
0000093781 00000 n 
0000093818 00000 n 
0000093948 00000 n 
0000093985 00000 n 
0000094115 00000 n 
0000094152 00000 n 
0000094282 00000 n 
0000094319 00000 n 
0000094449 00000 n 
0000094486 00000 n 
0000094616 00000 n 
0000094653 00000 n 
0000094783 00000 n 
0000094820 00000 n 
0000094950 00000 n 
0000094987 00000 n 
0000095117 00000 n 
0000095154 00000 n 
0000095284 00000 n 
0000095321 00000 n 
0000095451 00000 n 
0000095488 00000 n 
0000095618 00000 n 
0000095655 00000 n 
0000095783 00000 n 
0000095820 00000 n 
0000095948 00000 n 
0000095985 00000 n 
0000096113 00000 n 
0000096150 00000 n 
0000096589 00000 n 
0000125035 00000 n 
0000125165 00000 n 
0000125202 00000 n 
0000125332 00000 n 
0000125369 00000 n 
0000125499 00000 n 
0000125536 00000 n 
0000125666 00000 n 
0000125703 00000 n 
0000125833 00000 n 
0000125870 00000 n 
0000126000 00000 n 
0000126037 00000 n 
0000126167 00000 n 
0000126204 00000 n 
0000126334 00000 n 
0000126371 00000 n 
0000126501 00000 n 
0000126538 00000 n 
0000126668 00000 n 
0000126705 00000 n 
0000126833 00000 n 
0000126870 00000 n 
0000127000 00000 n 
0000127037 00000 n 
0000127167 00000 n 
0000127204 00000 n 
0000127334 00000 n 
0000127371 00000 n 
0000127501 00000 n 
0000127538 00000 n 
0000127668 00000 n 
0000127705 00000 n 
0000127835 00000 n 
0000127872 00000 n 
0000128002 00000 n 
0000128039 00000 n 
0000128169 00000 n 
0000128206 00000 n 
0000128336 00000 n 
0000128373 00000 n 
0000128503 00000 n 
0000128540 00000 n 
0000128670 00000 n 
0000128707 00000 n 
0000128837 00000 n 
0000128874 00000 n 
0000129004 00000 n 
0000129041 00000 n 
0000129171 00000 n 
0000129208 00000 n 
0000129336 00000 n 
0000129373 00000 n 
0000129503 00000 n 
0000129540 00000 n 
0000129670 00000 n 
0000129707 00000 n 
0000129837 00000 n 
0000129874 00000 n 
0000130004 00000 n 
0000130041 00000 n 
0000130171 00000 n 
0000130208 00000 n 
0000130338 00000 n 
0000130375 00000 n 
0000130505 00000 n 
0000130542 00000 n 
0000130672 00000 n 
0000130709 00000 n 
0000130839 00000 n 
0000130876 00000 n 
0000131006 00000 n 
0000131043 00000 n 
0000131173 00000 n 
0000131210 00000 n 
0000131340 00000 n 
0000131377 00000 n 
0000131507 00000 n 
0000131544 00000 n 
0000131674 00000 n 
0000131711 00000 n 
0000131839 00000 n 
0000131876 00000 n 
0000132006 00000 n 
0000132043 00000 n 
0000132173 00000 n 
0000132210 00000 n 
0000132340 00000 n 
0000132377 00000 n 
0000132507 00000 n 
0000132544 00000 n 
0000132647 00000 n 
0000154370 00000 n 
0000154498 00000 n 
0000154614 00000 n 
0000154742 00000 n 
0000154858 00000 n 
0000154986 00000 n 
0000155102 00000 n 
0000155253 00000 n 
0000172755 00000 n 
0000172883 00000 n 
0000173088 00000 n 
0000173216 00000 n 
0000173326 00000 n 
0000173454 00000 n 
0000173558 00000 n 
0000173686 00000 n 
0000173891 00000 n 
0000174019 00000 n 
0000174129 00000 n 
0000174257 00000 n 
0000174361 00000 n 
0000174489 00000 n 
0000174694 00000 n 
0000174822 00000 n 
0000174932 00000 n 
0000175060 00000 n 
trailer
<<
/Size 426
/Root 1 0 R
/Info 5 0 R
>>
startxref
175164
%%EOF