Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369: DOI: /NEJMoa

2 Supplementary Appendix Supplement to: Probability of Cancer in Pulmonary Nodules Detected on First Screening Computed Tomography. Annette McWilliams MB, Martin C. Tammemagi PhD, John R. Mayo MD, Heidi Roberts MD, Geoffrey Liu MD, Kam Soghrati MD, Kazuhiro Yasufuku MD PhD, Simon Martel MD, Francis Laberge MD, Michel Gingras MD, Sukhinder Atkar-Khattra BSc, Christine D. Berg MD, Ken Evans MD, Richard Finley MD, John Yee MD, John English MD, Paola Nasute MD, John Goffin MD, Serge Puksa MD, Lori Stewart MD, Scott Tsai MD, Michael R. Johnston MD, Daria Manos MD, Garth Nicholas MD, Glenwood D. Goss MD, Jean M Seely MD, Kayvan Amjadi MD, Alain Tremblay MDCM, Paul Burrowes MD, Paul MacEachern MD, Rick Bhatia MD, Ming-Sound Tsao MD, Stephen Lam MD. Contents Supplementary Text S1 page 2-3 Supplementary Figures S1-S3 page 4-6 Supplementary Tables S1-S3 page 7-9 1

3 Text S1. Summary of inclusion/exclusion criteria and low-dose computed tomography (LDCT) protocol in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). Study Subjects Inclusion Criteria Women or men age 50 to 75 years. Current or former smokers. A former smoker is defined as one who has stopped smoking for one or more years. An estimated 3-year lung cancer risk of 2% based on the risk prediction model. ECOG performance status 0 or 1. Capable of providing, informed consent for screening procedures Exclusion Criteria Any medical condition, such as severe heart disease (e.g. unstable angina, chronic congestive heart failure), acute or chronic respiratory failure, bleeding disorder, that in the opinion of the investigator could jeopardize the subject s safety during participation in the study or make the subject unlikely to benefit from screening due to shortened life-expectancy from the co-morbidities Have been previously diagnosed with lung cancer Have had other cancer with the exception of the following cancers which can be included in the study: non-melanomatous skin cancer, localized prostate cancer, carcinoma in situ (CIS) of the cervix, or superficial bladder cancer. Treatment of the exceptions must have ended >6 months before registration into this study Pregnancy Unwilling to have a spiral chest CT Chest CT within 2 years Unwilling to sign a consent Low-dose spiral CT (LDCT) A multi-detector row CT scanner with minimum section collimation of 1.25 mm and minimum number of data acquisition channels four were employed. The CT scans were performed at 120 kv, mas, rotation time <1 second. Low radiation dose acquisitions using less than 2 msv effective dose were obtained using reduced ma and a minimum gantry rotation time providing an average Dose Length Product less than 120 mgy cm. Images were acquired in a single inspiratory breath hold with the subject in the supine position. Images were reconstructed in the trans-axial plane using 1.25 mm or less section thickness and 1.25 mm or less spacing. Coronal and sagittal reconstructions were used if necessary at the radiologist s discretion. Two image reconstruction algorithms were employed, a high spatial frequency algorithm for lung parenchyma (e.g. bone (GE) or B60 (Siemens)) and an intermediate spatial frequency algorithm for mediastinal structures (e.g. standard (GE) or B35 (Siemens)). The mediastinal reconstruction algorithm was used to provide lower noise images on these reduced dose images. Images were archived to the hospital based PACS server with full annotation and 2

4 stored in local site for clinical use if needed. A second image file was saved with an anonymized study number. The file with the anonymized study number was sent to the central study data server. Calibration scans were performed at all participating sites using the body calibration phantoms supplied with the CT scanners at each site. These calibration scans were performed using the same technical parameters as the low dose CT protocol. Spatial resolution and image noise were measured on the submitted images and used for standardization of each site. Reference scans were repeated on a yearly basis and forwarded to the Vancouver coordinating center. Dr. John Mayo and Dr. John Aldrich, the VGH Radiation Protection Officer and Medical Physicist reviewed the data to ensure adequate scanner performance at each of the sites. A designated radiologist at each of the enrolling institutions reported all study CT scans (both baseline and follow up). The images were reviewed in a dedicated workstation with appropriate illumination and ergonomics. Lung and mediastinal images were reviewed using appropriate window and level settings (lung 1500/-750, mediastinum 450/35). Up to 10 lung nodules were identified and recorded on the radiology study work sheets indicating nodule type (solid, nonsolid {ground glass opacity (GGO)}, part-solid (sub-solid), peri-fissural) with measurement of the long and short axis diameters. The nodule(s) were described as well-defined, lobulated, spiculated, or demonstrating a halo, and their location as parenchymal, pleural or fissural. Patients with greater than 10 nodules had the 10 largest nodules measured and documented. In patients with innumerable nodules and no dominant nodule, no measurements were performed. The radiologist s visual assessment of the extent of emphysema was recorded on a six-point scale (none, trivial, mild, moderate, severe or very severe). The presence of non calcified enlarged mediastinal and hilar adenopathy, and chest wall, pleural and upper abdominal pathology were recorded. LDCT CT Quality Assurance A teaching set of 20 cases selected from BCCA Lung Health Study screening CT archive was established and reviewed by the designated reader at each center. A test set of 20 different cases were administered to each enrolling center to document an acceptable level of interobserver agreement prior to commencing study screening. Conferences were held periodically with all radiology readers in the study to review a random sample of scans, discuss difficulties with interpretation, report turn around time and to review pathologically/cytologically confirmed lung cancer cases (both prevalence and interval cancers). The first 60 patient images in each center were independently interpreted by a review chest radiologist (Dr. Nestor Muller) and a chest radiology fellow under his supervision working by consensus and without knowledge of the management plan of the patient. Clinically significant discrepancies were recorded and reviewed with follow up discussion with the initial reading radiologist by videoconference or in person. 3

5 Figure S1. Receiver operator characteristic area under the curves based on the parsimonious model without spiculation (article Table 2, Model 1a) in the development and validation full data and when limited to nodules of 10 mm in size Abbreviations: AUC, receiver operator characteristic area under the curve; BCCA, British Columbia Cancer Agency; PanCan, Pan-Canadian Early Detection of Lung Cancer Study. 4

6 Figure S2. Mean absolute errors between observed and predicted probabilities in PanCan (development) and BCCA (validation) data, by increasing deciles of Model 1a (article Table 2) predicted risk Abbreviations: BCCA, British Columbia Cancer Agency data; PanCan, Pan-Canadian Early Detection of Lung Cancer Study. 5

7 Figure S3. Sensitivity and specificity predicting if a nodule is lung cancer for the parsimonious prediction model with spiculation (article Table 2, Model 1b) in PanCan data as the probability cutpoint ranges for 0 to 1 Abbreviation: PanCan, Pan-Canadian Early Detection of Lung Cancer Study. 6

8 Table S1. Distribution of study variables in subjects in development and validation study datasets, by lung cancer status (personlevel data) Model Development Data - PanCan Model Validation Data - BCCA Benign Lung cancer Total P-value Benign Lung cancer Total P-value Variable n = 1769 n = 102 N = 1871 n = 1050 n = 40 N = 1090 Age in years (mean & SD) 62.4 (SD 5.8) 63.4 (SD 5.8) 62.4 (SD 5.8) p tt = (SD 6.5) 64.0 (SD 6.8) 61.7 (SD 6.6) p tt = Sex Female Male 828 (93.4%) 941 (95.5%) 58 (6.6%) 44 (4.5%) 886 (47.4%) 985 (52.6%) p FET = (96.0%) 570 (96.6%) 20 (4.0%) 20 (3.4%) 500 (45.9%) 590 (54.1%) p FET = Body mass index in kg/m (SD 4.3) 25.8 (SD 4.3) 26.3 (SD 4.3) p tt = (3.8) 26.2 (SD 3.5) 27.2 (3.8) p tt = Family history of lung cancer No Yes 1182 (95.0%) 560 (93.8%) 62 (5.0%) 37 (6.2%) 1244 (67.6%) 597 (32.4%) p FET = (95.8%) 198 (98.5%) 37 (4.2%) 3 (1.5%) 889 (81.6%) 201 (18.4%) p FET = Emphysema No Yes 703 (96.6%) 1034 (93.1%) 25 (3.4%) 76 (6.9%) 728 (39.6%) 1110 (60.4%) p FET = (98.4%) 692 (95.3%) 6 (1.7%) 34 (4.7%) 363 (33.3%) 726 (66.7%) p FET = FEV 1% predicted 0.81 (SD 0.19) 0.76 (SD 0.19) 0.81 (SD 0.19) p tt = (SD 19.7) 75.8 (SD 21.7) 86.9 (SD 19.9) p tt = Smoking status Former smoker Current smoker 690 (95.0%) 1079 (94.2%) 36 (5.0%) 66 (5.8%) 726 (38.8%) 1145 (61.2%) p FET = (96.7%) 196 (94.7%) 29 (3.3%) 11 (5.3%) 883 (81.0%) 207 (19.0%) p FET = Pack-years smoked, mean & SD 54.8 (SD 23.8) 56.1 (SD 26.1) 54.8 (SD 24.0) ptt = (SD 17.4) 49.5 (SD 17.6) 48.3 (SD 17.4) ptt = Abbreviations: BCCA, British Columbia Cancer Agency; PanCan, Pan-Canadian Early Detection of Lung Cancer Study; FEV 1 %, forced expiratory volume in 1 second percent predicted; IQR, inter-quartile range (from 25th to 75 th percentile); p FET, p-value for Fisher s exact test; p tt, p- value for t-test not assuming equal variance; R, range; SD, standard deviation. For categorical data, for No lung cancer and Lung cancer, row percentages are presented to provide lung cancer probabilities by exposure level, which facilitate estimation of relative risks. For Total, column percentages are presented. 7

9 Table S2. Area under the receiver operator characteristic curve (AUC) for parsimonious model and full nodule prediction models (article Table 2) in development (PanCan) and validation (BCCA) data, and p-values testing if differences in AUCs for selected contrasts equal zero Contrast AUC 1 (95% CI) AUC 2 (95% CI) p-value* Discrimination of parsimonious Model 1a in development and validation data 1a in PanCan.941 ( ) Discrimination of parsimonious Model 1a in 1a in PanCan, development and validation data, for.894 ( ) Discrimination of full Model 2a in development and 2a in PanCan validation data.942 ( ) Discrimination of full Model 2a in development and 2a in PanCan, validation data, for.891 ( ) Incremental value of spiculation in parsimonious 1a in PanCan models.941 ( ) Incremental value of spiculation in full models 2a in PanCan.942 ( ) Parsimonious versus full model in development data 1a in PanCan.940 ( ) Parsimonious versus full model in all validation data 1a in BCCA.960 ( ) Parsimonious versus full model in validation data, for 1a in BCCA,.907 ( ) 1a in BCCA NA.960 ( ) 1a in BCCA, NA.907 ( ) 2a in BCCA NA.970 ( ) 2a in BCCA, NA.938 ( ) 1b in PanCan ( ) 2b in PanCan ( ) 2a in PanCan ( ) 2a in BCCA ( ) 2a in BCCA, ( ) Abbreviations: AUC, receiver operator characteristic area under the curve, BCCA, British Columbia Cancer Agency,, delta or difference, NA, not applicable, PanCan, Pan-Canadian Early Detection of Lung Cancer Study. * P-value testing the null hypothesis that AUC 1 = AUC 2. 8

10 Table S3. Classification accuracy for predicting nodule malignancy at different model risk cut points for the parsimonious models 1a and 1b (article Table 2) (PanCan data, N = 6891) Table S3a. Model 1a (article Table 2) Proportion Risk Score Sensitivity Specificity PPV NPV Accuracy Nodules Positive* Threshold 2% % % Table S3b. Model 1b (article Table 2) Risk Score Sensitivity Specificity PPV NPV Accuracy Proportion Nodules Threshold Positive* 2% % % Abbreviations: PanCan, Pan-Canadian Early Detection of Lung Cancer Study; PPV, positive predictive value; N, number; NPV, negative predictive value. *In both the BCCA and PanCan cohorts, a CT scan was considered to be abnormal if it showed any non-calcified pulmonary nodule or area of non-solid density at least 1 mm in diameter on lung parenchymal windows. Of these, abnormalities this column provides the percent now positive suspicious for lung cancer requiring further evaluation 9