statistical analysis of biomarker data - queen's university€¦ · statistical analysis of...
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Statistical Analysis of Biomarker Data
Greg PondPh.D., P.Stat.
Ontario Clinical Oncology GroupEscarpment Cancer Research InstituteDepartment of Oncology, McMaster UniversityLevel II Investigator, Ontario Institute for Cancer Research
10 August 2017
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Conflicts
None
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Fig 2. Forest plots of hazard ratios (bevacizumab plus chemotherapy v placebo plus chemotherapy) for (A) overall survival and (B) progression-free survival by biomarker (dichotomized by median value or human epithelial growth factor receptor 2 [HER2] status). HER2-positive samples had an immunohistochemistry score of 3+ or were fluorescent in situ hybridization positive. BL, baseline; EGFR, epidermal growth factor receptor; NRP1, neuropilin-1; VEGFA, vascular endothelial growth factor-A; VEGFR1, VEGF receptor-1; VEGFR2, VEGF receptor-2.
Published in: Eric Van Cutsem; Sanne de Haas; Yoon-Koo Kang; Atsushi Ohtsu; Niall C. Tebbutt; Jian Ming Xu; Wei Peng Yong; Bernd Langer; Paul Delmar; Stefan J. Scherer; Manish A. Shah; JCO 2012, 30, 2119-2127. DOI: 10.1200/JCO.2011.39.9824 Copyright © 2012
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I have a new biomarker!!!
1. I am going to get a NEJM publication!2. I am going to save thousands of lives!3. Only select patients will get treatment (saving
thousands of people from unnecessary treatment)!
4. I will patent this and get rich!
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Remember
• 1 in 20 tests ‘significant by chance alone’ if no difference
• Is yours a chance observation, or real?
• Need to validate – what is involved?
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Replication (Ki-67)
• Most often over-looked detail
• Will you get the same result if repeated?
• Take multiple samples from the same patient over short/moderate time period
• May expect change from treatment
• Coefficient of Variation = σ/μ*100%
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Plausibility• Does it make biological sense?
• Is it clinically important (and not just statistically significant)?
• Pearson ρ – correlation coefficient assuming normal data. Spearman ρ for ranked data
• -1 (perfect negative relationship) to +1 (perfect positive relationship). 0=no relationship
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Figure 2. Effect of rosiglitazone on serum levels of inflammatory biomarkers.
Jürgen Hetzel et al. Arterioscler Thromb Vasc Biol. 2005;25:1804-1809 Copyright © American Heart Association, Inc. All rights reserved.
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Regression• Is marker prognostic for outcome?
• Linear (continuous outcome)
• Logistic (categorical outcome)
• Cox (time-to-event outcome)
• Univariable: Is there an association?
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Confounding• One variable affects both covariate and outcome causing a spurious relationship
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Interaction• The effect of two or more variables is not simply additive
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Multivariable Regression• Does it provide new information
• Adjust for known factors
• How best to pick factors?
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Factor Selection• Automated (forward/backward/stepwise)
• Dataset specific. May omit important factors / include spurious factors
• Clinical judgement (good)
• Full model – all possible factors. Significance => potentially new information.
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Concordance• Measure of discrimination ability
• Probability randomly selected person with outcome will have higher score than randomly selected person without outcome
• Ability of model to distinguish between those with and without outcome
• Nguyen & Kattan (2011) Eur Urol: c-statistic should improve >0.015 for new biomarker
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Calibration• Agreement between predicted and observed outcomes
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Re-Classification Plot
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Validation• Bootstrap
• Randomly sample population from dataset with replacement
• Sample size=724. Randomly sample 724 patients from dataset and re-calculate. Repeat 2000 times
• Gives measure of variability of outcomes
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External Validation• Even bootstrap is taking sample from same population
• Treatment patterns different for Canadians vs Americans
• Biomarker effect may be different
• Generalizability
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Prognostic vs Predictive Marker• Predictive marker can only be assessed using RCT data
• Treatment effect is different for patients depending on marker status
• Treatment effect only measurable if some patients receive treatment / control
• Prognostic marker more common, but usually less valuable (e.g. age, sex)
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REMARK Guidelines
• McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumour MARKer prognostic studies (REMARK) Br J Cancer. 2005;93:387–391. doi: 10.1038/sj.bjc.6602678
• What should be reported in publication
• Similar to CONSORT guidelines