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SOME ADDITIONAL POINTS ON MEASUREMENT ERROR IN EPIDEMIOLOGY. Sholom May 28, 2011 Supplement to Prof. Carroll’s talk II . Measurement error (ME) in epidemiology. ME may be more important than confounding Examples from my work Best solution based on my experience: Avoid or minimize ME.
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SOME ADDITIONAL POINTS ON MEASUREMENT ERROR IN EPIDEMIOLOGY Sholom May 28, 2011 Supplement to Prof. Carroll’s talk II
Measurement error (ME)in epidemiology • ME may be more important than confounding • Examples from my work • Best solution based on my experience: • Avoid or minimize ME
Examples (1) • Molecular epidemiology and biomarkers • Reduce Coefficient of Variation (CV) by reducing lab error • Population variation remains • Genetics • GWAS: power loss depends on LD between markers and tagging SNPs • Best characterized by • No theorems on D’ or recombination fraction • Kin cohort analysis • Known Mendelian rules allow inference of genotype from relative’s
Examples (2) • Misclassification of disease • E.g.: Screening leads to diagnosis • Misclassification of disease, differential by screening • Screening studies use mortality, not diagnosis, as endpoint
Differential misclassification • Standard research practices minimize differential misclassification • Occupational epidemiology: Industrial hygienists blinded to disease status • Molecular epidemiology: Blinding in the lab • Randomized controlled trial: • Double blind treatment assignment • Blinded (masked) ascertainment of disease
Differential misclassification:Case-control • Qx: “recall bias” is always a potential • Direct evidence of recall bias is weak • Molecular studies: biomarkers can be affected by disease progression • Pre-diagnostic biospecimens needed • Or perhaps from before disease initiation • Cohort studies needed • Genetics/genomics • Genotype calling, QC • DNA quality of cases and controls may be different • Obtained from different sources • Controls and cases from different studies • As in studies of rare cancers using shared controls with previous genotypes • Recall genotype from optical density?
Randomized Controlled Trials (1)Differential misclassification of tx: • Intention to treat (ITT) analysis • Effect of dose assigned • Controls confounding • Estimate of effect often biased • Effect of dose actually received • May be more interesting • Can be subject to confounding • Solutions? • ITT + understanding error model for dose received • ITT + instrumental variable approach
Randomized Controlled Trials (2):Differential misclassification • HPV vaccine to prevent CIN2 due to HPV16/18 • CIN2 is cervical precancer • Early trials used HPV assays only for HPV16/18 • Example of misclassification • CIN2 caused by HPV type not affected by vaccine • HPV16/18 found in lesion only in placebo arm • Contributes to apparent benefit from vaccination • NCI and other recent studies test for all oncogenic HPV types
Alloyed gold standard • Use of alloyed gold standard in validation studies can lead to overcorrection for bias in regression calibration models • Wacholder et al., 1993, PMID: 8322765 • Average of multiple 24h recalls can be distorted
Missing data (MD) vs. ME • MD and ME: absence of true value of the variable • ME: proxy variable available; • MD: No proxy • MD and ME: Statistical approaches available when you understand underlying mechanisms
Summary • Measurement error is pervasive • Even in trials, not just epidemiology • Understand the causes of measurement error • minimize bias; • increase power, efficiency • Understand mechanism generating observations via • Pilot studies • Validation studies • Replication studies • Inter-observer studies • Statistical insights can help at design and analysis stages