Nonparametric Adjustment for Measurement Error in Time-to-Event Data: Application to Risk Prediction Models

<p>Mismeasured time-to-event data used as a predictor in risk prediction models will lead to inaccurate predictions. This arises in the context of self-reported family history, a time-to-event predictor often measured with error, used in Mendelian risk prediction models. Using validation data, we propose a method to adjust for this type of error. We estimate the measurement error process using a nonparametric smoothed Kaplan–Meier estimator, and use Monte Carlo integration to implement the adjustment. We apply our method to simulated data in the context of both Mendelian and multivariate survival prediction models. Simulations are evaluated using measures of mean squared error of prediction (MSEP), area under the response operating characteristics curve (ROC-AUC), and the ratio of observed to expected number of events. These results show that our method mitigates the effects of measurement error mainly by improving calibration and total accuracy. We illustrate our method in the context of Mendelian risk prediction models focusing on misreporting of breast cancer, fitting the measurement error model on data from the University of California at Irvine, and applying our method to counselees from the Cancer Genetics Network. We show that our method improves overall calibration, especially in low risk deciles. Supplementary materials for this article are available online.</p

Additional file 1: of Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study

Table S1. Distributions of CASP8 SNPs in controls and cases, overall and by subtype. Samples in which genotype was unknown are not included in this table. (DOC 88 kb

Additional file 2: of Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study

Table S2. SNPs from Lin et al. [26] that are in strong LD (r2 > 0.5) with rs2293554. *Odds Ratio (OR), Lower Confidence Limit (LCL), and Upper Confidence Limit (UCL) as reported in Lin et at. [26]. (DOC 44 kb

List of participating studies and number of Caucasian subjects included in at least one GxE analysis.

<p>List of participating studies and number of Caucasian subjects included in at least one GxE analysis.</p

Odds ratios of gene-environment interaction for risk of breast cancer with p-value<10⁻³ by study.

<p>(A) <i>LSP1</i>-rs3817198 x Number of full-term births (among parous), (B) <i>LSP1</i>-rs3817198 x Number of full-term births (among parous), restricted to subjects not included in previous BCAC report, (C) 1p11-rs11249433 x Parous (yes/no), (D) <i>CASP8</i>-rs17468277 x mean lifetime intake of alcohol (<20 g/day versus > = 20 g/day).</p

Main effects for the epidemiologic variables included in the analyses, derived from population-based studies only¹.

<p>Main effects for the epidemiologic variables included in the analyses, derived from population-based studies only^{<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003284#nt104" target="_blank">1</a>}.</p

Associations between selected SNPs and breast cancer risk in Caucasians, overall and by ER status (estimated per-allele odds ratios and 95% confidence intervals)¹.

<p>Associations between selected SNPs and breast cancer risk in Caucasians, overall and by ER status (estimated per-allele odds ratios and 95% confidence intervals)^{<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003284#nt107" target="_blank">1</a>}.</p

Per-allele odds ratios and 95% confidence intervals for SNPs by environmental risk factors of breast cancer showing interaction P-value<10⁻³, overall and by estrogen receptor status.

<p>Per-allele odds ratios and 95% confidence intervals for SNPs by environmental risk factors of breast cancer showing interaction P-value<10⁻³, overall and by estrogen receptor status.</p

Per-allele SNP odds ratios and 95% confidence intervals stratified by environmental risk factors of breast cancer, and combined SNP main effect.

<p>(A) <i>LSP1</i>-rs3817198 x Number of full-term births (among parous), (B) 1p11-rs11249433 x Parous (yes/no), (C) <i>CASP8</i>-rs17468277 x mean lifetime intake of alcohol (<20 g/day versus > = 20 g/day).</p

Association of rs12662670 with breast cancer in European ER

<p>−<b>*versus ER+**cases and controls.</b> *Estrogen receptor negative; **Estrogen receptor positive.</p