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Consequences of Depletion of Susceptibles for Hazard Ratio Estimators Based on Propensity Scores.

ABSTRACT: We use simulated data to examine the consequences of depletion of susceptibles for hazard ratio (HR) estimators based on a propensity score (PS). First, we show that the depletion of susceptibles attenuates marginal HRs toward the null by amounts that increase with the incidence of the outcome, the variance of susceptibility, and the impact of susceptibility on the outcome. If susceptibility is binary then the Bross bias multiplier, originally intended to quantify bias in a risk ratio from a binary confounder, also quantifies the ratio of the instantaneous marginal HR to the conditional HR as susceptibles are depleted differentially. Second, we show how HR estimates that are conditioned on a PS tend to be between the true conditional and marginal HRs, closer to the conditional HR if treatment status is strongly associated with susceptibility and closer to the marginal HR if treatment status is weakly associated with susceptibility. We show that associations of susceptibility with the PS matter to the marginal HR in the treated (ATT) though not to the marginal HR in the entire cohort (ATE). Third, we show how the PS can be updated periodically to reduce depletion-of-susceptibles bias in conditional estimators. Although marginal estimators can hit their ATE or ATT targets consistently without updating the PS, we show how their targets themselves can be misleading as they are attenuated toward the null. Finally, we discuss implications for the interpretation of HRs and their relevance to underlying scientific and clinical questions. See video Abstract: http://links.lww.com/EDE/B727.

SUBMITTER: Fireman B

PROVIDER: S-EPMC7523577 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Consequences of Depletion of Susceptibles for Hazard Ratio Estimators Based on Propensity Scores.

Fireman Bruce B Gruber Susan S Zhang Zilu Z Wellman Robert R Nelson Jennifer Clark JC Franklin Jessica J Maro Judith J Murray Catherine Rogers CR Toh Sengwee S Gagne Joshua J Schneeweiss Sebastian S Amsden Laura L Wyss Richard R

Epidemiology (Cambridge, Mass.) 20201101 6

We use simulated data to examine the consequences of depletion of susceptibles for hazard ratio (HR) estimators based on a propensity score (PS). First, we show that the depletion of susceptibles attenuates marginal HRs toward the null by amounts that increase with the incidence of the outcome, the variance of susceptibility, and the impact of susceptibility on the outcome. If susceptibility is binary then the Bross bias multiplier, originally intended to quantify bias in a risk ratio from a bin ...[more]

PMID: 32841986

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Project description:Objective:Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods:Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. Results:Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ? 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ? 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation:Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ? 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Dataset Information

Consequences of Depletion of Susceptibles for Hazard Ratio Estimators Based on Propensity Scores.

Publications

Consequences of Depletion of Susceptibles for Hazard Ratio Estimators Based on Propensity Scores.

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