Stella Koutros

PhD, MPH

NCI

Senior Investigator

PLCO (Learn more about this study)

PLCO-1972

Aug 25, 2025

Validation of a bladder cancer risk model with lifestyle and environmental risk factors and polygenic risk score in two prospective cohorts

Cigarette smoking and occupational exposures are among the leading lifestyle/environmental risk factors for bladder cancer. Recent consortium-based efforts also focused on deriving polygenic risk scores (PRS) based on common genetic variants identified through meta-analysis of large genome-wide association studies. The development of an absolute risk model integrating information from lifestyle/environmental risk factors (e.g., smoking, occupational exposures) and PRS, could have important clinical implications in risk stratification and early detection efforts for bladder cancer. However, prior to clinical applications, an absolute risk model needs to be independently validated ideally in prospective cohort studies that did not contribute to model development and that involves an independent assessment of calibration and discrimination of the model. In this project, we propose to prospectively validate an integrated bladder cancer risk model with questionnaire-based risk factors and PRS in two prospective cohorts: the UK Biobank and the Prostrate, Lung, Colorectal, Ovarian (PLCO) studies.

The Individualized Coherent Absolute Risk Estimator (iCARE) software tool will be used to develop an absolute risk model for bladder cancer combining information from the relative risks of the risk factors based on literature, population-based age-specific disease incidence rates and competing mortality rates (due to causes other than bladder cancer) and population distribution of the risk factors. The model will be evaluated for calibration and discriminatory accuracy in two prospective cohorts: the UK Biobank and the PLCO studies.

We will use the standardized model validation methods implemented in the iCARE software tool for our study. Model validation typically involves an independent evaluation of model calibration and model discrimination in prospective cohorts that did not contribute to model development. Model calibration compares the observed proportion of incident bladder cancer cases with the average of model-based predicted risks in the overall study and specific risk subgroups. Typical measures include expected-to-observed (E/O) ratio and calibration intercept and slope. Model discrimination gives a quantification of the model’s ability to separate the cases and controls. An overall measure of risk discrimination is the Area Under the Curve (AUC), defined as the probability that for a case-control pair the risk of the case participant is greater than risk of the control participant. For a well calibrated model showing good discriminatory accuracy would ensure that there is a good amount of spread in the risk distribution of subjects to ensure risk stratification leading to a better characterization of the risk and benefits.

The Individualized Coherent Absolute Risk Estimator (iCARE) software tool will be used to develop an absolute risk model for bladder cancer combining information from the relative risks of the risk factors based on literature, population-based age-specific disease incidence rates and competing mortality rates (due to causes other than bladder cancer) and population distribution of the risk factors. The model will be evaluated for calibration and discriminatory accuracy in two prospective cohorts: the UK Biobank and the PLCO studies.

• Prospective validation of a bladder cancer risk model with lifestyle risk factors, smoking, PRS in the PLCO study
• Explore the feasibility of exploring this risk model according to relevant bladder cancer subtypes (non-muscle invasive, muscle-invasive) disease