Implications of Selection Bias Due to Delayed Study Entry in Clinical Genomic Studies

Abstract

Importance: Real-world data sets that combine clinical and genomic data may be subject to left truncation (when potential study participants are not included because they have already passed the milestone of interest at the time of study recruitment). The lapse between diagnosis and molecular testing can present analytic challenges and threaten the validity and interpretation of survival analyses.

Observations: Effects of ignoring left truncation when estimating overall survival are illustrated using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE BPC), and a straightforward risk-set adjustment approach is described. Ignoring left truncation results in overestimation of overall survival: unadjusted median survival estimates from diagnosis among patients with stage IV non-small cell lung cancer or stage IV colorectal cancer were overestimated by more than 1 year.

Conclusions and relevance: Clinicogenomic data are a valuable resource for evaluation of real-world cancer outcomes and should be analyzed using appropriate methods to maximize their potential. Analysts must become adept at application of appropriate statistical methods to ensure valid, meaningful, and generalizable research findings.

Figure 1:

A) Event history for overall survival from diagnosis among stage IV CRC patients (N=659). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV CRC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV CRC patients (N=285). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV CRC patients with and without adjustment for delayed study entry.

Figure 1:

A) Event history for overall survival from diagnosis among stage IV CRC patients (N=659). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV CRC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV CRC patients (N=285). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV CRC patients with and without adjustment for delayed study entry.

Figure 1:

A) Event history for overall survival from diagnosis among stage IV CRC patients (N=659). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV CRC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV CRC patients (N=285). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV CRC patients with and without adjustment for delayed study entry.

Figure 1:

A) Event history for overall survival from diagnosis among stage IV CRC patients (N=659). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV CRC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV CRC patients (N=285). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV CRC patients with and without adjustment for delayed study entry.

Figure 2:

A) Event history for overall survival from diagnosis among stage IV NSCLC patients (N=727). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV NSCLC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV NSCLC patients (N=137). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV NSCLC patients with and without adjustment for delayed study entry.

Figure 2:

A) Event history for overall survival from diagnosis among stage IV NSCLC patients (N=727). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV NSCLC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV NSCLC patients (N=137). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV NSCLC patients with and without adjustment for delayed study entry.

Figure 2:

A) Event history for overall survival from diagnosis among stage IV NSCLC patients (N=727). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV NSCLC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV NSCLC patients (N=137). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV NSCLC patients with and without adjustment for delayed study entry.

Figure 2:

A) Event history for overall survival from diagnosis among stage IV NSCLC patients (N=727). Each patient’s survival time from diagnosis is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. B) Kaplan-Meier curves illustrating overall survival from diagnosis among stage IV NSCLC patients with and without adjustment for delayed study entry. C) Event history for overall survival from most common first-line regimen among stage IV NSCLC patients (N=137). Each patient’s survival time from start of regimen is indicated by a blue line with a black line overlaid to illustrate duration of delayed study entry. D) Kaplan-Meier curves illustrating overall survival from start of most common first-line regimen among stage IV NSCLC patients with and without adjustment for delayed study entry.