Why Do Epidemiologic Studies Find an Inverse Association Between Intraprostatic Inflammation and Prostate Cancer: A Possible Role for Colliding Bias?

Abstract

Inflammation is an emerging risk factor for prostate cancer based largely on evidence from animal models and histopathologic observations. However, findings from patho-epidemiologic studies of intraprostatic inflammation and prostate cancer have been less supportive, with inverse associations observed in many studies of intraprostatic inflammation and prostate cancer diagnosis. Here, we propose collider stratification bias as a potential methodologic explanation for these inverse findings and provide strategies for conducting future etiologic studies of intraprostatic inflammation and prostate cancer.

Clinical consequences of a genetic predisposition toward higher benign prostate-specific antigen levels

“…This pattern of association is due to a well-described collider bias related to ascertaining prostate cancer status among individuals with an elevated PSA level. 22 , 23 This phenomenon was demonstrated in the data simulation. Thus, an inverse association would be expected for a genetic predictor that measures benign PSA elevations as these elevations are not due to underlying cancer.…”

Health inequity drives disease biology to create disparities in prostate cancer outcomes

“…Yet since peripheral zone prostatitis and early prostate cancer tend to be asymptomatic, epidemiology studies of the two conditions have proven difficult. Since inflammatory damage to the prostate epithelium and prostate cancer can both raise serum PSA levels, when prostate biopsies conditioned on serum PSA elevations are used to test correlations between prostatitis and prostate cancer, the inferred associations are prone to “collider stratification” bias ( 118 ). This type of bias can either falsely hint at an association or even incorrectly suggest an inverse association ( 118 ).…”

“…Since inflammatory damage to the prostate epithelium and prostate cancer can both raise serum PSA levels, when prostate biopsies conditioned on serum PSA elevations are used to test correlations between prostatitis and prostate cancer, the inferred associations are prone to “collider stratification” bias ( 118 ). This type of bias can either falsely hint at an association or even incorrectly suggest an inverse association ( 118 ). To minimize this methodologic hindrance, study cohorts in which men underwent prostate biopsy without a clinical indication per se have been examined, such as in the placebo arms of the Prostate Cancer Prevention Trial (PCPT) and ensuing Selenium and Vitamin E Cancer Prevention Trial (SELECT) ( 119 , 120 ).…”

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention

“…An explanation for these findings is the collider stratification bias, a form of selection bias occurring in studies where the study population is stratified or restricted by a collider-i.e., a shared effect of both the exposure and the outcome of interest. In this case, the PSA concentration is elevated in prostate inflammation as well as in prostate cancer [44]. More investigations of inflammation and prostate cancer risk, in the context of clinical studies with for-cause biopsies, will likely be subject to the same bias.…”