Adjusting for collider bias in genetic association studies using instrumental variable methods.

Genome-wide association studies have provided many genetic markers that can be used as instrumental variables to adjust for confounding in epidemiological studies. Recently, the principle has been applied to other forms of bias in observational studies, especially collider bias that arises when conditioning or stratifying on a variable that is associated with the outcome of interest. An important case is in studies of disease progression and survival. Here, we clarify the links between the genetic instrumental variable methods proposed for this problem and the established methods of Mendelian randomisation developed to account for confounding. We highlight the critical importance of weak instrument bias in this context and describe a corrected weighted least-squares procedure as a simple approach to reduce this bias. We illustrate the range of available methods on two data examples. The first, waist-hip ratio adjusted for body-mass index, entails statistical adjustment for a quantitative trait. The second, smoking cessation, is a stratified analysis conditional on having initiated smoking. In both cases, we find little effect of collider bias on the primary association results, but this may propagate into more substantial effects on further analyses such as polygenic risk scoring and Mendelian randomisation.

Reassessing the association of MUC5B with survival in idiopathic pulmonary fibrosis.

A variant in the mucin 5B gene (MUC5B) is strongly associated with the risk of idiopathic pulmonary fibrosis. However, the same variant is associated with increased survival time. Previous work suggested that this may be explained by index event bias, with the true effect being to decrease survival. Here, we reassessed this claim using more recent methods and datasets. We found that the statistical assumptions of the previous analysis did not hold, and instead, we applied recent methods of corrected weighted least squares, MR-RAPS and Slope-hunter to both the previous data and an updated consortium meta-analysis. However, these analyses did not yield robust evidence for increased or decreased survival. In simulations of a true effect of decreased survival, we did not observe any realistic scenario in which index event bias led to an observed effect of increased survival. We therefore regard as unsafe the claim that MUC5B has a true effect of decreased survival. Alternative explanations should be sought to explain the observed association with increased survival.

Assessing the impact of nodule features and software algorithm on pulmonary nodule measurement uncertainty for nodules sized 20 mm or less.

Background: Measurements are not exact, so that if a measurement is repeated, one would get a different value each time. The spread of these values is the measurement uncertainty. Understanding measurement uncertainty of pulmonary nodules is important for proper interpretation of size and growth measurements. Larger amounts of measurement uncertainty may require longer follow-up intervals to be confident that any observed growth is due to actual growth rather than measurement uncertainty. We examined the influence of nodule features and software algorithm on measurement uncertainty of small, solid pulmonary nodules. Methods: Volumes of 107 nodules were measured on 4-6 repeated computed tomography (CT) scans (Siemens Somatom AS, 100 kVp, 120 mA, 1.0 mm slice thickness reconstruction) prospectively obtained during CT-guided fine needle aspiration biopsy between 2015-2021 at Department of Diagnostic, Molecular, and Interventional Radiology in Icahn School of Medicine at Mount Sinai, using two different automated volumetric algorithms. For each, the coefficient of variation (standard deviation divided by the mean) of nodule volume measurements was determined. The following features were considered: diameter, location, vessel and pleural attachments, nodule surface area, and extent of the nodule in the three acquisition dimensions of the scanner. Results: Median volume of 107 nodules was 515.23 and 535.53 mm3 for algorithm #1 and #2, respectively with excellent agreement (intraclass correlation coefficient =0.98). Median coefficient of variation of nodule volume was low for the two algorithms, but significantly different (4.6% vs. 8.7%, P<0.001). Both algorithms had a trend of decreasing coefficient of variation of nodule volume with increasing nodule diameter, though only significant for algorithm #2. Coefficient of variation of nodule volume was significantly associated with nodule volume (P=0.02), attachment to blood vessels (P=0.02), and nodule surface area (P=0.001) for algorithm #2 using a multiple linear regression model. Correlation between the coefficient of variation (CoV) of nodule volume and the CoV of the x, y, z measurements for algorithm #1 were 0.29 (P=0.0021), 0.25 (P=0.009), and 0.80 (P<0.001) respectively, and for algorithm #2, 0.46 (P<0.001), 0.52 (P<0.001), and 0.58 (P<0.001), respectively. Conclusions: Even in the best-case scenario represented in this study, using the same measurement algorithm, scanner, and scanning protocol, considerable measurement uncertainty exists in nodule volume measurement for nodules sized 20 mm or less. We found that measurement uncertainty was affected by interactions between nodule volume, algorithm, and shape complexity.