An integrative multi-context Mendelian randomization method for identifying risk genes across human tissues.

Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often context- or tissue-specific eQTL effects challenge the MR assumption of consistent IV effects across eQTL and GWAS data. To address these challenges, we propose a multi-context multivariable integrative MR framework, mintMR, for mapping expression and molecular traits as joint exposures. It models the effects of molecular exposures across multiple tissues in each gene region, while simultaneously estimating across multiple gene regions. It uses eQTLs with consistent effects across more than one tissue type as IVs, improving IV consistency. A major innovation of mintMR involves employing multi-view learning methods to collectively model latent indicators of disease relevance across multiple tissues, molecular traits, and gene regions. The multi-view learning captures the major patterns of disease relevance and uses these patterns to update the estimated tissue relevance probabilities. The proposed mintMR iterates between performing a multi-tissue MR for each gene region and joint learning the disease-relevant tissue probabilities across gene regions, improving the estimation of sparse effects across genes. We apply mintMR to evaluate the causal effects of gene expression and DNA methylation for 35 complex traits using multi-tissue QTLs as IVs. The proposed mintMR controls genome-wide inflation and offers insights into disease mechanisms.

Using genetic association data to guide drug discovery and development: Review of methods and applications.

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

Twins, income, and happiness: Evidence from China.

We estimate the causal effect of income on happiness using a unique dataset of Chinese twins. This allows us to address omitted variable bias and measurement errors. Our findings show that individual income has a large positive effect on happiness, with a doubling of income resulting in an increase of 0.26 scales or 0.37 SDs in the four-scale happiness measure. We also find that income matters most for males and the middle-aged. Our results highlight the importance of accounting for various biases when studying the relationship between socioeconomic status and subjective well-being.

simmrd: An open-source tool to perform simulations in Mendelian randomization.

Mendelian randomization (MR) has become a popular tool for inferring causality of risk factors on disease. There are currently over 45 different methods available to perform MR, reflecting this extremely active research area. It would be desirable to have a standard simulation environment to objectively evaluate the existing and future methods. We present simmrd, an open-source software for performing simulations to evaluate the performance of MR methods in a range of scenarios encountered in practice. Researchers can directly modify the simmrd source code so that the research community may arrive at a widely accepted framework for researchers to evaluate the performance of different MR methods.

Cognitive Behavioral Program for the Prevention of Depression in At-Risk Adolescents: Isolating the Effects of Dose.

The current study estimated effects of intervention dose (attendance) of a cognitive behavioral prevention (CBP) program on depression-free days (DFD) in adolescent offspring of parents with a history of depression. As part of secondary analyses of a multi-site randomized controlled trial, we analyzed the complete intention-to-treat sample of 316 at-risk adolescents ages 13-17. Youth were randomly assigned to the CBP program plus usual care (n=159) or to usual care alone (n=157). The CBP program involved 8 weekly acute sessions and 6 monthly continuation sessions. Results showed that higher CBP program dose predicted more DFDs, with a key threshold of approximately 75% of a full dose in analyses employing instrumental variable methodology to control multiple channels of bias. Specifically, attending at more than 75% of acute phase sessions led to 45.3 more DFDs over the 9-month period post randomization, which accounted for over 12% of the total follow-up days. Instrument sets were informed by study variables and external data including weather and travel burden. In contrast, conventional analysis methods failed to find a significant dose-outcome relation. Application of the instrumental variable approach, which better controls the influence of confounding, demonstrated that higher CBP program dose resulted in more DFDs.

Addressing the credibility crisis in Mendelian randomization.

BACKGROUND: Genome-wide association studies have enabled Mendelian randomization analyses to be performed at an industrial scale. Two-sample summary data Mendelian randomization analyses can be performed using publicly available data by anyone who has access to the internet. While this has led to many insightful papers, it has also fuelled an explosion of poor-quality Mendelian randomization publications, which threatens to undermine the credibility of the whole approach. FINDINGS: We detail five pitfalls in conducting a reliable Mendelian randomization investigation: (1) inappropriate research question, (2) inappropriate choice of variants as instruments, (3) insufficient interrogation of findings, (4) inappropriate interpretation of findings, and (5) lack of engagement with previous work. We have provided a brief checklist of key points to consider when performing a Mendelian randomization investigation; this does not replace previous guidance, but highlights critical analysis choices. Journal editors should be able to identify many low-quality submissions and reject papers without requiring peer review. Peer reviewers should focus initially on key indicators of validity; if a paper does not satisfy these, then the paper may be meaningless even if it is technically flawless. CONCLUSIONS: Performing an informative Mendelian randomization investigation requires critical thought and collaboration between different specialties and fields of research.

Mendelian randomization: causal inference leveraging genetic data.

Mendelian randomization (MR) leverages genetic information to examine the causal relationship between phenotypes allowing for the presence of unmeasured confounders. MR has been widely applied to unresolved questions in epidemiology, making use of summary statistics from genome-wide association studies on an increasing number of human traits. However, an understanding of essential concepts is necessary for the appropriate application and interpretation of MR. This review aims to provide a non-technical overview of MR and demonstrate its relevance to psychiatric research. We begin with the origins of MR and the reasons for its recent expansion, followed by an overview of its statistical methodology. We then describe the limitations of MR, and how these are being addressed by recent methodological advances. We showcase the practical use of MR in psychiatry through three illustrative examples - the connection between cannabis use and psychosis, the link between intelligence and schizophrenia, and the search for modifiable risk factors for depression. The review concludes with a discussion of the prospects of MR, focusing on the integration of multi-omics data and its extension to delineating complex causal networks.

Using instrumental variables to correct for bias in real-world cohort studies of the effects of disease-modifying treatment in MS.

BACKGROUND: Estimating the effect of disease-modifying treatment of MS in observational studies is impaired by bias from unmeasured confounders, in particular indication bias. OBJECTIVE: To show how instrumental variables (IVs) reduce bias. METHODS: All patients with relapsing onset of MS 1996-2010, identified by the nationwide Danish Multiple Sclerosis Registry, were followed from onset. Exposure was treatment index throughout the first 12 years from onset, defined as a cumulative function of months without and with medium- or high-efficacy treatment, and outcomes were hazard ratios (HRs) per unit treatment index for sustained Expanded Disability Scale Score (EDSS) 4 and 6 adjusted for age at onset and sex, without and with an IV. We used the onset cohort (1996-2000; 2001-2005; 2006-2010) as an IV because treatment index increased across the cohorts. RESULTS: We included 6014 patients. With conventional Cox regression, HRs for EDSS 4 and 6 were 1.15 [95% CI: 1.13-1.18] and 1.17 [1.13-1.20] per unit treatment index. Only with IVs, we confirmed a beneficial effect of treatment with HRs of 0.86 [0.81-0.91] and 0.82 [0.74-0.90]. CONCLUSION: The use of IVs eliminates indication bias and confirms that treatment is effective in delaying disability. IVs could, under some circumstances, be an alternative to marginal structural models.

A Bayesian semi-parametric scalar-on-function regression with measurement error using instrumental variables.

Wearable devices such as the ActiGraph are now commonly used in research to monitor or track physical activity. This trend corresponds with the growing need to assess the relationships between physical activity and health outcomes, such as obesity, accurately. Device-based physical activity measures are best treated as functions when assessing their associations with scalar-valued outcomes such as body mass index. Scalar-on-function regression (SoFR) is a suitable regression model in this setting. Most estimation approaches in SoFR assume that the measurement error in functional covariates is white noise. Violating this assumption can lead to underestimating model parameters. There are limited approaches to correcting measurement errors for frequentist methods and none for Bayesian methods in this area. We present a non-parametric Bayesian measurement error-corrected SoFR model that relaxes all the constraining assumptions often involved with these models. Our estimation relies on an instrumental variable allowing a time-varying biasing factor, a significant departure from the current generalized method of moment (GMM) approach. Our proposed method also permits model-based grouping of the functional covariate following measurement error correction. This grouping of the measurement error-corrected functional covariate allows additional ease of interpretation of how the different groups differ. Our method is easy to implement, and we demonstrate its finite sample properties in extensive simulations. Finally, we applied our method to data from the National Health and Examination Survey to assess the relationship between wearable device-based measures of physical activity and body mass index in adults in the United States.

Estimating Time-Varying Exposure Effects Through Continuous-Time Modelling in Mendelian Randomization.

Mendelian randomization is an instrumental variable method that utilizes genetic information to investigate the causal effect of a modifiable exposure on an outcome. In most cases, the exposure changes over time. Understanding the time-varying causal effect of the exposure can yield detailed insights into mechanistic effects and the potential impact of public health interventions. Recently, a growing number of Mendelian randomization studies have attempted to explore time-varying causal effects. However, the proposed approaches oversimplify temporal information and rely on overly restrictive structural assumptions, limiting their reliability in addressing time-varying causal problems. This article considers a novel approach to estimate time-varying effects through continuous-time modelling by combining functional principal component analysis and weak-instrument-robust techniques. Our method effectively utilizes available data without making strong structural assumptions and can be applied in general settings where the exposure measurements occur at different timepoints for different individuals. We demonstrate through simulations that our proposed method performs well in estimating time-varying effects and provides reliable inference when the time-varying effect form is correctly specified. The method could theoretically be used to estimate arbitrarily complex time-varying effects. However, there is a trade-off between model complexity and instrument strength. Estimating complex time-varying effects requires instruments that are unrealistically strong. We illustrate the application of this method in a case study examining the time-varying effects of systolic blood pressure on urea levels.

Using instruments for selection to adjust for selection bias in Mendelian randomization.

Selection bias is a common concern in epidemiologic studies. In the literature, selection bias is often viewed as a missing data problem. Popular approaches to adjust for bias due to missing data, such as inverse probability weighting, rely on the assumption that data are missing at random and can yield biased results if this assumption is violated. In observational studies with outcome data missing not at random, Heckman's sample selection model can be used to adjust for bias due to missing data. In this paper, we review Heckman's method and a similar approach proposed by Tchetgen Tchetgen and Wirth (2017). We then discuss how to apply these methods to Mendelian randomization analyses using individual-level data, with missing data for either the exposure or outcome or both. We explore whether genetic variants associated with participation can be used as instruments for selection. We then describe how to obtain missingness-adjusted Wald ratio, two-stage least squares and inverse variance weighted estimates. The two methods are evaluated and compared in simulations, with results suggesting that they can both mitigate selection bias but may yield parameter estimates with large standard errors in some settings. In an illustrative real-data application, we investigate the effects of body mass index on smoking using data from the Avon Longitudinal Study of Parents and Children.

GENIUS-MAWII: for robust Mendelian randomization with many weak invalid instruments.

Mendelian randomization (MR) addresses causal questions using genetic variants as instrumental variables. We propose a new MR method, G-Estimation under No Interaction with Unmeasured Selection (GENIUS)-MAny Weak Invalid IV, which simultaneously addresses the 2 salient challenges in MR: many weak instruments and widespread horizontal pleiotropy. Similar to MR-GENIUS, we use heteroscedasticity of the exposure to identify the treatment effect. We derive influence functions of the treatment effect, and then we construct a continuous updating estimator and establish its asymptotic properties under a many weak invalid instruments asymptotic regime by developing novel semiparametric theory. We also provide a measure of weak identification, an overidentification test, and a graphical diagnostic tool.

Elucidating the causal landscape: Mendelian randomization analysis of lifestyle and physiological factors in stress urinary incontinence.

PURPOSE: To explore the potential causal links between obesity, type 2 diabetes (T2D), and lifestyle choices (such as smoking, alcohol and coffee consumption, and vigorous physical activity) on stress urinary incontinence (SUI), this study employs a Mendelian Randomization approach. This research aims to clarify these associations, which have been suggested but not conclusively established in prior observational studies. METHODS: Genetic instruments associated with the exposures at the genome-wide significance (p < 5 × 10-8) were selected from corresponding genome-wide association studies. Summary-level data for SUI, was obtained from the UK Biobank. A two-sample MR analysis was employed to estimate causal effects, utilizing the inverse-variance weighted (IVW) method as the primary analytical approach. Complementary sensitivity analyses including MR-PRESSO, MR-Egger, and weighted median methods were performed. The horizontal pleiotropy was detected by using MR-Egger intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran's Q statistics. RESULTS: Our findings demonstrate a significant causal relationship between higher body mass index (BMI) and the risk of SUI, with increased abdominal adiposity (WHRadjBMI) similarly linked to SUI. Smoking initiation is also causally associated with an elevated risk. However, our analysis did not find definitive causal connections for other factors, including T2D, alcohol consumption, coffee intake, and vigorous physical activity. CONCLUSIONS: These findings provide valuable insights for clinical strategies targeting SUI, suggesting a need for heightened awareness and potential intervention in individuals with higher BMI, WHR, and smoking habits. Further research is warranted to explore the complex interplay between genetic predisposition and lifestyle choices in the pathogenesis of SUI.

Non-classical measurement error in instrumental variables estimation: An application to the medical care costs of obesity.

Estimates of the impact of body mass index and obesity on health and labor market outcomes often use instrumental variables estimation (IV) to mitigate bias due to endogeneity. When these studies rely on survey data that include self- or proxy-reported height and weight, there is non-classical measurement error due to the tendency of individuals to under-report their own weight. Mean reverting errors in weight do not cause IV to be asymptotically biased per se, but may result in bias if instruments are correlated with additive error in weight. We demonstrate the conditions under which IV is biased when there is non-classical measurement error and derive bounds for this bias conditional on instrument strength and the severity of mean-reverting error. We show that improvements in instrument relevance alone cannot eliminate IV bias, but reducing the correlation between weight and reporting error mitigates the bias. A solution we consider is regression calibration (RC) of endogenous variables with external validation data. In simulations, we find IV estimation paired with RC can produce consistent estimates when correctly specified. Even when RC fails to match the covariance structure of reporting error, there is still a reduction in asymptotic bias.

Going beyond randomised controlled trials to assess treatment effect heterogeneity across target populations.

Methods have been developed for transporting evidence from randomised controlled trials (RCTs) to target populations. However, these approaches allow only for differences in characteristics observed in the RCT and real-world data (overt heterogeneity). These approaches do not recognise heterogeneity of treatment effects (HTE) according to unmeasured characteristics (essential heterogeneity). We use a target trial design and apply a local instrumental variable (LIV) approach to electronic health records from the Clinical Practice Research Datalink, and examine both forms of heterogeneity in assessing the comparative effectiveness of two second-line treatments for type 2 diabetes mellitus. We first estimate individualised estimates of HTE across the entire target population defined by applying eligibility criteria from national guidelines (n = 13,240) within an overall target trial framework. We define a subpopulation who meet a published RCT's eligibility criteria ('RCT-eligible', n = 6497), and a subpopulation who do not ('RCT-ineligible', n = 6743). We compare average treatment effects for pre-specified subgroups within the RCT-eligible subpopulation, the RCT-ineligible subpopulation, and within the overall target population. We find differences across these subpopulations in the magnitude of subgroup-level treatment effects, but that the direction of estimated effects is stable. Our results highlight that LIV methods can provide useful evidence about treatment effect heterogeneity including for those subpopulations excluded from RCTs.

Unpacking the care-related quality of life effect of England's publicly funded adult social care. A panel data analysis.

Adult Social Care (ASC) is the publicly-funded long-term care program in England that provides support with activities of daily living to people experiencing mental and/or physical challenges. Existing evidence suggests that ASC expenditure improves service users' care-related quality of life (CRQoL). However, less is known about the channels through which this effect exists and the effect on outcomes other than CRQoL. We fill this gap by analyzing survey data on ASC service users who received long-term support from 2014/15 to 2019/20 using panel data instrumental variable methods. We find that the beneficial impact of ASC expenditure on the CRQoL of both new and existing users is mostly driven by users aged 18-64 without any learning disability and users with no learning disability aged 65 or older receiving community-based ASC. Moreover, control over daily life, occupation, and social participation are the CRQoL domains that are improved the most. We also find that ASC expenditure has a beneficial effect on several other outcomes beyond CRQoL for both new and existing users including user satisfaction and experience, the ability to carry out activities of daily living independently, whether their home is designed around needs, accessibility to local places, general health, and mental health through reduced anxiety and depression. Greater ASC expenditure, however, does not address the need for other forms of support such as unpaid informal and privately-funded care.

Estimating the short-term effect of PM2.5 on the mortality of cardiovascular diseases based on instrumental variables.

BACKGROUND: PM2.5 can induce and aggravate the occurrence and development of cardiovascular diseases (CVDs). The objective of our study is to estimate the causal effect of PM2.5 on mortality rates associated with CVDs using the instrumental variables (IVs) method. METHODS: We extracted daily meteorological, PM2.5 and CVDs death data from 2016 to 2020 in Binzhou. Subsequently, we employed the general additive model (GAM), two-stage predictor substitution (2SPS), and control function (CFN) to analyze the association between PM2.5 and daily CVDs mortality. RESULTS: The 2SPS estimated the association between PM2.5 and daily CVDs mortality as 1.14% (95% CI: 1.04%, 1.14%) for every 10 µg/m3 increase in PM2.5. Meanwhile, the CFN estimated this association to be 1.05% (95% CI: 1.02%, 1.10%). The GAM estimated it as 0.85% (95% CI: 0.77%, 1.05%). PM2.5 also exhibited a statistically significant effect on the mortality rate of patients with ischaemic heart disease, myocardial infarction, or cerebrovascular accidents (P < 0.05). However, no significant association was observed between PM2.5 and hypertension. CONCLUSION: PM2.5 was significantly associated with daily CVDs deaths (excluding hypertension). The estimates from the IVs method were slightly higher than those from the GAM. Previous studies based on GAM may have underestimated the impact of PM2.5 on CVDs.

Exploring the impact of inflammatory cytokines on alcoholic liver disease: a Mendelian randomization study with bioinformatics insights into potential biological mechanisms.

Background: Alcoholic liver disease (ALD) significantly contributes to global morbidity and mortality. The role of inflammatory cytokines in alcohol-induced liver injury is pivotal yet not fully elucidated.Objectives: To establish a causal link between inflammatory cytokines and ALD using a Mendelian Randomization (MR) framework.Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between inflammatory cytokines and ALD risk, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, protein-protein interactions (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and analysis of immune cell infiltration.Results: Our findings reveal that increased levels of stem cell growth factor beta (SCGF-ß, beta = 0.141, p = .032) and interleukin-7 (IL-7, beta = 0.311, p = .002) are associated with heightened ALD risk, whereas higher levels of macrophage inflammatory protein-1α (MIP-1α, beta = -0.396, p = .004) and basic fibroblast growth factor (bFGF, beta = -0.628, p = .008) are linked to reduced risk. The sensitivity analyses support these robust causal relationships. Bioinformatics analyses around inflammatory cytokine-associated SNP loci suggest multiple pathways through which cytokines influence ALD.Conclusion: The genetic evidence from this study convincingly demonstrates that certain inflammatory cytokines play directional roles in ALD pathogenesis. These findings provide insights into the complex biological pathways involved and underscore the potential for developing targeted therapies that modulate these inflammatory responses, ultimately improving clinical outcomes for ALD patients.

Using Instrumental Variables to Measure Causation over Time in Cross-Lagged Panel Models.

Cross-lagged panel models (CLPMs) are commonly used to estimate causal influences between two variables with repeated assessments. The lagged effects in a CLPM depend on the time interval between assessments, eventually becoming undetectable at longer intervals. To address this limitation, we incorporate instrumental variables (IVs) into the CLPM with two study waves and two variables. Doing so enables estimation of both the lagged (i.e., "distal") effects and the bidirectional cross-sectional (i.e., "proximal") effects at each wave. The distal effects reflect Granger-causal influences across time, which decay with increasing time intervals. The proximal effects capture causal influences that accrue over time and can help infer causality when the distal effects become undetectable at longer intervals. Significant proximal effects, with a negligible distal effect, would imply that the time interval is too long to estimate a lagged effect at that time interval using the standard CLPM. Through simulations and an empirical application, we demonstrate the impact of time intervals on causal inference in the CLPM and present modeling strategies to detect causal influences regardless of the time interval in a study. Furthermore, to motivate empirical applications of the proposed model, we highlight the utility and limitations of using genetic variables as IVs in large-scale panel studies.

A Causal View on Bias in Missing Data Imputation: The Impact of Evil Auxiliary Variables on Norming of Test Scores.

Among the most important merits of modern missing data techniques such as multiple imputation (MI) and full-information maximum likelihood estimation is the possibility to include additional information about the missingness process via auxiliary variables. During the past decade, the choice of auxiliary variables has been investigated under a variety of different conditions and more recent research points to the potentially biasing effect of certain auxiliary variables, particularly colliders (Thoemmes & Rose, 2014). In this article, we further extend biasing mechanisms of certain auxiliary variables considered in previous research and thereby focus on their effects on individual diagnosis based on norming, in which the whole distribution of a variable is of interest rather than average coefficients (e.g., means). For this, we first provide the theoretical underpinnings of the mechanisms under study and then provide two focused simulations that (i) directly expand on the collider scenario in Thoemmes and Rose (2014, appendix A) by considering outcomes that are relevant to norming and (ii) extend the scenarios under consideration by instrumental variable mechanisms. We illustrate the bias mechanisms for two different norming approaches and exemplify the procedures by means of an empirical example. We end by discussing limitations and implications of our research.