Is low-level alcohol consumption really health-protective? A critical review of approaches to promote causal inference and recent applications.

Heavy and disordered alcohol consumption is a known risk factor for several health conditions and is associated with considerable disease burden. However, at low-to-moderate levels, evidence suggests that drinking is associated with reduced risk for certain health outcomes. Whether these findings represent genuine protective effects or mere methodological artifacts remains unclear, but has substantial consequences for policy and practice. This critical review introduces methodological advances capable of enhancing causal inference from observational research, focusing on the 'G-methods' and Mendelian Randomization. We also present and evaluate recent research applying these methods and compare findings to the existing evidence base. Future directions are proposed for improving our causal understanding of the relationships between alcohol and long-term health outcomes.

Risk factors and cognitive correlates of white matter hyperintensities in ethnically diverse populations without dementia: The COSMIC consortium.

INTRODUCTION: White matter hyperintensities (WMHs) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well documented in populations of different ethnicities and/or from different geographical regions. METHODS: We investigated how WMHs were associated with vascular risk factors and cognition in both Whites and Asians, using data from five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N = 1946). WMH volumes (whole brain, periventricular, and deep) were quantified with UBO Detector and harmonized using the ComBat model. We also harmonized various vascular risk factors and scores for global cognition and individual cognitive domains. RESULTS: Factors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake, and insufficient physical activity. Hypertension and stroke had stronger associations with WMH volumes in Whites than in Asians. No associations between WMH volumes and cognitive performance were found after correction for multiple testing. CONCLUSION: The current study highlights ethnic differences in the contributions of vascular risk factors to WMHs.

Affect and mental health across the lifespan during a year of the COVID-19 pandemic: The role of emotion regulation strategies and mental flexibility.

During the COVID-19 pandemic, there has been a rise in common mental health problems compared to prepandemic levels, especially in young people. Understanding the factors that place young people at risk is critical to guide the response to increased mental health problems. Here we examine whether age-related differences in mental flexibility and frequency of use of emotion regulation strategies partially account for the poorer affect and increased mental health problems reported by younger people during the pandemic. Participants (N = 2,367; 11-100 years) from Australia, the UK, and US were surveyed thrice at 3-month intervals between May 2020 and April 2021. Participants completed measures of emotion regulation, mental flexibility, affect, and mental health. Younger age was associated with less positive (b = 0.008, p < .001) and more negative (b = -0.015, p < .001) affect across the first year of the pandemic. Maladaptive emotion regulation partially accounted for age-related variance in negative affect (ß = -0.013, p = .020), whereby younger age was associated with more frequent use of maladaptive emotion regulation strategies, which, in turn, was associated with more negative affect at our third assessment point. More frequent use of adaptive emotion regulation strategies, and in turn, changes in negative affect from our first to our third assessment, partially accounted for age-related variance in mental health problems (ß = 0.007, p = .023). Our findings add to the growing literature demonstrating the vulnerability of younger people during the COVID-19 pandemic and suggest that emotion regulation may be a promising target for intervention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adolescent Neurodevelopment Within the Context of Impulsivity and Substance Use.

Purpose of Review: The aim of the present review is to provide an update on recent studies examining adolescent neurodevelopment in the context of impulsivity and substance use. We provide a review of the neurodevelopmental changes in brain structure and function related to impulsivity, substance use, and their intersection. Recent Findings: When examining brain structure, smaller gray matter volume coupled with lower white matter integrity is associated with greater impulsivity across three components: trait impulsivity, choice impulsivity, and response inhibition. Altered functional connectivity in networks including the inhibitory control network and reward processing network confers risk for greater impulsivity and substance use. Summary: Across brain structure and function, there is evidence to suggest that overlapping areas involved in the rise in impulsivity during adolescence contribute to early substance use initiation and escalation. These overlapping neurodevelopmental correlates have promising implications for prevention and early intervention efforts for adolescent substance use.

Transdiagnostic biomarkers of mental illness across the lifespan: A systematic review examining the genetic and neural correlates of latent transdiagnostic dimensions of psychopathology in the general population.

This systematic review synthesizes evidence from research investigating the biological correlates of latent transdiagnostic dimensions of psychopathology (e.g., the p-factor, internalizing, externalizing) across the lifespan. Eligibility criteria captured genomic and neuroimaging studies investigating general and/or specific dimensions in general population samples across all age groups. MEDLINE, Embase, and PsycINFO were searched for relevant studies published up to March 2023 and 46 studies were selected for inclusion. The results revealed several biological correlates consistently associated with transdiagnostic dimensions of psychopathology, including polygenic scores for ADHD and neuroticism, global surface area and global gray matter volume. Shared and unique associations between symptom dimensions are highlighted, as are potential age-specific differences in biological associations. Findings are interpreted with reference to key methodological differences across studies. The included studies provide compelling evidence that the general dimension of psychopathology reflects common underlying genetic and neurobiological vulnerabilities that are shared across diverse manifestations of mental illness. Substantive interpretations of general psychopathology in the context of genetic and neurobiological evidence are discussed.

Risk factors and cognitive correlates of white matter hyperintensities in ethnically diverse populations without dementia: the COSMIC consortium.

INTRODUCTION: White matter hyperintensities (WMH) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well-documented in populations of different ethnicities and/or from different geographical regions. METHOD: Magnetic resonance imaging data of five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N = 1,946) were examined for WMH and their associations with vascular risk factors and cognition. RESULT: Factors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake and insufficient physical activity. Participants with moderate or higher physical activity had less WMH than those who never exercised, but the former two groups did not differ. Hypertension and stroke had stronger associations with WMH volumes in the White, compared to Asian subsample. DISCUSSION: The current study highlighted the ethnic differences in the contributions of vascular risk factors to WMH.

Longitudinal relationships between lifestyle risk factors and neurodevelopment in early adolescence.

OBJECTIVE: The goal of this study is to investigate the cross-sectional and longitudinal relationships between clustered lifestyle risk factors (sleep, physical activity, body mass index [BMI], and screen time) and neurodevelopment over the early adolescent period. METHOD: Data from the ABCD Study Data Release 3.0 consisted of 11,878 participants (aged 9-10 years) at baseline and 6,571 participants (aged 11-12 years) at 2-year follow-up. The interrelationships between lifestyle risk factors and brain structure were analyzed using bivariate multiple indicator latent change score models. Using confirmatory factor analysis, a single lifestyle risk factor domain (measured by sleep, physical activity, BMI, and screen time) was shown to fit the data well. Using exploratory and confirmatory factor analysis, seven brain structure domains were extracted and labeled as temporal-parietal, frontotemporal, occipital, orbitofrontal, temporal, cingulate, parietal, and cuneus domains. All bivariate latent change score models accounted for age, sex at birth, race/ethnicity, parental education, and marital status. RESULTS: Higher lifestyle risk was associated with smaller brain volume at baseline. Higher baseline lifestyle risk was also associated with a greater rate of change (i.e., greater decreases) in brain volume for the temporal-parietal, frontotemporal, orbitofrontal, parietal, and cuneus domains. Effects were not reciprocal; baseline brain volume did not predict changes in lifestyle behaviors over time. CONCLUSION: These findings are important for understanding the biological mechanisms underpinning health risk factors and can be used to target interventions and improve brain health during this critical developmental phase. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Is the association between psychological distress and risky alcohol consumption shifting over time? An age-period-cohort analysis of the Australian population.

This study explored age, period, and cohort effects associated with trends in psychological distress and risky alcohol consumption. Data came from 108,536 Australians aged 14-79 years old from birth cohorts between 1925-2005, endorsing past year alcohol use in the 2004-2019 Australian National Drug Strategy Household Surveys. Risky alcohol consumption was split into exceeding weekly national drinking limits (>10 drinks per week) or daily limits (>4 drinks per day). An extended hierarchical age-period-cohort model was used to investigate differential effects on trends in psychological distress. Psychological distress showed an inverse U-shape throughout the lifespan with a peak in distress at age 60. Exceeding weekly alcohol limits was positively related to psychological distress prior to age 40 while exceeding daily alcohol limits remained positively related across the lifespan. There were relatively flat period effects, with no alcohol-related changes in psychological distress across years. Lastly, psychological distress gradually increased across birth cohorts until a notable spike among Australians born from 1980-2005 alongside weakening alcohol-related cohort effects. Overall, the recent increases in psychological distress did not appear to be meaningfully explained by risky alcohol consumption though risky alcohol consumption remained an important factor to consider alongside psychological distress.

The effect of intolerance of uncertainty on anxiety and depression, and their symptom networks, during the COVID-19 pandemic.

Individuals vary in their ability to tolerate uncertainty. High intolerance of uncertainty (the tendency to react negatively to uncertain situations) is a known risk factor for mental health problems. In the current study we examined the degree to which intolerance of uncertainty predicted depression and anxiety symptoms and their interrelations across the first year of the COVID-19 pandemic. We examined these associations across three time points (May 2020 - April 2021) in an international sample of adults (N = 2087, Mean age = 41.13) from three countries (UK, USA, Australia) with varying degrees of COVID-19 risk. We found that individuals with high and moderate levels of intolerance of uncertainty reported reductions in depression and anxiety symptoms over time. However, symptom levels remained significantly elevated compared to individuals with low intolerance of uncertainty. Individuals with low intolerance of uncertainty had low and stable levels of depression and anxiety across the course of the study. Network analyses further revealed that the relationships between depression and anxiety symptoms became stronger over time among individuals with high intolerance of uncertainty and identified that feeling afraid showed the strongest association with intolerance of uncertainty. Our findings are consistent with previous work identifying intolerance of uncertainty as an important risk factor for mental health problems, especially in times marked by actual health, economic and social uncertainty. The results highlight the need to explore ways to foster resilience among individuals who struggle to tolerate uncertainty, as ongoing and future geopolitical, climate and health threats will likely lead to continued exposure to significant uncertainty.

A comprehensive evaluation of the longitudinal association between alcohol consumption and a measure of inflammation: Multiverse and vibration of effects analyses.

BACKGROUND: Moderate alcohol consumption appears to be associated with reduced inflammation. Determining whether this association is robust to common variations in research parameters has wide-reaching implications for our understanding of disease aetiology and public health policy. We aimed to conduct comprehensive multiverse and vibration of effects analyses evaluating the associations between alcohol consumption and a measure of inflammation. METHODS: A secondary analysis of the 1970 British Birth Cohort Study was performed, using data from 1970 through 2016. Measurements of alcohol consumption were taken in early/mid-adulthood (ages 34 and 42), and level of inflammation marker high-sensitivity C-reactive protein (hsCRP) at age 46. Multiverse analyses were applied to comparisons of low-to-moderate consumption and consumption above various international drinking guidelines with an 'abstinent' reference. Research parameters of interest related to: definitions of drinking and reference groups; alcohol consumption measurement year; outcome variable transformation; and breadth of covariate adjustment. After identifying various analytic options within these parameters and running the analysis over each unique option combination, specification curve plots, volcano plots, effect ranges, and variance decomposition metrics were used to assess consistency of results. RESULTS: A total of 3101 individuals were included in the final analyses, with primary analyses limited to those where occasional consumers served as reference. All combinations of research specifications resulted in lower levels of inflammation amongst low-to-moderate consumers compared to occasional consumers (1st percentile effect: -0.21; 99th percentile effect: -0.04). Estimates comparing above-guidelines drinking with occasional consumers were less definitive (1st percentile effect: -0.26; 99th percentile effect: 0.43). CONCLUSIONS: The association between low-to-moderate drinking and lower hsCRP levels is largely robust to common variations in researcher-defined parameters, warranting further research to establish whether this relationship is causal. The association between above-guidelines drinking and hsCRP levels is less definitive.

Social and cognitive vulnerability to COVID-19-related stress in pregnancy: A case-matched-control study of antenatal mental health.

Emerging evidence shows that compared to pre-pandemic norms pregnant women report significant increases in clinical levels of depressive and anxiety symptoms during COVID-19. This pre-registered study examined cognitive and social vulnerability factors for poor mental health in pregnancy during COVID-19. Understanding vulnerability profiles is key to identifying women at risk for deteriorating peripartum mental health. N = 742 pregnant women and N = 742 age and country-matched controls from the COVID-19 Risks Across the Lifespan Study were included. Using a case-match control design allowed us to explore whether the cognitive vulnerability profiles would differ between pregnant and non-pregnant women. The findings showed that COVID-19-related stress was associated with heightened levels of depression and anxiety during pregnancy. Its impact was greatest in women with cognitive (i.e., higher intolerance of uncertainty and tendency to worry) and social (i.e., higher level of self-reported loneliness) vulnerabilities. Importantly, our data show that the mental health impacts of the pandemic were greater in pregnant women compared to women who were not pregnant, especially those with cognitive and social vulnerabilities. The results highlight the urgent need to prioritize mental health care for pregnant women to mitigate the impact of COVID-19-related stress on women's postpartum mental health and their infants' well-being.

Moderate Alcohol Consumption and Depression: A Marginal Structural Model Approach Promoting Causal Inference.

OBJECTIVE: Moderate alcohol consumption is associated with decreased risk for depression, but it remains unclear whether this is a causal relationship or a methodological artifact. To compare the effects of consistent abstinence and occasional, moderate, and above-guideline alcohol consumption throughout early to middle adulthood on depression at age 50, the authors conducted a secondary analysis of the National Longitudinal Survey of Youth 1979 cohort and employed a marginal structural model (MSM) approach. METHODS: Baseline was set at 1994, when individuals were ages 29-37. The MSM incorporated measurements of alcohol consumption in 1994, 2002, and 2006, baseline and time-varying covariates, and repeated measurements with the Center for Epidemiologic Studies Depression Scale-Short Form (CES-D-SF). A total of 5,667 eligible participants provided valid data at baseline, 3,593 of whom provided valid outcome data. The authors used all observed data to predict CES-D-SF means and rates of probable depression for hypothetical trajectories of consistent alcohol consumption. RESULTS: The results approximated J-curve relationships. Specifically, both consistent occasional and consistent moderate drinkers were predicted to have reduced CES-D-SF scores and rates of probable depression at age 50 compared with consistent abstainers (CES-D-SF scores: b=-0.84, 95% CI=-1.47, -0.11; probable depression: odds ratio=0.58, 95% CI=0.36, 0.88 for consistent occasional drinkers vs. abstainers; CES-D-SF scores: b=-1.08, 95% CI=-1.88, -0.20; probable depression: odds ratio=0.59, 95% CI=0.26, 1.13 for consistent moderate drinkers vs. consistent abstainers). Consistent above-guideline drinkers were predicted to have slightly increased risk compared with consistent abstainers, but this was not significant. In sex-stratified analyses, results were similar for females and males. CONCLUSIONS: This study contributes preliminary evidence that associations between moderate alcohol consumption and reduced risk for depression may reflect genuine causal effects. Further research using diverse methodologies that promote causal inference is required.

Social determinants of mental health during a year of the COVID-19 pandemic.

Belonging is a basic human need, with social isolation signaling a threat to biological fitness. Sensitivity to ostracism varies across individuals and the lifespan, peaking in adolescence. Government-imposed restrictions upon social interactions during COVID-19 may therefore be particularly detrimental to young people and those most sensitive to ostracism. Participants (N = 2367; 89.95% female, 11-100 years) from three countries with differing levels of government restrictions (Australia, UK, and USA) were surveyed thrice at three-month intervals (May 2020 - April 2021). Young people, and those living under the tightest government restrictions, reported the worst mental health, with these inequalities in mental health remaining constant throughout the study period. Further dissection of these results revealed that young people high on social rejection sensitivity reported the most mental health problems at the final assessment. These findings help account for the greater impact of enforced social isolation on young people's mental health, and open novel avenues for intervention.

Evaluating the effectiveness of a universal eHealth school-based prevention programme for depression and anxiety, and the moderating role of friendship network characteristics.

BACKGROUND: Lifetime trajectories of mental ill-health are often established during adolescence. Effective interventions to prevent the emergence of mental health problems are needed. In the current study we assessed the efficacy of the cognitive behavioural therapy (CBT)-informed Climate Schools universal eHealth preventive mental health programme, relative to a control. We also explored whether the intervention had differential effects on students with varying degrees of social connectedness. METHOD: We evaluated the efficacy of the Climate Schools mental health programme (19 participating schools; average age at baseline was 13.6) v. a control group (18 participating schools; average age at baseline was 13.5) which formed part of a large cluster randomised controlled trial in Australian schools. Measures of internalising problems, depression and anxiety were collected at baseline, immediately following the intervention and at 6-, 12- and 18-months post intervention. Immediately following the intervention, 2539 students provided data on at least one outcome of interest (2065 students at 18 months post intervention). RESULTS: Compared to controls, we found evidence that the standalone mental health intervention improved knowledge of mental health, however there was no evidence that the intervention improved other mental health outcomes, relative to a control. Student's social connectedness did not influence intervention outcomes. CONCLUSION: These results are consistent with recent findings that universal school-based, CBT-informed, preventive interventions for mental health have limited efficacy in improving symptoms of anxiety and depression when delivered alone. We highlight the potential for combined intervention approaches, and more targeted interventions, to better improve mental health outcomes.

The relationship between alcohol use and dementia in adults aged more than 60 years: a combined analysis of prospective, individual-participant data from 15 international studies.

AIM: To synthesize international findings on the alcohol-dementia relationship, including representation from low- and middle-income countries. METHODS: Individual participant data meta-analysis of 15 prospective epidemiological cohort studies from countries situated in six continents. Cox regression investigated the dementia risk associated with alcohol use in older adults aged over 60 years. Additional analyses assessed the alcohol-dementia relationship in the sample stratified by sex and by continent. Participants included 24 478 community dwelling individuals without a history of dementia at baseline and at least one follow-up dementia assessment. The main outcome measure was all-cause dementia as determined by clinical interview. RESULTS: At baseline, the mean age across studies was 71.8 (standard deviation = 7.5, range = 60-102 years), 14 260 (58.3%) were female and 13 269 (54.2%) were current drinkers. During 151 636 person-years of follow-up, there were 2124 incident cases of dementia (14.0 per 1000 person-years). When compared with abstainers, the risk for dementia was lower in occasional [hazard ratio (HR) = 0.78; 95% confidence interval (CI) = 0.68-0.89], light-moderate (HR = 0.78; 95% CI = 0.70-0.87) and moderate-heavy drinkers (HR = 0.62; 95% CI = 0.51-0.77). There was no evidence of differences between life-time abstainers and former drinkers in terms of dementia risk (HR = 0.98; 95% CI = 0.81-1.18). In dose-response analyses, moderate drinking up to 40 g/day was associated with a lower risk of dementia when compared with lif-time abstaining. Among current drinkers, there was no consistent evidence for differences in terms of dementia risk. Results were similar when the sample was stratified by sex. When analysed at the continent level, there was considerable heterogeneity in the alcohol-dementia relationship. CONCLUSIONS: Abstinence from alcohol appears to be associated with an increased risk for all-cause dementia. Among current drinkers, there appears to be no consistent evidence to suggest that the amount of alcohol consumed in later life is associated with dementia risk.

Harmonizing Ethno-Regionally Diverse Datasets to Advance the Global Epidemiology of Dementia.

Understanding dementia and cognitive impairment is a global effort needing data from multiple sources across diverse ethno-regional groups. Methodological heterogeneity means that these data often require harmonization to make them comparable before analysis. We discuss the benefits and challenges of harmonization, both retrospective and prospective, broadly and with a focus on data types that require particular sorts of approaches, including neuropsychological test scores and neuroimaging data. Throughout our discussion, we illustrate general principles and give examples of specific approaches in the context of contemporary research in dementia and cognitive impairment from around the world.

Investigating the molecular genetic, genomic, brain structural, and brain functional correlates of latent transdiagnostic dimensions of psychopathology across the lifespan: Protocol for a systematic review and meta-analysis of cross-sectional and longitudinal studies in the general population.

Background: Research using latent variable modelling has identified a superordinate general dimension of psychopathology, as well as several specific/lower-order transdiagnostic dimensions (e.g., internalising and externalising) within the meta-structure of psychiatric symptoms. These models can facilitate discovery in genetic and neuroscientific research by providing empirically derived psychiatric phenotypes, offering greater validity and reliability than traditional diagnostic categories. The prospective review outlined in this protocol aims to integrate and assess evidence from research investigating the biological correlates of general psychopathology and specific/lower-order transdiagnostic symptom dimensions. Cross-sectional and longitudinal studies investigating general population samples of any age group or developmental period will be included to capture evidence from across the lifespan. Methods and analysis: MEDLINE, Embase, and PsycINFO databases will be systematically searched for relevant literature. The review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligibility criteria were designed to capture psychiatric genetic (i.e., molecular genetic and genomic) and neuroimaging (i.e., brain structural and brain functional) studies investigating latent transdiagnostic dimension(s) or structural model(s) of psychopathology across any age group. Studies which include or exclude participants based on clinical symptoms, disorders, or relevant risk factors (e.g., history of abuse, neglect, and trauma) will be excluded. Biometric genetic research (e.g., twin and family studies), candidate gene studies, neurophysiology studies, and other non-imaging based neuroscientific studies (e.g., post-mortem studies) will be excluded. Study quality and risk of bias will be assessed using the Joanna Briggs Checklist for Analytical Cross-Sectional Studies, the Joanna Briggs Checklist for Cohort Studies, and the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. Meta-analysis will be conducted if sufficient data is available. Discussion: This protocol outlines the first systematic review to examine evidence from studies investigating the latent structure and underlying biology of psychopathology and to characterise these relationships developmentally across the lifespan. The prospective review will cover a broad range of statistical techniques and models used to investigate latent transdiagnostic dimensions of psychopathology, as well as a numerous genetic and neuroscientific methods. Systematic review registration: [https://www.crd.york.ac.uk/prospero/], identifier[CRD42021262717].

Definition matters: assessment of tolerance to the effects of alcohol in a prospective cohort study of emerging adults.

BACKGROUND AND AIMS: Tolerance to the effects of alcohol is an important element in the diagnosis of alcohol use disorders (AUD); however, there is ongoing debate about its utility in the diagnosis AUD in adolescents and young adults. This study aimed to refine the assessment of tolerance in young adults by testing different definitions of tolerance and their associations with longitudinal AUD outcomes. DESIGN: Prospective cohort study. SETTINGS: Australia. PARTICIPANTS: A contemporary cohort of emerging adults across Australia (n = 565, mean age = 18.9, range = 18-21 at baseline). MEASUREMENTS: Clinician-administered Structured Clinical Interview for DSM-IV Research Version (SCID-IV-RV) assessed for AUD criteria across five interviews, at 6-month intervals over 2.5 years. Tolerance definitions were operationalized using survey-type response (yes/no), clinician judgement (SCID-IV-RV), different initial drinking quantity and percentage increase thresholds and average heavy consumption metrics. AUD persistence was operationalized by the number of times AUD was present across the 2.5-year study period (n = 491), and new-onset AUD was operationalized as any new incidence of AUD during the follow-up period (n = 461). FINDINGS: The (i) SCID-IV-RV clinician judgement [odds ratio (OR) = 2.50, P = 0.005], (ii) an initial drinking quantity threshold of four to five drinks and 50% minimum increase (OR = 2.48, P = 0.007) and (iii) 50% increase only (OR = 2.40, P = 0.005) were the tolerance definitions more strongly associated with any new onset of AUD throughout the four follow-up time-points than other definitions. However, these definitions were not associated with persistent AUD (Ps > 0.05). Average heavy consumption definitions of tolerance were most strongly associated with persistent AUD (OR = 6.66, P = 0.001; OR = 4.65, P = 0.004) but not associated with new-onset AUD (Ps > 0.05). CONCLUSIONS: Initial drink and percentage change thresholds appear to improve the efficacy of change-based tolerance as an indicator for new-onset alcohol use disorder diagnosis in self-report surveys of young adults. When predicting persistent alcohol use disorder, average heavy consumption-based indicators appear to be a better way to measure tolerance than self-reported change-based definitions.

Are there non-linear relationships between alcohol consumption and long-term health?: a systematic review of observational studies employing approaches to improve causal inference.

BACKGROUND: Research has long found 'J-shaped' relationships between alcohol consumption and certain health outcomes, indicating a protective effect of moderate consumption. However, methodological limitations in most studies hinder causal inference. This review aimed to identify all observational studies employing improved approaches to mitigate confounding in characterizing alcohol-long-term health relationships, and to qualitatively synthesize their findings. METHODS: Eligible studies met the above description, were longitudinal (with pre-defined exceptions), discretized alcohol consumption, and were conducted with human populations. MEDLINE, PsycINFO, Embase and SCOPUS were searched in May 2020, yielding 16 published manuscripts reporting on cancer, diabetes, dementia, mental health, cardiovascular health, mortality, HIV seroconversion, and musculoskeletal health. Risk of bias of cohort studies was evaluated using the Newcastle-Ottawa Scale, and a recently developed tool was used for Mendelian Randomization studies. RESULTS: A variety of functional forms were found, including reverse J/J-shaped relationships for prostate cancer and related mortality, dementia risk, mental health, and certain lipids. However, most outcomes were only evaluated by a single study, and few studies provided information on the role of alcohol consumption pattern. CONCLUSIONS: More research employing enhanced causal inference methods is urgently required to accurately characterize alcohol-long-term health relationships. Those studies that have been conducted find a variety of linear and non-linear functional forms, with results tending to be discrepant even within specific health outcomes. TRIAL REGISTRATION: PROSPERO registration number CRD42020185861.