Data-Driven Simulations to Assess the Impact of Study Imperfections in Time-to-Event Analyses.

Quantitative bias analysis (QBA) permits assessment of the expected impact of various imperfections of the available data on the results and conclusions of a particular real-world study. This article extends QBA methodology to multivariable time-to-event analyses with right-censored endpoints, possibly including time-varying exposures or covariates. The proposed approach employs data-driven simulations, which preserve important features of the data at hand while offering flexibility in controlling the parameters and assumptions that may affect the results. First, the steps required to perform data-driven simulations are described, and then two examples of real-world time-to-event analyses illustrate their implementation and the insights they may offer. The first example focuses on the omission of an important time-invariant predictor of the outcome in a prognostic study of cancer mortality, and permits separating the expected impact of confounding bias from non-collapsibility. The second example assesses how imprecise timing of an interval-censored event - ascertained only at sparse times of clinic visits - affects its estimated association with a time-varying drug exposure. The simulation results also provide a basis for comparing the performance of two alternative strategies for imputing the unknown event times in this setting. The R scripts that permit the reproduction of our examples are provided.

Causal Inference Challenges in the Relationship Between Social Determinants and Cardiovascular Outcomes.

The effects of social determinants on cardiovascular outcomes are frequently estimated in epidemiologic analyses, but the profound causal and statistical challenges of this research program are not widely discussed. Here, we carefully review definitions and measures for social determinants of cardiovascular health and then examine the various assumptions required for valid causal inference in multivariable analyses of observational data, such as what one would typically encounter in cohorts, population surveys, health care databases, and vital statistics databases. We explain the necessity of the "well-defined exposure" and show how this goal relates to the "consistency assumption" that is necessary for valid causal inference. Well-defined exposure is especially challenging for social determinants of health because they are seldom simple atomistic interventions that are easily conceptualized and measured. We then review threats to valid inference that arise from confounding, selection bias, information bias, and positivity violations. Other causal considerations are reviewed and explained, such as correct model specification, absence of immortal time, and avoidance of the "Table 2 Fallacy," and their application to social determinants of cardiovascular outcomes are discussed. Fruitful approaches, including focusing on policy interventions and the "target trial" frameworks are proposed and provide a pathway for a more efficacious research program that can more reliably improve population health. Valid causal inference in this setting is quite challenging, but-with clever design and thoughtful analysis-the important role of social factors in patterning cardiovascular outcomes can be quantified and reported.

Differential Participation, a Potential Cause of Spurious Associations in Observational Cohorts in Environmental Epidemiology.

Differential participation in observational cohorts may lead to biased or even reversed estimates. In this article, we describe the potential for differential participation in cohorts studying the etiologic effects of long-term environmental exposures. Such cohorts are prone to differential participation because only those who survived until the start of follow-up and were healthy enough before enrollment will participate, and many environmental exposures are prevalent in the target population and connected to participation via factors such as geography or frailty. The relatively modest effect sizes of most environmental exposures also make any bias induced by differential participation particularly important to understand and account for. We discuss key points to consider for evaluating differential participation and use causal graphs to describe two example mechanisms through which differential participation can occur in health studies of long-term environmental exposures. We use a real-life example, the Canadian Community Health Survey cohort, to illustrate the non-negligible bias due to differential participation. We also demonstrate that implementing a simple washout period may reduce the bias and recover more valid results if the effect of interest is constant over time. Furthermore, we implement simulation scenarios to confirm the plausibility of the two mechanisms causing bias and the utility of the washout method. Since the existence of differential participation can be difficult to diagnose with traditional analytical approaches that calculate a summary effect estimate, we encourage researchers to systematically investigate the presence of time-varying effect estimates and potential spurious patterns (especially in initial periods in the setting of differential participation).

Impact of Decarceration Plus Alcohol, Substance Use, and Mental Health Screening on Life Expectancies of Black Sexual Minority Men and Black Transgender Women Living With HIV in the United States: A Simulation Study Based on HPTN 061.

BACKGROUND: Given the disproportionate rates of incarceration and lower life expectancy (LE) among Black sexual minority men (BSMM) and Black transgender women (BTW) with HIV, we modeled the impact of decarceration and screening for psychiatric conditions and substance use on LE of US BSMM/BTW with HIV. METHODS: We augmented a microsimulation model previously validated to predict LE and leading causes of death in the US with estimates from the HPTN 061 cohort and the Veteran's Aging Cohort Studies. We estimated independent associations among psychiatric and substance use disorders, to simulate the influence of treatment of one condition on improvement on others. We used this augmented simulation to estimate LE for BSMM/BTW with HIV with a history of incarceration under alternative policies of decarceration (ie, reducing the fraction exposed to incarceration), screening for psychiatric conditions and substance use, or both. RESULTS: Baseline LE was 61.3 years. Reducing incarceration by 25%, 33%, 50%, and 100% increased LE by 0.29, 0.31, 0.53, and 1.08 years, respectively, versus no reductions in incarceration. When reducing incarceration by 33% and implementing screening for alcohol, tobacco, substance use, and depression, in which a positive screen triggers diagnostic assessment for all psychiatric and substance use conditions and linkage to treatment, LE increased by 1.52 years compared with no screening or decarceration. DISCUSSION: LE among BSMM/BTW with HIV is short compared with other people with HIV. Reducing incarceration and improving screening and treatment of psychiatric conditions and substance use could substantially increase LE in this population.

CanCHD Study of Hematopoietic Cancers in Children With and Without Genetic Syndromes.

BACKGROUND: Individuals with genetic syndromes can manifest both congenital heart disease (CHD) and cancer attributable to possible common underlying pathways. To date, reliable risk estimates of hematopoietic cancer (HC) among children with CHD based on large population-based data remain scant. This study sought to quantify the risk of HC by the presence of genetic syndrome among children with CHD. METHODS AND RESULTS: Data sources were the Canadian CHD database, a nationwide database on CHD (1999-2017), and the CCR (Canadian Cancer Registry). Standardized incidence ratios were calculated for comparing HC incidences in children with CHD with the general pediatric population. A modified Kaplan-Meier curve was used to estimate the cumulative incidence of HC with death as a competing risk. A total of 143 794 children (aged 0-17 years) with CHD were followed up from birth to age 18 years for 1 314 603 person-years. Of them, 8.6% had genetic syndromes, and 898 HC cases were observed. Children with known syndromes had a substantially higher risk of incident HC than the general pediatric population (standardized incidence ratio, 13.4 [95% CI, 11.7-15.1]). The cumulative incidence of HC was 2.44% (95% CI, 2.11-2.76) among children with a syndrome and 0.79% (95% CI, 0.72-0.87) among children without a syndrome. Acute myeloid leukemia had a higher cumulative incidence during early childhood than acute lymphoblastic leukemia. CONCLUSIONS: This is the first large population-based analysis documenting that known genetic syndromes in children with CHD are a significant predictor of HC. The finding could be essential in informing risk-stratified policy recommendations for cancer surveillance in children with CHD.

Uncovering the impact of COVID-19 on the place of death of cancer patients in South America.

The COVID-19 pandemic has significantly impacted healthcare systems worldwide, especially on the management of chronic diseases such as cancer. This study explores the effects of COVID-19 on cancer mortality trends in Brazil, Chile, and Peru. The monthly age-standardized mortality rates in different places of death (hospital/clinic or home) were estimated using vital statistics and death certificate databases. An interrupted time series analysis was performed for each country, using the date of lockdown implementation as the intervention point. Overall cancer mortality rates reduced after the implementation of pandemic restrictions, with a significant decrease in Brazil. In total, 75.3%, 55.4%, and 45.7% of deaths in Brazil, Peru, and Chile, respectively, occurred in hospitals. After lockdowns were implemented, at-home deaths increased in all countries, and in-hospital deaths correspondingly decreased only in Chile. Our results suggest that COVID-19 has significantly affected rates of cancer mortality and place of death in Latin America.

Associations between police harassment and distrust in and reduced access to healthcare among Black sexual minority men: A longitudinal analysis of HPTN 061.

OBJECTIVE: Evaluate associations between racialized and homophobia-based police harassment (RHBPH) and healthcare distrust and utilization among Black Sexual Minority Men (BSMM). METHODS: We utilized data from a longitudinal cohort study from HIV Prevention Trials Network (HPTN) 061 with baseline, six and 12 month follow-up assessments. Using multivariable analysis, we evaluated associations between RHBPH and healthcare distrust and utilization reported at the 6 and 12 month visits. RESULTS: Of 1553 BSMM present at baseline, 1160 were available at six-month follow-up. In multivariable analysis, increasing frequency of RHBPH was associated with increasing levels of distrust in healthcare providers (aOR 1.31, 95% CI: 1.00, 1.74) and missing 50% or more of healthcare visits at six-month follow-up (aOR 1.93, 95% CI: 1.09, 3.43). CONCLUSIONS: Recent experiences of RHBPH are associated with reduced trust in and access to healthcare among BSMM, with more frequent RHBPH associated with greater vulnerability.

Pregnancy, fetal, and neonatal outcomes after a first booster dose of covid-19 vaccine during pregnancy in Ontario, Canada: population based, retrospective cohort study.

Objective: To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had completed both doses of primary covid-19 vaccine series before pregnancy. Design: Population based, retrospective cohort study. Setting: Ontario, Canada, from 20 December 2021 to 31 August 2022. Participants: Individuals were included if they were pregnant with an expected date of delivery from 20 December 2021 (start date of third dose eligibility for everyone ≥18 years) to 31 August 2022, who had completed the two doses of primary covid-19 messenger RNA vaccine series before pregnancy, and became eligible for a third dose (≥six months since dose two) before the end of pregnancy. Main outcome measures: Pregnancy outcomes included hypertensive disorders of pregnancy, placental abruption, caesarean delivery, chorioamnionitis, and postpartum hemorrhage. Fetal and neonatal outcomes included stillbirth, preterm birth, admission to neonatal intensive care unit for >24 h, newborn 5 min Apgar score <7, and small-for-gestational age infant (<10th percentile). We estimated hazard ratios and 95% confidence intervals for study outcomes, treating dose three as a time varying exposure and adjusting for confounding using inverse probability weighting. Results: Among 32 689 births, 18 491 (56.6%) were born to individuals who received a third covid-19 dose during pregnancy. Compared with eligible individuals who did not receive a third dose during pregnancy, no increased risks were associated with receiving a third covid-19 vaccine dose during pregnancy for placental abruption (adjusted hazard ratio 0.84 (95% confidence interval 0.70 to 1.02)), chorioamnionitis (0.67 (0.49 to 0.90)), postpartum haemorrhage (1.01 (0.89 to 1.16)), caesarean delivery (0.90 (0.87 to 0.94)), stillbirth (0.56 (0.39 to 0.81)), preterm birth (0.91 (0.84 to 0.99)), neonatal intensive care unit admission (0.96 (0.90 to 1.03)), 5 min Apgar score<7 (0.96 (0.82 to 1.14)), or small-for-gestational age infant (0.86 (0.79 to 0.93)). Conclusion: Receipt of a third covid-19 vaccine dose during pregnancy was not associated with an increased risk of adverse pregnancy, fetal, or neonatal outcomes. These findings can help to inform evidence based decision making about the risks and benefits of covid-19 booster doses during pregnancy.

Investigating the Shape and Strength of the Relationship Between Maternal Weight Gain and Gestational Age at Delivery in Twin and Singleton Pregnancies.

Both inadequate and excessive maternal weight gain are correlated with preterm delivery in singleton pregnancies, yet this relationship has not been adequately studied in twins. We investigated the relationship between time-varying maternal weight gain and gestational age at delivery in twin pregnancies and compared it with that in singletons delivered in the same study population. We used serial weight measurements abstracted from charts for twin and singleton pregnancies delivered during 1998-2013 in Pittsburgh, Pennsylvania. Our exposure was time-varying weight gain z score, calculated using gestational age-standardized and prepregnancy body mass index-stratified twin- and singleton-specific charts, and our outcome was gestational age at delivery. Our analyses used a flexible extension of the Cox proportional hazards model that allowed for nonlinear and time-dependent effects. We found a U-shaped relationship between weight gain z score and gestational age at delivery among twin pregnancies (lowest hazard of delivery observed at z score = 1.2), which we attributed to increased hazard of early preterm spontaneous delivery among pregnancies with low weight gain and increased hazard of late preterm delivery without labor among pregnancies with high weight gain. Our findings may be useful for updating provisional guidelines for maternal weight gain in twin pregnancies.

Reevaluating the protective effect of smoking on preeclampsia risk through the lens of bias.

Preeclampsia is a hypertensive disorder that is usually diagnosed after 20 weeks' gestation. Despite the deleterious effect of smoking on cardiovascular disease, it has been frequently reported that smoking has a protective effect on preeclampsia risk and biological explanations have been proposed. However, in this manuscript, we present multiple sources of bias that could explain this association. First, key concepts in epidemiology are reviewed: confounder, collider, and mediator. Then, we describe how eligibility criteria, losses of women potentially at risk, misclassification, or performing incorrect adjustments can create bias. We provide examples to show that strategies to control for confounders may fail when they are applied to variables that are not confounders. Finally, we outline potential approaches to manage this controversial effect. We conclude that there is probably no single epidemiological explanation for this counterintuitive association.

Structural determinants explain caries differences among preschool children in Chile's Metropolitan Region.

OBJECTIVE: To estimate the association between Social Determinants of Health (structural and intermediate) and caries indicators in Chile's Metropolitan Region preschool children. METHODS: A multilevel cross-sectional study of Social Determinants of Health (SDH) and caries in children aged 1 to 6 years in Chile's Metropolitan Region was conducted in 2014-2015, with three levels: district, school and child. Caries were assessed by the dmft-index and the prevalence of untreated caries. The structural determinants analyzed were Community Human Development Index (CHDI), urban/rural location, school type, caregiver's education and family income. Poisson multilevel regression models were fit. RESULTS: The sample size was 2,275 children from 40 schools in 13 districts. While the highest CHDI district had an untreated caries prevalence of 17.1% (12.3-22.7%), in the most disadvantaged district it was 53.9% (95% CI 46.0-61.6%). As family income increased, the probability of untreated caries prevalence decreased (PR = 0.9 95% CI 0.8-1.0). Rural districts had an average dmft-index of 7.3 (95% CI 7.2-7.4), while in urban districts, it was 4.4 (95% CI 4.3-4.5). Higher probabilities of untreated caries prevalence (PR = 3.0 95% CI 2.3-3.9) were observed in rural children. Greater probabilities of untreated caries prevalence (PR = 1.3 95% CI 1.1-1.6) and prevalence of caries experience (PR = 1.3 95% CI 1.1-1.5) were observed in children whose caregivers had a secondary educational level. CONCLUSIONS: A strong association was observed between the social determinants of health, specifically the structural ones, and the caries indicators studied in children of the Metropolitan Region of Chile. There were notable differences in caries between districts according to social advantage. Rurality and caregiver's education were the most consistent predictors.

Using Parametric g-Computation to Estimate the Effect of Long-Term Exposure to Air Pollution on Mortality Risk and Simulate the Benefits of Hypothetical Policies: The Canadian Community Health Survey Cohort (2005 to 2015).

BACKGROUND: Numerous epidemiological studies have documented the adverse health impact of long-term exposure to fine particulate matter [particulate matter ≤2.5µm in aerodynamic diameter (PM2.5)] on mortality even at relatively low levels. However, methodological challenges remain to consider potential regulatory intervention's complexity and provide actionable evidence on the predicted benefits of interventions. We propose the parametric g-computation as an alternative analytical approach to such challenges. METHOD: We applied the parametric g-computation to estimate the cumulative risks of nonaccidental death under different hypothetical intervention strategies targeting long-term exposure to PM2.5 in the Canadian Community Health Survey cohort from 2005 to 2015. On both relative and absolute scales, we explored the benefits of hypothetical intervention strategies compared with the natural course that a) set the simulated exposure value at each follow-up year to a threshold value if exposure was above the threshold (8.8 µg/m3, 7.04 µg/m3, 5 µg/m3, and 4 µg/m3), and b) reduced the simulated exposure value by a percentage (5% and 10%) at each follow-up year. We used the 3-y average PM2.5 concentration with 1-y lag at the postal code of respondents' annual mailing addresses as their long-term exposure to PM2.5. We considered baseline and time-varying confounders, including demographics, behavior characteristics, income level, and neighborhood socioeconomic status. We also included the R syntax for reproducibility and replication. RESULTS: All hypothetical intervention strategies explored led to lower 11-y cumulative mortality risks than the estimated value under the natural course without intervention, with the smallest reduction of 0.20 per 1,000 participants (95% CI: 0.06, 0.34) under the threshold of 8.8 µg/m3, and the largest reduction of 3.40 per 1,000 participants (95% CI: -0.23, 7.03) under the relative reduction of 10% per interval. The reductions in cumulative risk, or numbers of deaths that would have been prevented if the intervention was employed instead of maintaining the status quo, increased over time but flattened toward the end of the follow-up period. Estimates among those ≥65 years of age were greater with a similar pattern. Our estimates were robust to different model specifications. DISCUSSION: We found evidence that any intervention further reducing the long-term exposure to PM2.5 would reduce the cumulative mortality risk, with greater benefits in the older population, even in a population already exposed to low levels of ambient PM2.5. The parametric g-computation used in this study provides flexibilities in simulating real-world interventions, accommodates time-varying exposure and confounders, and estimates adjusted survival curves with clearer interpretation and more information than a single hazard ratio, making it a valuable analytical alternative in air pollution epidemiological research. https://doi.org/10.1289/EHP11095.

Mediation of the Effect of Incarceration on Selling Sex Among Black Sexual Minority Men and Black Transgender Women in the HPTN 061 Study.

Incarceration among Black sexual minority men and Black transgender women (BSMM/BTW) is disproportionately high in the United States. Limited research has documented the disruptive effect of incarceration on sexual networks and sexual partnership exchange among BSMM/BTW. We estimate the influence of incarceration on selling sex and mediating pathways among 1169 BSMM/BTW enrolled in the HIV Prevention Trials Network (HPTN) 061 cohort to assess this relationship. Mediators investigated were social support, violence, illicit drug use, and distress due to experienced racism and homophobia. During the 6 months following baseline, 14% of the cohort was incarcerated, including 24% of BTW. After adjustment, recent incarceration was associated with 1.57 (95% CI 1.02, 2.42) times the risk of subsequently selling sex. The hypothesized mediators together explained 25% of the relationship, with an indirect effect risk ratio of 1.09 (95% CI 0.97, 1.24). Our results document an association and call for more research investigating mechanisms.

The burden of low back pain and its association with socio-demographic variables in the Middle East and North Africa region, 1990-2019.

BACKGROUND: Low back pain (LBP) is the most common musculoskeletal disorder globally. Providing region- and national-specific information on the burden of low back pain is critical for local healthcare policy makers. The present study aimed to report, compare, and contextualize the prevalence, incidence and years lived with disability (YLDs) of low back pain in the Middle East and North Africa (MENA) region by age, sex and sociodemographic index (SDI), from 1990 to 2019. METHODS: Publicly available data were obtained from the Global Burden of Disease (GBD) study 2019. The burden of LBP was reported for the 21 countries located in the MENA region, from 1990 to 2019. All estimates were reported as counts and age-standardised rates per 100,000 population, together with their corresponding 95% uncertainty intervals (UIs). RESULTS: In 2019, the age-standardised point prevalence and incidence rate per 100,000 in MENA were 7668.2 (95% UI 6798.0 to 8363.3) and 3215.9 (95%CI 2838.8 to 3638.3), which were 5.8% (4.3 to 7.4) and 4.4% (3.4 to 5.5) lower than in 1990, respectively. Furthermore, the regional age-standardised YLD rate in 2019 was 862.0 (605.5 to 1153.3) per 100,000, which was 6.0% (4.2 to 7.7) lower than in 1990. In 2019, Turkey [953.6 (671.3 to 1283.5)] and Lebanon [727.2 (511.5 to 966.0)] had the highest and lowest age-standardised YLD rates, respectively. There was no country in the MENA region that showed increases in the age-standardised prevalence, incidence or YLD rates of LBP over the measurement period. Furthermore, in 2019 the number of prevalent cases were highest in the 35-39 age group, with males having a higher number of cases in all age groups. In addition, the age-standardised YLD rates for males in the MENA region were higher than the global estimates in almost all age groups, in both 1990 and 2019. Furthermore, the burden of LBP was not associated with the level of socio-economic development during the measurement period. CONCLUSION: The burden attributable to LBP in the MENA region decreased slightly from 1990 to 2019. Furthermore, the burden among males was higher than the global average. Consequently, more integrated healthcare interventions are needed to more effectively alleviate the burden of low back pain in this region.

The burden of lower respiratory infections and their underlying etiologies in the Middle East and North Africa region, 1990-2019: results from the Global Burden of Disease Study 2019.

BACKGROUND: Lower respiratory infections (LRIs) cause substantial mortality and morbidity. The present study reported and analysed the burden of LRIs in the Middle East and North Africa (MENA) region between 1990 and 2019, by age, sex, etiology, and socio-demographic index (SDI). METHODS: The data used in this study were sourced from the Global Burden of Disease (GBD) study 2019. The annual incidence, deaths, and disability-adjusted life-years (DALYs) due to LRIs were presented as counts and age-standardised rates per 100,000 population, along with their 95% uncertainty intervals (UIs). The average annual percent changes (AAPC) in the age-standardised incidence, death and DALYs rates were calculated using Joinpoint software and correlations (Pearson's correlation coefficient) between the AAPCs and SDIs were calculated using Stata software. RESULTS: In 2019, there were 34.1 million (95% UI 31.7-36.8) incident cases of LRIs in MENA, with an age-standardised rate of 6510.2 (95% UI 6063.6-6997.8) per 100,000 population. The number of regional DALYs was 4.7 million (95% UI 3.9-5.4), with an age-standardised rate of 888.5 (95% UI 761.1-1019.9) per 100,000 population, which has decreased since 1990. Furthermore, Egypt [8150.8 (95% UI 7535.8-8783.5)] and Afghanistan [61.9 (95% UI 52.1-72.6)] had the highest age-standardised incidence and death rates, respectively. In 2019, the regional incidence and DALY rates were highest in the 1-4 age group, in both females and males. In terms of deaths, pneumococcus and H. influenza type B were the most and least common types of LRIs, respectively. From 1990 to 2019, the burden of LRIs generally decreased with increasing SDI. There were significant positive correlations between SDI and the AAPCs for the age-standardised incidence, death and DALY rates (p < 0.05). Over the 1990-2019 period, the regional incidence, deaths and DALYs attributable to LRIs decreased with AAPCs of - 1.19% (- 1.25 to - 1.13), - 2.47% (- 2.65 to - 2.28) and - 4.21% (- 4.43 to - 3.99), respectively. CONCLUSIONS: The LRI-associated burden in the MENA region decreased between 1990 and 2019. SDI had a significant positive correlation with the AAPC and pneumococcus was the most common underlying cause of LRIs. Afghanistan, Yemen and Egypt had the largest burdens in 2019. Further studies are needed to investigate the effectiveness of healthcare interventions and programs to control LRIs and their risk factors.

A brief primer on conducting regression-based causal mediation analysis.

OBJECTIVE: We provide an overview of regression-based causal mediation analysis in the field of traumatic stress and guidance on how to conduct mediation analysis using our R package regmedint. METHOD: We discuss the causal interpretations of the quantities that causal mediation analysis estimates, including total, direct, and indirect effects, especially when the interaction between exposure and mediator is permitted. We discuss the assumptions that must be fulfilled for mediation analyses to validly estimate these causal quantities, discuss suitable study designs for assessing mediation, and describe how causal mediation analysis differs from traditional methods of mediation. To illustrate how to conduct and interpret mediation analysis using our R package regmedint, we use data from a published longitudinal study to assess the extent to which children's externalizing behavior mediates changes in parental negative feelings during the COVID-19 lockdown. We compare the results to those obtained using traditional methods, thus illustrating the importance of accounting for exposure-mediator interaction when an interaction may be present. RESULTS: When the exposure and the mediator interact, traditional methods can provide estimates of direct and indirect effects that differ from those provided by more flexible causal mediation methods. When the exposure and the mediator do not interact, traditional methods and causal mediation method may estimate similar direct and indirect effects depending on the model specification. CONCLUSIONS: In contrast to traditional methods of mediation analysis, regression-based causal mediation methods seek to estimate specific interventional quantities, not mere associations, and the causal methods explicitly allow for exposure-mediator interactions. We recommend using these methods by default rather than using more restrictive traditional methods. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Multilevel modelling for measuring interaction of effects between multiple categorical variables: An illustrative application using risk factors for preeclampsia.

BACKGROUND: Measuring multiple and higher-order interaction effects between multiple categorical variables proves challenging. OBJECTIVES: To illustrate a multilevel modelling approach to studying complex interactions. METHODS: We apply a two-level random-intercept linear regression to a binary outcome for individuals (level-1) nested within strata (level-2) defined by all observed combinations of multiple categorical exposure variables. As a pedagogic application, we analyse 36 strata defined by five risk factors of preeclampsia (parity, previous preeclampsia, chronic hypertension, multiple pregnancies, body mass index category) among 652,603 women in the Swedish Medical Birth Registry between 2002 and 2010. RESULTS: The absolute risk of preeclampsia was 4% but was predicted to vary from 1% to 44% across strata. The stratum discriminatory accuracy was 30% according to the variance partition coefficient (VPC) and 0.73 according to the area under the receiver operating characteristic curve (AUC). While the risk heterogeneity across strata was primarily due to the main effects of the categories defining the strata, 5% of the variation was attributable to their two- and higher-way interaction effects. One stratum presented a positive interaction, and two strata presented negative interaction. CONCLUSIONS: Multilevel modelling is an innovative tool for identifying and analysing higher-order interaction effects. Further work is needed to explore how this approach can best be applied to making causal inferences.

The Burden of Gout and Its Attributable Risk Factors in the Middle East and North Africa Region, 1990 to 2019.

OBJECTIVE: This study reported the burden of gout and its attributable risk factors in the Middle East and North Africa (MENA) region between 1990 and 2019 by age, sex, and sociodemographic index (SDI). METHODS: Data on the prevalence, incidence, and years lived with disability (YLD) due to gout were obtained from the Global Burden of Disease 2019 study for the 21 countries in the MENA region, from 1990 to 2019. RESULTS: In 2019, the regional age-standardized point prevalence and annual incidence rates of gout were 509.1 and 97.7 per 100,000 population, which represent a 12% and 11.1% increase since 1990, respectively. Moreover, in 2019 the regional age-standardized YLD rate was 15.8 per 100,000 population, an 11.7% increase since 1990. In 2019, Qatar and Afghanistan had the highest and lowest age-standardized YLD rates, respectively. Regionally, the age-standardized point prevalence of gout increased with age up to the oldest age group, and it was more prevalent among males in all age groups. In addition, there was an overall positive association between SDI and the burden of gout between 1990 and 2019. In 2019, high BMI (46.1%) was the largest contributor to the burden of gout in the MENA region. CONCLUSION: There were large intercountry variations in the burden of gout, but in general, it has increased in MENA over the last 3 decades. This increase is in line with the global trends of gout. However, the age-standardized YLD rate change was higher in MENA than at the global level.