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PurposeSocial policies are important determinants of population health but may have varying effects on subgroups of people. Evaluating heterogeneous treatment effects (HTEs) of social policies is critical to determine how social policies will affect health inequities. Methods for evaluating HTEs are not standardized. Little is known about how often and by what methods HTEs are assessed in social policy and health research.MethodsA sample of 55 articles from 2019 on the health effects of social policies were evaluated for frequency of reporting HTEs; for what subgroupings HTEs were reported; frequency of a priori specification of intent to assess HTEs; and methods used for assessing HTEs.ResultsA total of 24 (44%) studies described some form of HTE assessment, including by age, gender, education, race/ethnicity, and/or geography. Among studies assessing HTEs, 63% specified HTE assessment a priori, and most (71%) used descriptive methods such as stratification; 21% used statistical tests (e.g., interaction terms in a regression); and no studies used data-driven algorithms.ConclusionsAlthough understanding HTEs could enhance policy and practice-based efforts to reduce inequities, it is not routine research practice. Increased evaluation of HTEs across relevant subgroups is needed.

Emerging adults (18–25 years), particularly racially/ethnically diverse and sexual and gender minority populations, may experience loneliness following major life transitions. How loneliness relates to health and health disparities during this developmental period is not well understood. We examine associations of loneliness with physical (self-rated health), behavioral (alcohol/marijuana consequences; nicotine dependence), and health behavior outcomes (weekday and weekend sleep; trouble sleeping), and investigate moderating effects by sex, race/ethnicity, and sexual/gender minority (SGM) status. Adjusted models using cross-sectional data from 2,534 emerging adults, predominantly in California, examined associations between loneliness and each outcome and tested interactions of loneliness with sex, race/ethnicity, and SGM status. Higher loneliness was significantly associated with worse self-rated health, higher marijuana consequences, less weekday sleep, and greater odds of feeling bothered by trouble sleeping. None of the interactions were significant. Findings suggest that interventions to reduce loneliness may help promote healthy development among emerging adults across subgroups. Supplementary Information The online version contains supplementary material available at 10.1007/s10865-021-00267-1.

Background and Objectives: The average treatment effect estimate from a randomized controlled trial (RCT) may not be valid for deciding what treatment is best for individual patients with specific characteristics. Characteristics may include contextual factors related to the person (e.g. age), disease (e.g. disease duration), or environmental (e.g. healthcare system). However, individual RCTs rarely report results stratified by potentially important contextual factors in a consistent manner. In this study we will summarize existing guidance from key organizations and other research initiatives, and subsequently demonstrate how subgroup results from RCTs can be presented in a consistent manner that enables future evidence synthesis. Study Design and Setting: We will use a tutorial-type approach to explain and demonstrate the recommended presentation of subgroup results from RCTs. In part 1, we will systematically review papers and official documents. Relevant guidance will be identified via a broad search strategy, including searching MEDLINE (via PubMed) and Web of Science, reviewing official websites of FDA, EMA, ICH, Equator Network etc., ‘asking around’, and snowball methods. Recommendations will be extracted and summarized. In part 2, we will demonstrate the recommendations in practice. We will use data from four previously published RCTs of rheumatic and musculoskeletal conditions from the Parker Institute, Bispebjerg and Frederiksberg Hospital, Denmark. For each RCT, we will reanalyze the data by stratifying according to proposed potential candidates of effect modifying contextual factors and apply the reporting guidance described in part 1. Dissemination and perspectives: This study will be disseminated in a peer-reviewed publication and conference presentations. It is anticipated that this tutorial can guide researchers in reporting trial results stratified by effect modifying contextual factors in a consistent manner, allowing for investigation of subgroup effects in future meta-analyses, potentially leading to more patient-specific evidence-based management of patients with rheumatic conditions.

Evidence on the potential interactive effects of heat and ambient air pollution on cause-specific mortality is inconclusive and limited to selected locations., Masna Rai, Massimo Stafoggia, Francesca K. de’ Donato, Sofia Zafeiratou, Liliana Vazquez Fernandez, Siqi Zhang, Klea Katsouyanni, Evangelia Samoli, Shilpa Rao, Antonio Gasparrini, Pierre Masselot, and Alexandra Schneider were supported by the European Union’s Horizon 2020 Project Exhaustion (Grant ID: 820655). Joana Madureira was supported by the Fundação para a Ciência e a Tecnologia (FCT) (Grant SFRH/BPD/115112/2016).

Mind My Mind (MMM) cognitive behavioral therapy (CBT) manualized treatment is effective in the management of common emotional and behavioral mental health problems in youth, yet not all individuals respond satisfactorily to treatment. This study explored potential effect modifiers, i.e., baseline factors associated with a differential treatment effect. We conducted secondary effect modifier analyses with MMM trial data, which involved randomization of 396 youths aged 6–16 years to either MMM CBT treatment (9–13 sessions) or management as usual in local community settings. We examined sociodemographic- (sex, age, family composition, ethnicity, parental education, and income) and clinical variables (mental disorders and duration of mental health problems) as potential effect modifiers of the a) change in parent-rated impact of mental health problems measured by the Strengths and Difficulties Questionnaire (SDQ) or b) response (reduction of ≥1 on SDQ-impact). In intention-to-treat analyses, superior treatment (net) benefits from the MMM intervention were found among youths who met criteria for any mental disorder at baseline (-1.25 [95%CI: -1.67;-0.82]) compared to youths that did not meet diagnostic criteria (-0.22 [95%CI:-1.09;0.65]). Comorbidity vs no comorbidity (-1.84 [95%CI:-2.58;-1.10] vs -0.72 [95%CI:-1.15;-0.29]) and longer duration of untreated mental health problems, i.e., more vs less than 6 months (-1.16 [95%CI:-1.55;-0.78] vs 0.43 [95%CI:-1.01;1.86]) were also associated with superior treatment benefits. The sociodemographic factors were not associated with differential treatment effects in the intention-to-treat analyses. These findings suggest that community-based programs like the MMM are well-suited for youths with substantial mental health problems. Clinical Trials Identifier: NCT03535805 Mind My Mind (MMM) cognitive behavioral therapy (CBT) manualized treatment is effective in the management of common emotional and behavioral mental health problems in youth, yet not all individuals respond satisfactorily to treatment. This study explored potential effect modifiers, i.e., baseline factors associated with a differential treatment effect. We conducted secondary effect modifier analyses with MMM trial data, which involved randomization of 396 youths aged 6-16 years to either MMM CBT treatment (9-13 sessions) or management as usual in local community settings. We examined sociodemographic- (sex, age, family composition, ethnicity, parental education, and income) and clinical variables (mental disorders and duration of mental health problems) as potential effect modifiers of the a) change in parent-rated impact of mental health problems measured by the Strengths and Difficulties Questionnaire (SDQ) or b) response (reduction of ≥1 on SDQ-impact). In intention-to-treat analyses, superior treatment (net) benefits from the MMM intervention were found among youths who met criteria for any mental disorder at baseline (-1.25 [95%CI: -1.67;-0.82]) compared to youths that did not meet diagnostic criteria (-0.22 [95%CI:-1.09;0.65]). Comorbidity vs no comorbidity (-1.84 [95%CI:-2.58;-1.10] vs -0.72 [95%CI:-1.15;-0.29]) and longer duration of untreated mental health problems, i.e., more vs less than 6 months (-1.16 [95%CI:-1.55;-0.78] vs 0.43 [95%CI:-1.01;1.86]) were also associated with superior treatment benefits. The sociodemographic factors were not associated with differential treatment effects in the intention-to-treat analyses. These findings suggest that community-based programs like the MMM are well-suited for youths with substantial mental health problems. Clinical Trials Identifier: NCT03535805.

Background: During the COVID-19 pandemic, several illnesses were reduced. In Japan, heat-related illnesses were reduced by 22% compared to pre-pandemic period. However, it is uncertain as to what has led to this reduction. Here, we model the association of maximum temperature and heat-related illnesses in the 47 Japanese prefectures. We specifically examined how the exposure and lag associations varied before and during the pandemic. Methods: We obtained the summer-specific, daily heat-related illness ambulance transport (HIAT), exposure variable (maximum temperature) and covariate data from relevant data sources. We utilized a stratified (pre-pandemic and pandemic), two-stage approach. In each stratified group, we estimated the 1) prefecture-level association using a quasi-Poisson regression coupled with a distributed lag non-linear model, which was 2) pooled using a random-effects meta-analysis. The difference between pooled pre-pandemic and pandemic associations was examined across the exposure and the lag dimensions. Results: A total of 321,655 HIAT cases was recorded in Japan from 2016 to 2020. We found an overall reduction of heat-related risks for HIAT during the pandemic, with a wide range of reduction (10.85 to 57.47%) in the HIAT risk, across exposure levels ranging from 21.69 °C to 36.31 °C. On the contrary, we found an increment in the delayed heat-related risks during the pandemic at Lag 2 (16.33%; 95% CI: 1.00, 33.98%). Conclusion: This study provides evidence of the impact of COVID-19, particularly on the possible roles of physical interventions and behavioral changes, in modifying the temperature-health association. These findings would have implications on subsequent policies or heat-related warning strategies in light of ongoing or future pandemics., Environmental Health: A Global Access Science Source, 20, art. no. 122; 2021

Research suggests that high intake of supplemental vitamin B12 may be associated with increased risk of cancer, with some evidence that this association may vary by gender and smoking status. This investigation evaluates if similar patterns in association are observed for data for 11,757 adults from the National Health and Nutrition Examination Survey (1999-2006). Survey-weighted multivariable-adjusted linear regression was used to evaluate the association between regular B12 supplement use and log-transformed serum B12 levels. Persons taking vitamin B12 through a multivitamin/multimineral (MVMM) had a median supplemental intake of 12 mcg/day (Q1: 6, Q3: 25), compared to 100 mcg/day (Q1: 22, Q3: 500) for persons reporting supplemental B12 intake through a MVMM-exclusive source. MVMM users had a geometric mean serum B12 26% (95% CI: 23%-30%) higher than nonusers, whereas MVMM-exclusive users' geometric mean was 61% (95% CI: 53%-70%) higher than nonusers (p-trend < 0.001). Although a positive trend (p-trend < 0.001) was observed for both men and women, the association was stronger among women (p-interaction < 0.001). No interaction was observed for smoking status (p-interaction = 0.45). B12 supplementation is associated with higher levels of serum B12, with significant interaction by gender but not smoking. Further work is needed to better understand the interplay of B12 and gender.

BACKGROUND The health effects of fine particulate matter (PM2.5) may be worse at higher temperatures. OBJECTIVE To investigate temperature's effect on PM2.5-mortality/morbidity associations in Lima, Peru. METHODS Time-series regressions relating PM2.5 and temperature to mortality and emergency room (ER) visits during 2010-2016. Daily PM2.5 levels (assigned to 40 Lima districts) and daily maximum temperature (Lima-wide) were estimated based on ground monitors, remote sensing, and modeling. We analyzed all-cause, cardiovascular (ICD codes I00-I99), and respiratory (ICD codes J00-J99) mortality, and cardiovascular and respiratory causes for ER visits. RESULTS The average PM2.5 concentration was 20.9 µg/m3 (IQR 17.5-23.5). The mean daily maximum temperature was 23.8 °C (IQR 20.8-26.9). PM2.5's effect on all-cause, respiratory, and circulatory disease mortality was significantly (p

To investigate the association between religious participation and memory in persons aged 45-85 years. Using the Canadian Longitudinal Study on Aging, frequency of religious participation was measured from "daily" to "never"; immediate and delayed recall memory were assessed with the Rey Auditory Verbal Learning Test. We regressed memory onto religious participation for persons aged < 65 years and persons aged ≥ 65 years. We found some evidence of effect modification: among persons < 65 years, monthly to yearly participation versus never attending was positively associated with immediate and delayed recall memory; among persons aged ≥ 65 years, weekly or more participation versus never attending was negatively associated with immediate and delayed recall memory. However, regression coefficients were small (-0.09 ≤ B ≤ 0.06) and most were not statistically significant (p < 0.05). Insufficient evidence existed to conclude that religious participation was associated with memory in our sample.

Objectives: Life's Simple 7 (LS7) metrics provide insight into improving cardiovascular health (CVH) and help reduce mortality risks. Edentulous older adults have a higher mortality risk than dentulous ones, probably due to worse oral function. It is reported that wearing dentures will decrease the mortality risk factor by improving oral function. This prospective study aimed to investigate if denture wearing could modify the association between CVH profile and mortality risk among edentulous elderly.Methods: From the Third National Health and Nutrition Examination Survey (NHANES III), 1,735 edentulous older adults (mean age 69.4 years old) with CVH profiles and data on denture wearing status were selected for this study. CVH profiles according to LS7 metrics were classified into poor, intermediate, or ideal. Denture wearers were defined as those wearing complete dentures in both arches all the time or only when awake. Multivariable Cox proportional-hazards regression was conducted to estimate the association of CVH profiles with all-cause and cardiovascular mortality. Stratified analyses and the testing of interaction terms were used to evaluate the difference between the association in edentulous patients with and without dentures.Results: A total of 1,420 (81.8%) older adults died during the 27-year follow-up, with 478 (27.6%) cases attributable to heart disease. After controlling for potential confounders, edentulous patients with an ideal CVH (LS7 = 10–14) had a lower mortality risk than those with poor CVH (LS7 = 0–4). Furthermore, we observed an effect modification by denture use (P interaction = 0.046), with the role of ideal CVH in mitigating mortality among the denture wearers (Hazard Ratio = 0.440 [0.329–0.588]), while no significant association among those without dentures. Similar results were achieved for cardiovascular mortality, but there was no effect modification of denture use (P interaction = 0.352).Conclusion: In this study, a favorable cardiovascular health profile presents a protective effect on all-cause mortality only among edentulous patients wearing dentures instead of non-wearer. Clinical Significance: Denture usage could improve oral function (e.g., chewing, smiling, speaking, etc.) and promote general health. Effect modification found in this study indicates having ideal CVH alone cannot substantially reduce mortality risk among edentulous patients. Therefore, health care professionals should keep an eye on the elderly not wearing dentures as they are probably more at risk for adverse health outcomes. It remains unclear if denture wearing has a causal relation with lower mortality risks, and further research is needed.

BackgroundMaternal exposure to air pollution has been associated with birth outcomes; however, few studies examined biologically critical exposure windows shorter than trimesters or potential effect modifiers.ObjectivesTo examine associations of prenatal fine particulate matter (PM2.5), by trimester and in biologically critical windows, with birth outcomes and assess potential effect modifiers.MethodsThis study used two pregnancy cohorts (CANDLE and TIDES; N=2099) in the ECHO PATHWAYS Consortium. PM2.5 was estimated at the maternal residence using a fine-scale spatiotemporal model, averaged over pregnancy, trimesters, and critical windows (0-2 weeks, 10-12 weeks, and last month of pregnancy). Outcomes were preterm birth (PTB

Measuring the effect of a treatment on outcomes is an important goal for research in pediatric/congenital interventional cardiology. The breadth of anatomic and physiologic variations, patient ages, and genetic syndromes and noncardiac comorbid conditions all represent sources of potential confounding and effect modification that are major obstacles to this goal. If not accounted for, these factors can obscure the "true" treatment effect and lead to spurious conclusions about the relative efficacy and/or safety of therapies. In this review, we discuss the importance of confounding and effect modification in pediatric/congenital interventional cardiology research. We define these terms and discuss strategies (both in study design and data analysis) to mitigate error introduced by confounding and effect modification. The importance of confounding by indication in pediatric/congenital cardiology is discussed along with specific methods to address it.

Examining the role of environmental enteric dysfunction (EED) in child growth requires noninvasive, field-appropriate biomarkers. Alternatives to the traditionally used lactulose:mannitol (L:M) test have been explored, but few studies have compared the L:M test to host fecal mRNA transcripts. The objectives of this study were to examine whether 1) host fecal mRNA transcripts could predict presence and severity of EED, measured using the L:M test, and 2) EED modifies the effect of specialized nutritious foods (SNFs) on recovery from moderate acute malnutrition (MAM). This substudy was nested within a cluster randomized trial comparing four SNFs in the treatment of MAM among children 6 to 59 months in Sierra Leone. EED was assessed at enrollment using the L:M test and 15 host fecal mRNA transcripts on 522 children. Recovery from MAM was defined as achieving mid-upper arm circumference ≥ 12.5 cm within 12 weeks of supplementation. Random forest classification models were used to examine prediction of presence and severity of EED by host fecal mRNA transcripts. Logistic regression was used to test for effect modification by L:M test variables including % lactulose excreted (%L). Eight host fecal mRNA transcripts (AQP9, REG3A, IFI30, DECR1, BIRC3, SELL, PIK3AP1, DEFA6) identified EED (%L ≥ 0.2) and severe EED (%L ≥ 0.45) with high sensitivity and specificity. The L:M test variables did not modify the effect of SNFs on recovery from MAM. In this study, we found host fecal mRNA transcripts that could be biomarkers of EED but did not find EED to modify the effect of SNFs on MAM treatment.

Supplemental Digital Content is available in the text., Background: Randomized controlled trials (RCTs) with continuous outcomes usually only examine mean differences in response between trial arms. If the intervention has heterogeneous effects, then outcome variances will also differ between arms. Power of an individual trial to assess heterogeneity is lower than the power to detect the same size of main effect. Methods: We describe several methods for assessing differences in variance in trial arms and apply them to a single trial with individual patient data and to meta-analyses using summary data. Where individual data are available, we use regression-based methods to examine the effects of covariates on variation. We present an additional method to meta-analyze differences in variances with summary data. Results: In the single trial, there was agreement between methods, and the difference in variance was largely due to differences in prevalence of depression at baseline. In two meta-analyses, most individual trials did not show strong evidence of a difference in variance between arms, with wide confidence intervals. However, both meta-analyses showed evidence of greater variance in the control arm, and in one example, this was perhaps because mean outcome in the control arm was higher. Conclusions: Using meta-analysis, we overcame low power of individual trials to examine differences in variance using meta-analysis. Evidence of differences in variance should be followed up to identify potential effect modifiers and explore other possible causes such as varying compliance.

BACKGROUND Over the last several decades in the United States, socioeconomic life-expectancy inequities have increased 1-2 years. Declining labor-union density has fueled growing income inequities across classes and exacerbated racial income inequities. Using Panel Study of Income Dynamics (PSID) data, we examined the longitudinal union-mortality relationship and estimated whether declining union density has also exacerbated mortality inequities. METHODS Our sample included respondents ages 25-66 to the 1979-2015 PSID with mortality follow-up through age 68 and year 2017. To address healthy-worker bias, we used the parametric g-formula. First, we estimated how a scenario setting all (versus none) of respondents' employed-person-years to union-member employed-person-years would have affected mortality incidence. Next, we examined gender, racial, and educational effect modification. Finally, we estimated how racial and educational mortality inequities would have changed if union-membership prevalence had remained at 1979 (vs. 2015) levels throughout follow-up. RESULTS In the full sample (respondents = 23,022, observations = 146,681), the union scenario was associated with lower mortality incidence than the nonunion scenario (RR = 0.90, 95% CI = 0.80, 0.99; RD per 1,000 = -19, 95% CI = -37, -1). This protective association generally held across subgroups, although it was stronger among the more-educated. However, we found little evidence mortality inequities would have lessened if union membership had remained at 1979 levels. CONCLUSIONS To our knowledge, this was the first individual-level US-based study with repeated union-membership measurements to analyze the union-mortality relationship. We estimated a protective union-mortality association, but found little evidence declining union density has exacerbated mortality inequities; importantly, we did not incorporate contextual-level effects. See video abstract at, http://links.lww.com/EDE/B839.

We aimed to estimate the non-accidental and cause-specific mortality burden attributed to diurnal temperature range (DTR) and the relative contributions of low, high, and extremely low and extremely high DTR in Yunnan, southwest China. Furthermore, we explored the possible effect modification of the DTR-mortality association by season, sex, age, ethnicity, marital status, and occupation. A standard time-series quasi-Poisson regression model combined with a distributed lag nonlinear model was used to derive estimates of city-specific DTR-mortality associations, then random effects meta-analysis was used to pool the estimated city-specific overall cumulative DTR-mortality association, estimating empirical confidence intervals (eCIs). The overall fraction of non-accidental mortality caused by DTR was 11.00% (95% eCI 3.40-17.28): high DTR accounted for most of burden (total estimate 10.03%, 95% eCI 2.59-16.32). The estimated mortality risk attributable to DTR was significantly associated with cardiovascular and respiratory mortality, with attributable fractions of 13.61% (95% eCI 3.91-21.13) and 14.32% (95% eCI 0.47-21.44), respectively. The estimated risk attributable to DTR was slightly greater for males, people ≥75 years old, married people, and non-farmers than their corresponding categories. Most of the DTR-related mortality burden was attributable to high DTR, and the mortality risk attributable to DTR might be modified by specific causes, sex, age, marital status, and occupation.

Background Comprehensive evidence synthesis on the associations between comorbidities and behavioural factors with hospitalisation, intensive care unit (ICU) admission, and death due to COVID-19 is required for deriving national and international recommendations on primary targets for non-pharmacological interventions (NPI) and vaccination strategies. Methods We performed a rapid systematic review and meta-analysis on studies and publicly accessible data to quantify associations between predisposing health conditions, demographics, behavioural factors on the one hand and hospitalisation, ICU admission, and death from COVID-19 on the other hand. We provide ranges of reported and calculated effect estimates and pooled relative risks derived from a meta-analysis and meta-regression. Results Seventy-five studies were included in qualitative and 74 in quantitative synthesis, with study populations ranging from 19 to 44,672 COVID-19 cases. The risk of dying from COVID-19 was significantly associated with cerebrovascular [pooled relative risk (RR) 2.7 (95% CI 1.7–4.1)] and cardiovascular [RR 3.2 (CI 2.3–4.5)] diseases, hypertension [RR 2.6 (CI 2.0–3.4)], and renal disease [RR 2.5 (CI 1.8–3.4)], with high heterogeneity in pooled estimates, partly but not solely explained by age of study participants. For some comorbidities, our meta-regression showed a decrease in effect on the severity of disease with a higher median age of the study population. Compared to death, associations between several comorbidities and hospitalisation and ICU admission were less pronounced. Conclusions We obtained robust estimates on the magnitude of risk for COVID-19 hospitalisation, ICU admission, and death associated with comorbidities, demographic, and behavioural risk factors and show that these estimates are modified by age of study participants. This interaction is an important finding to be kept in mind for current vaccination strategies and for the protection of individuals with high risk for a severe COVID-19 course.

Background: Previous studies have confirmed that both healthy diets and physical exercise have preventive effects with respect to cognitive decline with aging. The aim of this study was to investigate whether the associations of physical exercise with cognitive impairment differ in community-dwelling older adults with different dietary habits. Methods: In the 2008/2009 wave of the Chinese Longitudinal Healthy Longevity Survey, 14,966 community-dwelling older adults (≥65 years) were included for analyses. Dietary habits (including daily intake of fruits, vegetables, tea, meat, fish, eggs, food made from beans, salt-preserved vegetables, sugar, garlic, milk products, nut products, mushroom or algae, vitamins and medicinal plants) and physical exercise were assessed. Cognitive impairment was evaluated using the Chinese version of the MMSE in the 2008/2009 and 2011/2012 waves. The effect modifications of physical exercise on cognitive impairment by dietary habits were estimated using logistic regression models. Results: Older adults who practiced physical exercise exhibited a trend of decreased probability of cognitive impairment at baseline and follow-up (OR = 0.92, 95% CI = 0.80–1.06, p = 0.273; OR = 0.83, 95% CI = 0.65–1.05, p = 0.123, respectively) compared with those who did not practice physical exercise. When stratified by dietary habits, physical exercise had a protective effect with respect to prevalent cognitive impairment in older adults who ate fruits (OR = 0.74, 95% CI = 0.58–0.94, p = 0.016), ate food made from beans (OR = 0.76, 95% CI = 0.62–0.93, p = 0.007), did not eat sugar (OR = 0.81, 95% CI = 0.68–0.98, p = 0.028) and ate milk products (OR = 0.75, 95% CI = 0.57–0.97, p = 0.030); in the longitudinal analyses, physical exercise had a protective effect with respect to incident cognitive impairment in older adults who ate fruits (OR = 0.63, 95% CI = 0.41–0.98, p = 0.040) and milk products (OR = 0.57, 95% CI = 0.35–0.94, p = 0.027). Fruits, food made from beans and milk products modified the associations of physical exercise with prevalent cognitive impairment (p values for interaction = 0.008, 0.005 and 0.082, respectively). Conclusions: The associations of physical exercise with cognitive impairment could be modified by certain dietary habits. Physical exercise was not found to be significantly protective with respect to cognitive impairment in older adults unless they had specific dietary habits. Thus, dietary habits should be emphasized when investigating the beneficial effects of physical exercise on cognitive function in community-dwelling older adults.

Lead exposure and neighborhoods can affect children’s behavior, but it is unclear if neighborhood characteristics modify the effects of lead on behavior. Understanding these modifications has important intervention implications. Blood lead levels (BLLs) in children (~7 years) from Montevideo, Uruguay, were categorized at 2 µg/dL. Teachers completed two behavior rating scales (n = 455). At one-year follow-up (n = 380), caregivers reported child tantrums and parenting conflicts. Multilevel generalized linear models tested associations between BLLs and behavior, with neighborhood disadvantage, normalized difference vegetation index (NDVI), and distance to nearest greenspace as effect modifiers. No effect modification was noted for neighborhood disadvantage or NDVI. Children living nearest to greenspace with BLLs < 2 µg/dL were lower on behavior problem scales compared to children with BLLs ≥ 2 µg/dL. When furthest from greenspace, children were similar on behavior problems regardless of BLL. The probability of daily tantrums and conflicts was ~20% among children with BLLs < 2 µg/dL compared to ~45% among children with BLLs ≥ 2 µg/dL when closest to greenspace. Furthest from greenspace, BLLs were not associated with tantrums and conflicts. Effect modification of BLL on child behavior by distance to greenspace suggests that interventions should consider both greenspace access and lead exposure prevention.

Introduction: Women have historically been under-represented in medical literature, particularly prominent in authorship of invited commentaries. With the instantaneous change in work environment forcing Americans to adapt to working at home, many theorize that women will be more adversely affected due to traditional concepts of women being more responsible for the home in addition to work responsibilities. Objective: Understand how women contributed to coronavirus disease 2019 (COVID-19) literature early in the pandemic. Methods: Cross-sectional analysis of manuscripts published in three high-impact U.S. medical journals from February to May 2020 was performed. We used log-binomial regression to examine for an association between COVID-19 status and likelihood of having at least one female first author, and evaluated for effect modification according to whether the manuscript was invited. Results: Among 980 manuscripts, 313 (31.9%) listed at least one female first author, 203 were written on COVID-19 (20.7%), and 144 (14.7%) were invited. There was no association between COVID-19 status and having at least one female first author overall (adjusted risk ratio [RR] 0.93, 95% confidence interval [CI] 0.72-1.19). The relationship between COVID-19 status and first-author sex was 0.23 (95% CI 0.06-0.92) for invited manuscripts and 1.04 (95% CI 0.81-1.35) for noninvited manuscripts (p for interaction 0.02). Discussion: We demonstrate that women were not less likely to be first authors on COVID-19 manuscripts but were less likely to be first authors on invited COVID-19 manuscripts. Early career female researchers are the most vulnerable for inability to meet metrics for promotion, accounting for the continued under-representation of women in senior academic roles. COVID-19 has the potential to exacerbate this disparity.

A common goal in comparative effectiveness research is to estimate treatment effects on pre-specified subpopulations of patients. Though widely used in medical research, causal inference methods for such subgroup analysis remain underdeveloped, particularly in observational studies. In this article, we develop a suite of analytical methods and visualization tools for causal subgroup analysis. First, we introduce the estimand of subgroup weighted average treatment effect and provide the corresponding propensity score weighting estimator. We show that balancing covariates within a subgroup bounds the bias of the estimator of subgroup causal effects. Second, we design a new diagnostic graph -- the Connect-S plot -- for visualizing the subgroup covariate balance. Finally, we propose to use the overlap weighting method to achieve exact balance within subgroups. We further propose a method that combines overlap weighting and LASSO, to balance the bias-variance tradeoff in subgroup analysis. Extensive simulation studies are presented to compare the proposed method with several existing methods. We apply the proposed methods to the Patient-centered Results for Uterine Fibroids (COMPARE-UF) registry data to evaluate alternative management options for uterine fibroids for relief of symptoms and quality of life., Comment: 17 pages, 6 figures

Ishtiaq Ahmad,1 Myo Nyein Aung,2 Satomi Ueno,1 Ei Thinzar Khin,1 Tint Swe Latt,3 Saiyud Moolphate,4 Motoyuki Yuasa1,5 1Department of Public Health, Graduate School of Medicine, Juntendo University, Tokyo, Japan; 2Advanced Research Institute for Health Sciences and Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan; 3Myanmar Diabetes Association (MMDA), Yangon, Myanmar; 4Department of Public Health, Chiang Mai Rajabhat University, Chiang Mai, Thailand; 5Faculty of International Liberal Arts, Juntendo University, Tokyo, JapanCorrespondence: Myo Nyein AungAdvanced Research Institute for Health Sciences and Faculty of International Liberal Arts, Juntendo University, Bunkyo City, Hongo, 2 Chome-1-1, Tokyo, 〒113-8421, JapanTel +813-3813-3111Email myo@juntendo.ac.jpBackground: Despite the evidence that physical activity (PA) can prevent type 2 diabetes mellitus (T2DM), limited research investigated the level of PA among diabetes and non-diabetes in Myanmar, where there is the escalating prevalence of diabetes recently. We investigated PA as modified the risk of diabetes, in a case-control study.Methods: We conducted a case-control study which included 150 cases and 150 controls age 25– 74 years (Mean age 43.3± 14.7 years) among the cases and (55.1± 10.9 years) among the controls, both sex and residence in Yangon. Cases were newly diagnosed with T2DM within six months before data collection, with laboratory-confirmed fasting blood glucose level ≥ 126mg/dl. Controls were community residents, without diabetes, confirmed with a laboratory test. The IPAQ-S was used to assess the PA level. Multiple logistic regression analysis was applied in STATA 15, using the interaction terms for age and PA, adjusting age, sex and BMI.Results: In comparison to controls, cases were older and having less PA knowledge. The levels of vigorous PA were mean 254.9±standard deviations (SD) 845.6 METsmin.wk− 1 among controls, 73.06± 392.1 cases, moderate PA 631.5± 1240.8 METsmin.wk− 1 among controls and 1050.9± 1601.6 cases and walking PA 569.8± 1060 METsmin.wk− 1 among controls and 777.4± 1249 cases, respectively. The multiple logistic regression analysis showed adjusted odds ratios (aOR) 3.84, 95% confidence interval (CI) 1.18– 12.42 (P< 0.05) for those aged 40 and older, with moderate PA and aOR 18.01, Cl 6.45– 50.26 (P< 0.001) for those aged 40 and older, with low PA. Comparing the strength of association, the risk of T2DM among people aged 40 and older with moderate PA is lower than age over 40 with low PA.Conclusion: PA lessened the risk of T2DM, posted by increasing age. The findings highlighted the importance of promoting PA to reduce the T2DM prevalence in the context of Yangon, Myanmar, a low- and middle-income Asian country.Keywords: METs, effect modification, non-communicable disease; risk of diabetes, global health, public health

Ishtiaq Ahmad,1 Myo Nyein Aung,2 Satomi Ueno,1 Ei Thinzar Khin,1 Tint Swe Latt,3 Saiyud Moolphate,4 Motoyuki Yuasa1,5 1Department of Public Health, Graduate School of Medicine, Juntendo University, Tokyo, Japan; 2Advanced Research Institute for Health Sciences and Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan; 3Myanmar Diabetes Association (MMDA), Yangon, Myanmar; 4Department of Public Health, Chiang Mai Rajabhat University, Chiang Mai, Thailand; 5Faculty of International Liberal Arts, Juntendo University, Tokyo, JapanCorrespondence: Myo Nyein AungAdvanced Research Institute for Health Sciences and Faculty of International Liberal Arts, Juntendo University, Bunkyo City, Hongo, 2 Chome-1-1, Tokyo, 〒113-8421, JapanTel +813-3813-3111Email myo@juntendo.ac.jpBackground: Despite the evidence that physical activity (PA) can prevent type 2 diabetes mellitus (T2DM), limited research investigated the level of PA among diabetes and non-diabetes in Myanmar, where there is the escalating prevalence of diabetes recently. We investigated PA as modified the risk of diabetes, in a case-control study.Methods: We conducted a case-control study which included 150 cases and 150 controls age 25– 74 years (Mean age 43.3± 14.7 years) among the cases and (55.1± 10.9 years) among the controls, both sex and residence in Yangon. Cases were newly diagnosed with T2DM within six months before data collection, with laboratory-confirmed fasting blood glucose level ≥ 126mg/dl. Controls were community residents, without diabetes, confirmed with a laboratory test. The IPAQ-S was used to assess the PA level. Multiple logistic regression analysis was applied in STATA 15, using the interaction terms for age and PA, adjusting age, sex and BMI.Results: In comparison to controls, cases were older and having less PA knowledge. The levels of vigorous PA were mean 254.9±standard deviations (SD) 845.6 METsmin.wk− 1 among controls, 73.06± 392.1 cases, moderate PA 631.5± 1240.8 METsmin.wk− 1 among controls and 1050.9± 1601.6 cases and walking PA 569.8± 1060 METsmin.wk− 1 among controls and 777.4± 1249 cases, respectively. The multiple logistic regression analysis showed adjusted odds ratios (aOR) 3.84, 95% confidence interval (CI) 1.18– 12.42 (P< 0.05) for those aged 40 and older, with moderate PA and aOR 18.01, Cl 6.45– 50.26 (P< 0.001) for those aged 40 and older, with low PA. Comparing the strength of association, the risk of T2DM among people aged 40 and older with moderate PA is lower than age over 40 with low PA.Conclusion: PA lessened the risk of T2DM, posted by increasing age. The findings highlighted the importance of promoting PA to reduce the T2DM prevalence in the context of Yangon, Myanmar, a low- and middle-income Asian country.Keywords: METs, effect modification, non-communicable disease; risk of diabetes, global health, public health

Qiuping Li, Xi Chen, Binru Han Department of Nursing, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Binru HanXuanwu Hospital, Capital Medical University, Chang Chun St.45, Xicheng District, Beijing, 100053, People’s Republic of ChinaTel +86 10-83198219Fax +86 10-83198258Email kinv246@126.comBackground: Hemoglobin concentration differs by sex, possibly affecting any association between hemoglobin and frailty. This study aimed to evaluate the potential interaction effect of hemoglobin and sex on frailty in Chinese older inpatients.Methods: A cross-sectional study was conducted between February 2015 and November 2017 in a tertiary hospital. Frailty was defined by the Fried phenotype. Hemoglobin concentration was measured with a standard procedure. Covariates included demographics, clinical characteristics, and serum biomarkers. Logistic regression was applied to examine the association between hemoglobin concentration and frailty. The relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI) were used to evaluate the additive interaction.Results: A total of 619 older inpatients [mean age 69.26± 7.44 years; 334 men, 285 women] were included. The mean hemoglobin concentration was significantly lower in the elderly who were frail (11.9 g/L in frail versus 13.1g/L in non-frail; p< 0.001). In the multivariable regression models, lower hemoglobin in patients was significantly associated with frailty (adjusted odds ratio (OR) = 2.51, 95% CI:1.37, 4.60). The stratified analyses indicated that lower hemoglobin was associated with frailty among older inpatients with different characteristics. Female inpatients with lower hemoglobin had the highest risk of frailty (adjusted OR=6.43, 95%: 2.38, 17.3); there were interactions between hemoglobin and sex on the development of frailty (RERI=4.30, 95% CI=− 1.41, 10.01; AP=0.67, 95% CI=0.37, 0.97;SI=4.80, 95% CI=1.22, 18.84).Conclusions and Implications: Our study provided evidence that sex and lower hemoglobin have an interaction effect on frailty; it is suggested that clinicians may consider sex-specific strategies for the elderly to conform the concept of precision medicine.Keywords: hemoglobin concentration, frailty phenotype, older inpatient, interaction effect

BACKGROUND: Although many studies demonstrated reduced mortality risk with higher greenness, few studies examined the modifying effect of greenness on air pollution–health associations. We evaluated residential greenness as an effect modifier of the association between long-term exposure to fine particles (PM(2.5)) and mortality. METHODS: We used data from all Medicare beneficiaries in North Carolina (NC) and Michigan (MI) (2001–2016). We estimated annual PM(2.5) averages using ensemble prediction models. We estimated mortality risk per 1 μg/m(3) increase using Cox proportional hazards modeling, controlling for demographics, Medicaid eligibility, and area-level covariates. We investigated health disparities by greenness using the Normalized Difference Vegetation Index (NDVI) with measures of urbanicity and socioeconomic status. RESULTS: PM(2.5) was positively associated with mortality risk. Hazard ratios (HRs) were 1.12 (95% confidence interval (CI) 1.12, 1.13) for NC and 1.01 (95% CI 1.00, 1.01) for MI. HRs were higher for rural than urban areas. Within each category of urbanicity, HRs were generally higher in less green areas. For combined disparities, HRs were higher in low greenness or low SES areas, regardless of the other factor. HRs were lowest in high-greenness and high-SES areas for both states. CONCLUSIONS: In our study, those in low SES and high greenness areas had lower associations between PM(2.5) and mortality than those in low SES and low greenness areas. Multiple aspects of disparity factors and their interactions may affect health disparities from air pollution exposures. Findings should be considered in light of uncertainties, such as our use of modeled PM(2.5) data, and warrant further investigation.

Current knowledge of the link between dietary carbohydrate intake and insulin regulation in individuals after an attack of pancreatitis is limited. We aimed to investigate the associations between dietary carbohydrate intake and insulin traits in post-pancreatitis versus healthy individuals, taking into account intrapancreatic fat deposition (IPFD).All participants underwent magnetic resonance imaging (using the same protocol and 3T scanner) to quantify IPFD. Dietary carbohydrate intake was assessed using a validated 131-item food frequency questionnaire. Insulin, HOMA-IR, HOMA-β were determined in the fasted state. Linear regression and effect modification analyses were conducted in unadjusted and adjusted models (accounting for age, sex, body mass index, daily energy intake, use of anti-diabetic medications, and recurrence of acute pancreatitis).The study included 111 post-pancreatitis individuals (categorized into low IPFD (n = 33), moderate IPFD (n = 40), high IPFD (n = 38)) and 47 healthy controls. In the high IPFD group, starch intake was negatively associated with fasting insulin and HOMA-β in both the unadjusted (p 0.001 both) and fully adjusted models (p 0.001 both); and with HOMA-IR in the fully adjusted model (p 0.001) only. Total sugar intake was positively associated with fasting insulin (p = 0.015) and HOMA-β (p = 0.007) in the fully adjusted model but not associated with HOMA-IR. None of the above associations was statistically significant in the low IPFD, moderate IPFD, and healthy controls groups. The studied associations were more pronounced in the high IPFD group but not in the moderate IPFD or low IPFD groups (when compared with the healthy controls group).Dietary carbohydrate intake is differentially associated with insulin traits in individuals after an attack of pancreatitis and the associations are modified by IPFD. These findings will be helpful for the development of dietary guidelines specifically for individuals after an attack of pancreatitis.

Background and aims To elucidate the effect modification of general and central obesity by sex and age on the risk of cardiovascular events. Methods The analysis included 14,983 males and females aged 45–75 years from the Atherosclerosis Risk in Communities study. Obesity was defined with body mass index (BMI), waist-to-hip ratio (WHR) and body shape index (BSI) which categorized the participants as obese and non-obese. Targeted maximum likelihood estimation was used to estimate the risk ratio (RR) with the tmle package in R software. Results After adjustment, the strongest effect of BMI on CHD was in females (RR (95%CI): 1.26 (1.11, 1.42)) and in age>54 (RR (95%CI): 1.16 (1.06, 1.27)) and for HF it was in age>54 (RR (95%CI): 1.18 (1.10, 1.26)) and in females (RR (95%CI): 1.17 (1.08, 1.28)). Regarding central obesity, WHR (RR (95%CI): 1.19 (1.05, 1.34)) had the strongest effects on CHD for males and BSI (RR (95%CI): 1.140 (1.02, 1.26)) for age ≤ 54, and for HF the WHR (RR (95%CI): 1.22 (1.10, 1.36)) and BSI (RR (95%CI): 1.18 (1.07, 1.30)) had the strongest effects for age≤54, respectively. Conclusion Among males and age≤54, WHR index was associated with a higher risk of CHD and HF while BMI was so for females and age>54.

Background: Obesity is a leading risk factor for breast cancer in post-menopausal women and is associated with greater risk of recurrence and cancer-specific mortality. There are over 3 million female breast cancer survivors in the United States, and nearly 65% are either overweight or obese. Lifestyle intervention studies have been shown to be effective in achieving clinically meaningful weight loss for breast cancer survivors with a BMI > 25 kg/m2. However, individual variability in body weight response to diet or exercise interventions has been previously reported among carriers of common obesity-genetic variants. Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB moderated the effects of an exercise and nutrition intervention on weight change among breast cancer survivors. Methods: A total of 151 breast cancer survivors with a body mass index (BMI) ≥ 25 kg/m2 at baseline were randomly assigned to a 6-month weight loss intervention (n=93) or usual care group (n=58). The weight loss intervention included eleven 30-min counseling sessions on improving nutrition and increasing physical activity. Height, weight and body composition (via dual energy X-ray absorptiometry) were measured at baseline and six months. Genotyping of FTO rs9939609, MC4R rs6567160, BDNF rs11030104, CREB1 rs17203016 was performed using Taqman® SNP genotyping assays. Association analyses were performed in SAS version 9.4, separately for each SNP and assuming a dominant genetic model. Linear mixed models were used to analyze the main effects of genotype and the intervention on weight, BMI, and percent body fat changes at 6 months, with adjustment for age. Appropriate cross product terms were included in each regression model to analyze the potential interaction between genotype and treatment arm. All statistical tests were evaluated against a Bonferroni-corrected alpha of 0.0125. Results: The genetic distributions of the FTO SNP rs9939609, MC4R SNP rs6567160, BDNF SNP rs11030104, CREB1 SNP rs17203016 did not differ significantly by treatment arm. Changes in weight, BMI, and percent body fat did not differ significantly between carriers of the FTO SNP rs9939609, MC4R SNP rs6567160, BDNF SNP rs11030104, and CREB1 SNP rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each SNP and across all outcomes). Women in the intervention group achieved significantly greater weight loss than the usual care group (-4.8 kg vs -0.6 kg, p < 0.001) regardless of genotype. Conclusions: Common variants of known obesity-associated genes (FTO, MC4R, BDNF, and MC4R) did not modify the effect of the nutrition and exercise intervention on changes in body weight and body fat. Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may benefit from lifestyle changes similarly to women who are not genetically predisposed to obesity. Our findings may help guide the incorporation of lifestyle interventions and weight loss counseling into breast cancer survivorship care. Citation Format: ThaiHien Nguyen, Melinda L Irwin, Andrew T Dewan, Maura Harrigan, Brenda Cartmel, Tara Sanft, Lingeng Lu, Fangyong Li, Yasmmyn D Salinas. Assessing effect modification of obesity-associated genes variants in FTO, MC4R, BDNF, and CREB1 on weight loss among breast cancer survivors enrolled in the randomized lifestyle, exercise, and nutrition (LEAN) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-17.

We offer a non-parametric plug-in estimator for an important measure of treatment effect variability and provide minimum conditions under which the estimator is asymptotically efficient. The stratum specific treatment effect function or so-called blip function, is the average treatment effect for a randomly drawn stratum of confounders. The mean of the blip function is the average treatment effect (ATE), whereas the variance of the blip function (VTE), the main subject of this paper, measures overall clinical effect heterogeneity, perhaps providing a strong impetus to refine treatment based on the confounders. VTE is also an important measure for assessing reliability of the treatment for an individual. The CV-TMLE provides simultaneous plug-in estimates and inference for both ATE and VTE, guaranteeing asymptotic efficiency under one less condition than for TMLE. This condition is difficult to guarantee a priori, particularly when using highly adaptive machine learning that we need to employ in order to eliminate bias. Even in defiance of this condition, CV-TMLE sampling distributions maintain normality, not guaranteed for TMLE, and have a lower mean squared error than their TMLE counterparts. In addition to verifying the theoretical properties of TMLE and CV-TMLE through simulations, we point out some of the challenges in estimating VTE, which lacks double robustness and might be unavoidably biased if the true VTE is small and sample size insufficient. We will provide an application of the estimator on a data set for treatment of acute trauma patients., Comment: Presented at JSM 2018

Introduction: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare the effects of hemodialysis (HD) given 6 versus 3 times per week. More frequent in-center HD significantly reduced left-ventricular mass (LVM), with more pronounced effects in patients with low urine volumes. In this study, we aimed to explore another potential effect modifier: the predialysis serum sodium (SNa) and related proxies of plasma tonicity. Methods: Using data from the FHN Daily and Nocturnal Trials, we compared the effects of frequent HD on LVM among patients stratified by SNa, dialysate-to-predialysis serum-sodium gradient (GNa), systolic and diastolic blood pressure, time-integrated sodium-adjusted fluid load (TIFL), and extracellular fluid volume estimated by bioelectrical impedance analysis. Results: In 197 enrolled subjects in the FHN Daily Trial, the treatment effect of frequent HD on ∆LVM was modified by SNa. When the FHN Daily Trial participants are divided into lower and higher predialysis SNa groups (less and greater than 138 mEq/L), the LVM reduction in the lower group was substantially higher (−28.0 [95% CI −40.5 to −15.4] g) than in the higher predialysis SNa group (−2.0 [95% CI −15.5 to 11.5] g). Accounting for GNa, TIFL also showed more pronounced effects among patients with higher GNa or higher TIFL. Results in the Nocturnal Trial were similar in direction and magnitude but did not reach statistical significance. Discussion/Conclusion: In the FHN Daily Trial, the favorable effects of frequent HD on left-ventricular hypertrophy were more pronounced among patients with lower predialysis SNa and higher GNa and TIFL. Whether these metrics can be used to identify patients most likely to benefit from frequent HD or other dialytic or nondialytic interventions remains to be determined. Prospective, adequately powered studies studying the effect of GNa reduction on mortality and hospitalization are needed.

Physical activity and cardiorespiratory fitness are inversely associated with markers of cardiometabolic risk in children and adolescents, but the interplay between these variables in relation to the cardiometabolic risk profile is unclear. We systematically reviewed the literature to examine whether the association between physical activity and cardiometabolic health differs by levels of cardiorespiratory fitness in youth. A literature search was conducted in PubMed and EMBASE, filtered from 2001 up until July 2019. We obtained 8980 citations, with 6915 remaining after removal of duplicates. Estimates were retrieved from 18 studies. All included articles went through a risk of bias assessment. We found that 14 out of 20 (70%) effect-estimates supported stronger associations between physical activity and cardiometabolic health markers among low-fit youth as compared to their high-fit peers. The most consistent findings were observed with biochemical markers and blood pressure as outcomes. However, substantial uncertainty is associated with these findings as most of the included studies (~72%) had a high risk of bias. More than two-thirds of the findings supported greatest benefits of physical activity on cardiometabolic risk markers in youth with low cardiorespiratory fitness, although the clinical importance of this difference is unclear.

Andreas D Meid,1 Carmen Ruff,1 Lucas Wirbka,1 Felicitas Stoll,1 Hanna M Seidling,1,2 Andreas Groll,3 Walter E Haefeli1,2 1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg 69120, Germany; 2Cooperation Unit Clinical Pharmacy, University of Heidelberg, Heidelberg 69120, Germany; 3Department of Statistics, TU Dortmund University, Dortmund 44227, GermanyCorrespondence: Andreas D MeidDepartment of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, GermanyTel +49 6221 56 37113Fax +49 6221 56 4642Email Andreas.Meid@med.uni-heidelberg.deAbstract: When healthcare professionals have the choice between several drug treatments for their patients, they often experience considerable decision uncertainty because many decisions simply have no single “best” choice. The challenges are manifold and include that guideline recommendations focus on randomized controlled trials whose populations do not necessarily correspond to specific patients in everyday treatment. Further reasons may be insufficient evidence on outcomes, lack of direct comparison of distinct options, and the need to individually balance benefits and risks. All these situations will occur in routine care, its outcomes will be mirrored in routine data, and could thus be used to guide decisions. We propose a concept to facilitate decision-making by exploiting this wealth of information. Our working example for illustration assumes that the response to a particular (drug) treatment can substantially differ between individual patients depending on their characteristics (heterogeneous treatment effects, HTE), and that decisions will be more precise if they are based on real-world evidence of HTE considering this information. However, such methods must account for confounding by indication and effect measure modification, eg, by adequately using machine learning methods or parametric regressions to estimate individual responses to pharmacological treatments. The better a model assesses the underlying HTE, the more accurate are predicted probabilities of treatment response. After probabilities for treatment-related benefit and harm have been calculated, decision rules can be applied and patient preferences can be considered to provide individual recommendations. Emulated trials in observational data are a straightforward technique to predict the effects of such decision rules when applied in routine care. Prediction-based decision rules from routine data have the potential to efficiently supplement clinical guidelines and support healthcare professionals in creating personalized treatment plans using decision support tools.Keywords: claims data, decision-making, heterogeneous treatment effects, effect modification, confounding by indication, prediction-based decision rules

Andreas D Meid,1 Carmen Ruff,1 Lucas Wirbka,1 Felicitas Stoll,1 Hanna M Seidling,1,2 Andreas Groll,3 Walter E Haefeli1,2 1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg 69120, Germany; 2Cooperation Unit Clinical Pharmacy, University of Heidelberg, Heidelberg 69120, Germany; 3Department of Statistics, TU Dortmund University, Dortmund 44227, GermanyCorrespondence: Andreas D MeidDepartment of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, GermanyTel +49 6221 56 37113Fax +49 6221 56 4642Email Andreas.Meid@med.uni-heidelberg.deAbstract: When healthcare professionals have the choice between several drug treatments for their patients, they often experience considerable decision uncertainty because many decisions simply have no single “best” choice. The challenges are manifold and include that guideline recommendations focus on randomized controlled trials whose populations do not necessarily correspond to specific patients in everyday treatment. Further reasons may be insufficient evidence on outcomes, lack of direct comparison of distinct options, and the need to individually balance benefits and risks. All these situations will occur in routine care, its outcomes will be mirrored in routine data, and could thus be used to guide decisions. We propose a concept to facilitate decision-making by exploiting this wealth of information. Our working example for illustration assumes that the response to a particular (drug) treatment can substantially differ between individual patients depending on their characteristics (heterogeneous treatment effects, HTE), and that decisions will be more precise if they are based on real-world evidence of HTE considering this information. However, such methods must account for confounding by indication and effect measure modification, eg, by adequately using machine learning methods or parametric regressions to estimate individual responses to pharmacological treatments. The better a model assesses the underlying HTE, the more accurate are predicted probabilities of treatment response. After probabilities for treatment-related benefit and harm have been calculated, decision rules can be applied and patient preferences can be considered to provide individual recommendations. Emulated trials in observational data are a straightforward technique to predict the effects of such decision rules when applied in routine care. Prediction-based decision rules from routine data have the potential to efficiently supplement clinical guidelines and support healthcare professionals in creating personalized treatment plans using decision support tools.Keywords: claims data, decision-making, heterogeneous treatment effects, effect modification, confounding by indication, prediction-based decision rules

Background Self-reported time spent standing has been associated with lower risk of mortality. No previous studies have examined this association using device-measured standing. Method This was a prospective cohort study of 5878 older (median age = 80 years), racial/ethnically diverse, community-dwelling women in the WHI Objective Physical Activity and Cardiovascular Health Study (OPACH). Women wore accelerometers for 1 week and were followed for mortality. The study applied previously validated machine learning algorithms to ActiGraph GT3X+ accelerometer data to separately measure time spent standing with and without ambulation. Cox proportional hazards models were used to estimate mortality risk adjusting for potential confounders. Effect modification by age, body mass index, moderate-to-vigorous physical activity, sedentary time, physical functioning, and race/ethnicity was evaluated. Results There were 691 deaths during 26 649 person-years of follow-up through March 31, 2018 (mean follow-up = 4.8 years). In fully adjusted models, all-cause mortality risk was lower among those with more standing without ambulation (quartile [Q] 4 vs Q1 HR = 0.63; 95% CI = 0.49–0.81, p-trend = .003) and more standing with ambulation (Q4 vs Q1 HR = 0.50; 95% CI = 0.35–0.71, p-trend < .001). Associations of standing with ambulation and mortality were stronger among women with above-median sedentary time (HR = 0.51; 95% CI = 0.38–0.68) compared to women with below-median sedentary time (HR = 0.80; 95% CI = 0.59–1.07; p-interaction = .02). Conclusions In this prospective study among older women, higher levels of accelerometer-measured standing were associated with lower risks of all-cause mortality. Standing is an achievable approach to interrupting prolonged sedentary time, and if not contraindicated, is a safe and feasible behavior that appears to benefit health in older ages.

Standard network meta-analysis and indirect comparisons combine aggregate data from multiple studies on treatments of interest, assuming that any factors that interact with treatment effects (effect modifiers) are balanced across populations. Population adjustment methods such as multilevel network meta-regression (ML-NMR), matching-adjusted indirect comparison (MAIC), and simulated treatment comparison (STC) relax this assumption using individual patient data from one or more studies, and are becoming increasingly prevalent in health technology appraisals and the applied literature.Motivated by an applied example and two recent reviews of applications, we undertook an extensive simulation study to assess the performance of these methods in a range of scenarios under various failures of assumptions. We investigated the impact of varying sample size, missing effect modifiers, strength of effect modification and validity of the shared effect modifier assumption, validity of extrapolation and varying between-study overlap, and different covariate distributions and correlations.ML-NMR and STC performed similarly, eliminating bias when the requisite assumptions were met. Serious concerns are raised for MAIC, which performed poorly in nearly all simulation scenarios and may even increase bias compared to standard indirect comparisons. All methods incur bias when an effect modifier is missing, highlighting the necessity of careful selection of potential effect modifiers prior to analysis. When all effect modifiers are included, ML-NMR and STC are robust techniques for population adjustment. ML-NMR offers additional advantages over MAIC and STC, including extending to larger treatment networks and producing estimates in any target population, making this an attractive choice in a variety of scenarios.

PURPOSE Previous work has demonstrated that home care patients have an increased risk of visiting the emergency department after a home nursing visit on the same day. We investigated whether this association is modified by greater access to after-hours primary care. METHODS We conducted a population-based case-crossover study of home care patients in Ontario, Canada in 2014-2016. Emergency department visits after 5:00 pm were selected as case periods and matched, within the same patient, to control periods within the previous week. The association between home nursing visits and same-day emergency department visits was estimated with conditional logistic regression. Access to after-hours primary care, measured on the patient and practice level, was tested for effect modification using an interaction term approach. Analysis was performed separately for all emergency department visits and a less urgent subset not admitted to hospital. RESULTS A total of 11,840 patients contributed cases to the analysis. Patients with a history of after-hours primary care use had a smaller increased risk of a same-day after-hours emergency department visit (OR = 1.18; 95% CI, 1.06-1.30) compared with patients with no after-hours care (OR = 1.31; 95% CI, 1.25-1.39). The modifying effect was stronger among emergency department visits not admitted to hospital (OR = 1.11; 95% CI, 0.97-1.28 vs OR = 1.41; 95% CI, 1.31-1.51). CONCLUSION Greater access to after-hours primary care reduced the risk of less-urgent emergency department use associated with home nursing visits. These findings suggest increasing access to after-hours primary care could prevent some less-urgent emergency department visits.

The article summarizes the most recent results from the cohorts of uranium miners, particularly the risks at low exposures and the risk models with modifying effects of exposure rate, age and time since exposure, which are used for the calculation of lifetime risks (LRs). The excess relative risks per unit exposure (ERR/WLM) arising from low exposures were found up to 10 times higher than the crude risk coefficients. For studies that reported models with modifying effect of age, time since exposure and exposure rate, LRs were calculated using the BEIR VI projection. These LRs were also calculated for a model with effect modification on the annual exposure rate. The results were prepared for the UNSCEAR report on ‘Lung cancer from exposure to radon.’(1)

Resident operative involvement is an integral aspect of general surgery residency training. However, current data examining the effect of resident autonomy on perioperative outcomes remain limited. Patient and operator-specific data were collected from 344 adult laparoscopic cholecystectomies at a tertiary academic institution and its regional affiliates between 2018 and 2019. Multivariate modeling compared postoperative outcomes between cases completed with or without resident involvement and its effect modification by resident seniority and autonomy per Zwisch scale. Outcomes include 30-day postoperative complications, hospital readmission rate, and operative time. Multivariate analysis revealed resident involvement in laparoscopic cholecystectomy did not significantly change odds of 30-day postoperative complications (OR 2.52, p = 0.185, 95% CI 0.64–9.92) or hospital readmission (OR 1.61, p = 0.538, 95% CI 0.36–7.23). Operative time is significantly increased compared to faculty-only cases (IRR 1.37, p

International audience; The role of progesterone receptor (PR) status on the association between obesity and prognosis of estrogen receptor positive (ER+) breast cancer (BC) remains poorly understood. We aim to examine whether this association varies according to the tumor PR status. Data for 3,747 women diagnosed with nonmetastatic ER+ invasive BC between 1995 and 2010 were analyzed. Women were classified according to their body mass index (BMI) (

Background Food packages provided by the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) were revised in 2009 to better align them with the Dietary Guidelines for Americans. This study was conducted to evaluate whether the effect of the food package change on childhood obesity varied by the food environment in the neighborhoods where WIC-participating children live. Methods Administrative data from participating children in Los Angeles County, California (2003–2016) were merged with geocoded food vendor information by neighborhood of residence. Obesity risk at age 4 was compared between children receiving old (2003–2009) and new (2010–2016) WIC food packages using sex-stratified Poisson regression models, with interaction terms between WIC package and neighborhood density (number per square mile) of healthy and unhealthy food outlets. Results The new food package was associated with a significant decrease in obesity risk. Among boys, the new food package was associated with 8 to 18% lower obesity risk at all healthy and unhealthy food outlet densities, and the association was not modified by neighborhood food outlet density. Among girls, the association of the new food package with obesity risk was protective in neighborhoods with high healthy and low unhealthy food outlet densities, and adverse in neighborhoods with high unhealthy and low healthy food outlet densities. The effect of the new food package among girls was modified by unhealthy food outlet density, with significantly smaller (p-value = 0.004) decreases in obesity risk observed in neighborhoods with higher unhealthy food outlet density. Conclusions The impact of the food package change was modified by the neighborhood food environment among girls only. Future policy changes should incorporate consideration of ways to mitigate potentially inequitable geographic distribution of the health benefits of policy changes.

Indirect comparisons are used to obtain estimates of relative effectiveness between two treatments that have not been compared in the same randomised controlled trial, but have instead been compared against a common comparator in separate trials. Standard indirect comparisons use only aggregate data, under the assumption that there are no differences in effect-modifying variables between the trial populations. Population-adjusted indirect comparisons aim to relax this assumption by using individual patient data (IPD) from one trial to adjust for differences in effect modifiers between populations. At present, the most commonly used approach is matching-adjusted indirect comparison (MAIC), where weights are estimated that match the covariate distributions of the reweighted IPD to the aggregate trial.MAIC was originally proposed using the method of moments to estimate the weights, but more recently entropy balancing has been proposed as an alternative. Entropy balancing has an additional "optimality" property ensuring that the weights are as uniform as possible, reducing the standard error of the estimates.In this brief method note, we show that MAIC weights are mathematically identical whether estimated using entropy balancing or the method of moments. Importantly, this means that the standard MAIC (based on the method of moments) also enjoys the "optimality" property. Moreover, the additional flexibility of entropy balancing suggests several interesting avenues for further research, such as combining population adjustment via MAIC with adjustments for treatment switching or non-parametric covariate adjustment.

Background Although recently published randomised controlled trials did not confirm significant positive effect of ART-123 or polymyxin B‑immobilised haemoperfusion (PMX-HP) on survival outcome, previous studies using a dataset of 3195 patients with sepsis registered at 42 intensive care units throughout Japan revealed significantly reduced mortality following these treatments. A study has suggested the efficacy of combination therapy with ART-123 and PMX-HP; however, it did not evaluate the effect modification between them. We hypothesised that coadministration of ART-123 and PMX-HP has a significant positive effect modification on survival outcome. The purpose of this study was to evaluate the effect modification between ART-123 and PMX-HP treatment on the survival outcome of sepsis using post hoc analysis of the dataset of the Japan Septic Disseminated Intravascular Coagulation registry. Results Of the 3195 patients recorded in the registry, 2350 were analysed. The product term between ART-123 and PMX-HP was analysed by the Cox regression model to evaluate significance. The primary outcome of this study was hospital mortality. Although the administration of ART-123 was independently positively associated with survival outcome (adjusted hazard ratio [HR]: 0.834, 95% confidence interval [CI] 0.695–0.999; P = 0.049) in the model prior to the introduction of the product term, a significant effect modification on survival outcome was observed between the administration of ART-123 and PMX-HP treatment (adjusted HR: 0.667, 95% CI 0.462–0.961; P = 0.030). Conclusions The main effect of the administration of ART-123 may be beneficial for survival outcome in patients with sepsis. In addition, a significant beneficial effect modification on survival outcome was observed between the administration of ART-123 and PMX-HP treatment.

The majority of research within reproductive and gynecologic health, or investigating ART, is observational in design. One of the most critical challenges for observational studies is confounding, while one of the most important for discovery and inference is effect modification. In this commentary, we explain what confounding and effect modification are and why they matter. We present examples illustrating how failing to adjust for a confounder leads to invalid conclusions, as well as examples where adjusting for a factor that is not a confounder also leads to invalid or imprecise conclusions. Careful consideration of which factors may act as confounders or modifiers of the association of interest is critical to conducting sound research, particularly with complex observational studies in reproductive medicine.

Objective Overuse of diagnostic tests is of particular concern for pediatric academic medical centers. Our objective was to measure variation in testing based on proportion of hospitalization during the day versus night and the association between attending in-house coverage on the teaching service and test utilization for hospitalized pediatric patients. Methods Electronic health record data from 11,567 hospitalizations to a large, Northeastern, academic pediatric hospital were collected between January 2007 and December 2010. The patient-level dataset included orders for laboratory and imaging tests, information about who placed the order, and the timing of the order. Using a cross-sectional effect modification analysis, we estimated the difference in test utilization attributable to attending in-house coverage. Results We found that admission to the teaching service was independently associated with higher utilization of laboratory and imaging tests. However, the number of orders was 0.76 lower (95% confidence interval:−1.31 to −0.21, P = .006) per 10% increase in the proportion in the share of the hospitalization that occurred during daytime hours on the teaching services, which is attributable to direct attending supervision. Conclusions Direct attending care of hospitalized pediatric patients at night was associated with slightly lower diagnostic test utilization.

Background Serum gamma-glutamyl transferase (GGT) is a marker of oxidative stress, associated with increased cardiovascular (CV) risk. The impact of smoking on oxidative stress may be aggravated in individuals with non-alcoholic fatty liver disease (NAFLD). We aimed to ascertain the association of smoking on GGT levels in the presence or absence of NAFLD. Methods We evaluated 6,354 healthy subjects (43 ± 10 years, 79% males) without clinical cardiovascular disease (CVD) undergoing an employer-sponsored physical between December 2008 and December 2010. NAFLD was diagnosed by ultrasound and participants were categorized as current or non-smokers by self report. A multivariate linear regression of the cross-sectional association between smoking and GGT was conducted based on NAFLD status. Results The prevalence of NAFLD was 36% (n = 2,299) and 564 (9%) were current smokers. Smokers had significantly higher GGT levels in the presence of NAFLD (P < 0.001). After multivariable adjustment, current smoking was associated with 4.65 IU/L higher GGT level, P < 0.001, compared to non-smokers. When stratified by NAFLD, the magnitude of this association was higher in subjects with NAFLD (β-coefficient: 11.12; 95% confidence interval (CI): 5.76 - 16.48; P < 0.001); however, no such relationship was observed in those without NAFLD (β: -0.02; 95% CI: -3.59, 3.56; P = 0.992). Overall the interaction of NAFLD and smoking with GGT levels as markers of oxidative stress was statistically significant. Conclusions Smoking is independently associated with significantly increased oxidative stress as measured by GGT level. This association demonstrates effect modification by NAFLD status, suggesting that smoking may intensify CV risk in individuals with NAFLD.

This study aims to (1) assess the associations between sugar-sweetened beverages (SSB) consumption and C-reactive protein (CRP) levels, and (2) evaluate the modifying effect of body mass index (BMI) on the association between SSB consumption and CRP levels. A total of 6856 eligible adults were selected from the 2007–2010 National Health and Nutrition Examination Survey (NHANES). Average quantity of SSB consumption was calculated from 2-day 24-h dietary recalls. All data analyses were performed with appropriate sampling weights. Compared with non-SSB drinkers, a 0.26 mg/l higher CRP was observed in heavy SSB drinkers after adjusting for demographic characteristics, lifestyle patterns, and BMI. An effect modification of BMI on SSB intake and CRP levels was detected (P

Background Male infants have a higher incidence of invasive group B Streptococcus disease (iGBS) compared with female infants; however, data on sex differences in mortality and long-term outcomes after iGBS are lacking. We assessed whether a child’s sex influences the effects of iGBS on mortality and risk of neurodevelopmental impairments (NDIs). Methods We used Danish and Dutch registry data to conduct a nationwide cohort study of infants with a history of iGBS. A comparison cohort, children without a history of iGBS, was randomly selected and matched on relevant factors. Effect modification by sex was assessed on additive and multiplicative scales. Results Our analyses included data from children with a history of iGBS in Denmark (period 1997 -2017; n = 1432) and the Netherlands (2000 -2017; n = 697) and from 21 172 children without iGBS. There was no clear evidence of between-sex heterogeneity in iGBS-associated mortality. Boys had a higher risk of NDI, with evidence for effect modification on additive scale at the age of 5 years for any NDI (relative excess risk due to interaction = 1.28; 95% confidence interval [CI], -0.53 to 3.09 in Denmark and 1.14; 95% CI, -5.13 to 7.41 in the Netherlands). A similar pattern was observed for moderate/severe NDI at age 5 years in Denmark and age 10 years in the Netherlands. Conclusion Boys are at higher risk of NDI ; our results suggest this is disproportionally increased in those who develop iGBS. Future studies should investigate mechanisms of this effect modification by sex.

Objective: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. Design: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. Setting: Population-based. Patient(s): We included 8,500 women with ovarian cancer, 13,592 control women. Intervention(s): Ten well-established ovarian cancer risk factors. Main Outcome Measure(s): Risk of ovarian cancer for women with and without endometriosis. Result(s): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25–2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00–1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91–1.05) when compared with BMI 18.5–2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94–1.57) to women without (OR = 1.13; 95% CI, 1.04–1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04–1.84 vs. OR = 1.12; 95% CI, 1.01–1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09–3.24 vs. OR = 1.42; 95% CI, 1.14–1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). Conclusion(s): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

Background Hand, foot, and mouth disease (HFMD) is an epidemic infectious disease in China. Relationship of neighborhood greenness with human health has been widely studied, yet its association with severe HFMD has not yet been established. Methods Individual HFMD cases that occurred in Guangdong province in 2010 were recruited and were categorised into mild and severe cases. Residential greenness was assessed using global land cover data. We used a case-control design (i.e., severe versus mild cases) with logistic regression models to assess the association between neighborhood greenness and HFMD severity. Effect modification was also examined. Results A total of 131,606 cases were included, of whom 130,840 were mild cases and 766 were severe cases. In an unadjusted model, HFMD severity increased with higher proportion of neighborhood greenness (odds ratio, OR = 1.029, 95%CI: 1.009–1.050). The greenness-HFMD severity association remained (OR = 1.031, 95%CI: 1.006–1.057) after adjusting for population density, demographic variables and climate variables. Both population density (Z = 4.148, P P 2. While in both the subgroups of population density being higher than 5, the greenness had hazard effects (subgroup of > 5 & ≤7: OR = 1.071, 95%CI: 1.024–1.120; subgroup of > 7: OR = 1.065, 95%CI: 1.034–1.097) on HFMD severity. As to relative humidity, statistically significant association between greenness and HFMD severity was only observed in the subgroup of being lower than and equal to 76% (OR = 1.059, 95%CI: 1.023–1.096). Conclusions Our study found that HFMD severity is associated with the neighborhood greenness in Guangdong, China. This study provides evidence on developing a prevention strategy of discouraging the high-risk groups from going to the crowded green spaces during the epidemic period.