Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression

<b>Background:b> Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.<br /><b><br />Methods/Design:b> To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.<br /><br /><i>Study eligibility criteria:i> Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.<br /><br /><i>Data sources:i> This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.&nbsp; The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.<br /><b><br />Discussion: b>Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.

A meta-analysis of the effects of measuring theory of planned behaviour constructs on behaviour within prospective studies

Measurement reactivity effects, such as the mere measurement effect, have been proposed as a reason for behavioural changes in a number of theory of planned behaviour intervention studies. However, it is unclear whether such changes are the result of the mere measurement effect or of other artefacts of intervention study design. The aim of this study is to determine the size and direction of changes in health behaviours from baseline to follow-up in prospective studies using the theory of planned behaviour. Electronic databases were searched for the theory of planned behaviour studies which measured health behaviours at two or more time points. Change in behaviour was calculated for all studies. Sixty-six studies were included. Mean effect sizes across all studies were small and negative (d = -.03). Effect size was moderated by behaviour, behaviour type and follow-up length. Subgroup analyses showed significant decreases in socially undesirable behaviour (d = -.28), binge drinking (d = -.17), risk driving (d = -.20), sugar snack consumption (d = -.43) and sun-protective behaviour (d = -.18). Measurement of intention at baseline resulted in significant decreases in undesirable behaviour. Changes in undesirable behaviours reported in other studies may be the result of the mere measurement effect.

Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications

It has been postulated that schizophrenia (SZ) is related to a lower expression of brain-derived neurotrophic factor (BDNF). In the past few years, an increasing number of divergent clinical studies assessing BDNF in serum and plasma have been published. It is now possible to verify the relationship between BDNF levels and severity of symptoms in SZ as well as the effects of antipsychotic drugs on BDNF using meta-analysis. The aims of this study were to verify if peripheral BDNF is decreased in SZ, whether its levels are correlated with positive and negative symptomatology and if BDNF levels change after antipsychotic treatment. This report consists of two distinct meta-analyses of peripheral BDNF in SZ including a total of 41 studies and more than 7000 participants: (1) peripheral BDNF levels in serum and plasma were moderately reduced in SZ compared with controls. Notably, this decrease was accentuated with the disease duration. However, the extent of peripheral BDNF level decrease did not correlate with the severity of positive and negative symptoms. (2) In plasma, but not serum, peripheral BDNF levels are consistently increased after antipsychotic treatment irrespective of the patient's response to medication. In conclusion, there is compelling evidence that there are decreased levels of peripheral BDNF in SZ, in parallel to previously described reduced cerebral BDNF expression. It remains unclear whether these systemic changes are causally related to the development of SZ or if they are merely a pathologic epiphenomenon.Molecular Psychiatry advance online publication, 30 September 2014; doi:10.1038/mp.2014.117.

Adipokines as emerging depression biomarkers: a systematic review and meta-analysis

Adiponectin, leptin and resistin may play a role in the pathophysiology of major depressive disorder (MDD). However, differences in peripheral levels of these hormones are inconsistent across diagnostic and intervention studies. Therefore, we performed meta-analyses of diagnostic studies (i.e., MDD subjects versus healthy controls) and intervention investigations (i.e., pre-vs. post-antidepressant treatment) in MDD. Adiponectin (N=1278; Hedge's g=-0.35; P=0.16) and leptin (N=893; Hedge's g=-0.018; P=0.93) did not differ across diagnostic studies. Meta-regression analyses revealed that gender and depression severity explained the heterogeneity observed in adiponectin diagnostic studies, while BMI and the difference in BMI between MDD individuals and controls explained the heterogeneity of leptin diagnostic studies. Subgroup analyses revealed that adiponectin peripheral levels were significantly lower in MDD participants compared to controls when assayed with RIA, but not ELISA. Leptin levels were significantly higher in individuals with mild/moderate depression versus controls. Resistin serum levels were lower in MDD individuals compared to healthy controls (N=298; Hedge's g=-0.25; P=0.03). Leptin serum levels did not change after antidepressant treatment. However, heterogeneity was significant and sample size was low (N=108); consequently meta-regression analysis could not be performed. Intervention meta-analyses could not be performed for adiponectin and resistin (i.e., few studies met inclusion criteria). In conclusion, this systematic review and meta-analysis underscored that relevant moderators/confounders (e.g., BMI, depression severity and type of assay) should be controlled for when considering the role of leptin and adiponectin as putative MDD diagnostic biomarkers.

Multivitamin-multimineral supplementation and mortality: a meta-analysis of randomized controlled trials

BACKGROUND: Multivitamins are the most commonly used supplement in the developed world. Recent epidemiologic findings suggest that multivitamin use increases the risk of mortality. OBJECTIVE: We aimed to determine whether multivitamin-multimineral treatment, used for primary or secondary prevention, increases the risk of mortality in independently living adults. DESIGN: We performed a meta-analysis of randomized controlled trials. Multiple electronic databases were systematically searched from March to October 2012. Randomized controlled primary or secondary prevention trials were considered for inclusion. Eligible trials investigated daily multivitamin-multimineral supplementation for &ge;1 y. Cohorts described as institutionalized or as having terminal illness (tertiary prevention) were excluded. The number of deaths and the sample size of each study arm were extracted independently by 2 researchers. Twenty-one articles were included in the analysis, which generated a total pooled sample of 91,074 people and 8794 deaths. These trials were pooled in a meta-analysis, and the outcomes were expressed as RRs and 95% CIs. RESULTS: The average age of the pooled sample was 62 y, and the average duration of supplementation was 43 mo. Across all studies, no effect of multivitamin-multimineral treatment on all-cause mortality (RR: 0.98; 95% CI: 0.94, 1.02) was observed. There was a trend for a reduced risk of all-cause mortality across primary prevention trials (RR: 0.94; 95% CI: 0.89, 1.00). Multivitamin-multimineral treatment had no effect on mortality due to vascular causes (RR: 1.01; 95% CI: 0.93, 1.09) or cancer (RR: 0.96; 95% CI: 0.88, 1.04). No statistical evidence of heterogeneity or publication bias was observed. CONCLUSION: Multivitamin-multimineral treatment has no effect on mortality risk.

The effects of multivitamins on cognitive performance: a systematic review and meta-analysis

Complementary medicine use is becoming increasingly popular with multivitamins being the most commonly used vitamin supplement. Although adequate vitamin and nutrient concentrations are necessary for optimal health and cognitive functioning, there is no scientific consensus as to whether multivitamin use prevents cognitive decline or improves mental functioning. The aim of the present study was to determine if multivitamins can be used efficaciously to improve cognitive abilities. A systematic review of randomized controlled trials was performed. Meta-analysis was performed on those cognitive tests used across the largest number of studies. Multiple electronic databases were searched until July 2011 by two authors. Randomized, placebo-controlled trials were considered appropriate if they reported on the chronic effects (&ge;1 month) of oral multivitamin supplementation on any valid cognitive outcomes. Ten trials were included in review (n = 3,200). Meta-analysis indicated that multivitamins were effective in improving immediate free recall memory (SMD = 0.32; 95% CI: 0.09-0.56, p &lt; 0.01) but not delayed free recall memory (SMD = -0.14; 95% CI: -0.43-0.14, p = 0.33) or verbal fluency (SMD = 0.06; 95% CI: -0.05-0.18, p = 0.26). There was no evidence of publication bias or heterogeneity. Other cognitive abilities sensitive to AD pathology, such as executive and visuospatial functions, were found to be under researched. In conclusion, multivitamins were found to enhance immediate free recall memory but no other cognitive domains.

Peripheral vascular endothelial growth factor as a novel depression biomarker: a meta-analysis

BACKGROUND: The neurotrophic hypothesis of major depressive disorder (MDD) postulates that the pathology of this illness incorporates a down-regulation of neurotrophin signaling. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic mediator regarding the neurobiology of MDD. Nevertheless, emerging evidence has implicated the multi-competent angiogenic and neurogenic molecule - vascular endothelial growth factor (VEGF) - in hippocampal neurogenesis and depression pathophysiology. OBJECTIVE: To compare peripheral levels of VEGF between individuals with MDD and healthy controls. METHODS: We performed a systematic review and meta-analysis of original studies measuring peripheral levels of VEGF in participants with MDD compared to healthy controls. We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases for studies published in any language through December 16th, 2014. RESULTS: Fourteen studies met eligibility criteria (N=1633). VEGF levels were significantly elevated in individuals with MDD when compared to healthy controls (Hedges's g=0.343; 95% CI: 0.146-0.540; P&lt;0.01). Funnel plot inspection and the Egger's test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P&lt;0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, sample for assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender emerged as significant sources of heterogeneity. CONCLUSIONS: Taken together, extant data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD.

Prevalence of psychiatric co-morbidity in treatment-seeking problem gamblers: A systematic review and meta-analysis

OBJECTIVE: The aim of this paper was to systematically review and meta-analyse the prevalence of co-morbid psychiatric disorders (DSM-IV Axis I disorders) among treatment-seeking problem gamblers. METHODS: A systematic search was conducted for peer-reviewed studies that provided prevalence estimates of Axis I psychiatric disorders in individuals seeking psychological or pharmacological treatment for problem gambling (including pathological gambling). Meta-analytic techniques were performed to estimate the weighted mean effect size and heterogeneity across studies. RESULTS: Results from 36 studies identified high rates of co-morbid current (74.8%, 95% CI 36.5-93.9) and lifetime (75.5%, 95% CI 46.5-91.8) Axis I disorders. There were high rates of current mood disorders (23.1%, 95% CI 14.9-34.0), alcohol use disorders (21.2%, 95% CI 15.6-28.1), anxiety disorders (17.6%, 95% CI 10.8-27.3) and substance (non-alcohol) use disorders (7.0%, 95% CI 1.7-24.9). Specifically, the highest mean prevalence of current psychiatric disorders was for nicotine dependence (56.4%, 95% CI 35.7-75.2) and major depressive disorder (29.9%, 95% CI 20.5-41.3), with smaller estimates for alcohol abuse (18.2%, 95% CI 13.4-24.2), alcohol dependence (15.2%, 95% CI 10.2-22.0), social phobia (14.9%, 95% CI 2.0-59.8), generalised anxiety disorder (14.4%, 95% CI 3.9-40.8), panic disorder (13.7%, 95% CI 6.7-26.0), post-traumatic stress disorder (12.3%, 95% CI 3.4-35.7), cannabis use disorder (11.5%, 95% CI 4.8-25.0), attention-deficit hyperactivity disorder (9.3%, 95% CI 4.1-19.6), adjustment disorder (9.2%, 95% CI 4.8-17.2), bipolar disorder (8.8%, 95% CI 4.4-17.1) and obsessive-compulsive disorder (8.2%, 95% CI 3.4-18.6). There were no consistent patterns according to gambling problem severity, type of treatment facility and study jurisdiction. Although these estimates were robust to the inclusion of studies with non-representative sampling biases, they should be interpreted with caution as they were highly variable across studies. CONCLUSIONS: The findings highlight the need for gambling treatment services to undertake routine screening and assessment of psychiatric co-morbidity and provide treatment approaches that adequately manage these co-morbid disorders. Further research is required to explore the reasons for the variability observed in the prevalence estimates.

Association between apolipoprotein E polymorphisms and age-related macular degeneration: a HuGE review and meta-analysis

A possible association between apolipoprotein E polymorphisms and age-related macular degeneration has been investigated numerous times, with conflicting results. A previous analysis pooling results from four studies (Schmidt et al., Ophthalmic Genet 2002;23:209-23) suggested an association, but those investigators did not document allele frequencies, the magnitude of the association, or the possible genetic mode of action. Thus, the authors searched MEDLINE from 1966 to December 2005 for any English-language studies reporting genetic associations. Data and study quality were assessed in duplicate. Pooling was performed while checking for heterogeneity and publication bias. Frequencies of the E2 and E4 alleles in Caucasians were approximately 8% and 15%, respectively. Allele- and genotype-based tests of association indicated a risk effect of up to 20% for E2 and a protective effect of up to 40% for E4. E2 appeared to act in a recessive mode and E4 in a dominant mode. There appears to be a differential effect of the E2 and E4 alleles on the risk of age-related macular degeneration, although the possibility of survivor bias needs to be ruled out more definitively.

Meta-analysis of the income and price elasticities of gasoline demand: public policy implications for Latin America

By means of a meta-analysis, this article sets out to estimate average values for the income and price elasticities of gasoline demand and to analyse the reasons for the variations in the elasticities reported by the literature. The findings show that there is publication bias, that the volatility of elasticity estimates is not due to sampling errors alone, and that there are systematic factors explaining these differences. The income and price elasticities of gasoline demand differ between the short and long run and by region, and the estimation can appropriately include the vehicle fleet and the prices of substitute goods, the data types and the estimation methods used. The presence of a low price elasticity suggests that a fuel tax will be inadequate to control rising consumption in a context of rapid economic growth.

Association Between Use of Lung-Protective Ventilation With Lower Tidal Volumes and Clinical Outcomes Among Patients Without Acute Respiratory Distress Syndrome A Meta-analysis

Context Lung-protective mechanical ventilation with the use of lower tidal volumes has been found to improve outcomes of patients with acute respiratory distress syndrome (ARDS). It has been suggested that use of lower tidal volumes also benefits patients who do not have ARDS. Objective To determine whether use of lower tidal volumes is associated with improved outcomes of patients receiving ventilation who do not have ARDS. Data Sources MEDLINE, CINAHL, Web of Science, and Cochrane Central Register of Controlled Trials up to August 2012. Study Selection Eligible studies evaluated use of lower vs higher tidal volumes in patients without ARDS at onset of mechanical ventilation and reported lung injury development, overall mortality, pulmonary infection, atelectasis, and biochemical alterations. Data Extraction Three reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus. Data Synthesis Twenty articles (2822 participants) were included. Meta-analysis using a fixed-effects model showed a decrease in lung injury development (risk ratio [RR], 0.33; 95% CI, 0.23 to 0.47; I-2, 0%; number needed to treat [NNT], 11), and mortality (RR, 0.64; 95% CI, 0.46 to 0.89; I-2, 0%; NNT, 23) in patients receiving ventilation with lower tidal volumes. The results of lung injury development were similar when stratified by the type of study (randomized vs nonrandomized) and were significant only in randomized trials for pulmonary infection and only in nonrandomized trials for mortality. Meta-analysis using a random-effects model showed, in protective ventilation groups, a lower incidence of pulmonary infection (RR, 0.45; 95% CI, 0.22 to 0.92; I-2, 32%; NNT, 26), lower mean (SD) hospital length of stay (6.91 [2.36] vs 8.87 [2.93] days, respectively; standardized mean difference [SMD], 0.51; 95% CI, 0.20 to 0.82; I-2, 75%), higher mean (SD) PaCO2 levels (41.05 [3.79] vs 37.90 [4.19] mm Hg, respectively; SMD, -0.51; 95% CI, -0.70 to -0.32; I-2, 54%), and lower mean (SD) pH values (7.37 [0.03] vs 7.40 [0.04], respectively; SMD, 1.16; 95% CI, 0.31 to 2.02; I-2, 96%) but similar mean (SD) ratios of PaO2 to fraction of inspired oxygen (304.40 [65.7] vs 312.97 [68.13], respectively; SMD, 0.11; 95% CI, -0.06 to 0.27; I-2, 60%). Tidal volume gradients between the 2 groups did not influence significantly the final results. Conclusions Among patients without ARDS, protective ventilation with lower tidal volumes was associated with better clinical outcomes. Some of the limitations of the meta-analysis were the mixed setting of mechanical ventilation (intensive care unit or operating room) and the duration of mechanical ventilation. JAMA. 2012;308(16):1651-1659 www.jama.com

A systematic review with procedural assessments and meta-analysis of Low Level Laser Therapy in lateral elbow tendinopathy (tennis elbow)

Abstract Background Recent reviews have indicated that low level level laser therapy (LLLT) is ineffective in lateral elbow tendinopathy (LET) without assessing validity of treatment procedures and doses or the influence of prior steroid injections. Methods Systematic review with meta-analysis, with primary outcome measures of pain relief and/or global improvement and subgroup analyses of methodological quality, wavelengths and treatment procedures. Results 18 randomised placebo-controlled trials (RCTs) were identified with 13 RCTs (730 patients) meeting the criteria for meta-analysis. 12 RCTs satisfied half or more of the methodological criteria. Publication bias was detected by Egger's graphical test, which showed a negative direction of bias. Ten of the trials included patients with poor prognosis caused by failed steroid injections or other treatment failures, or long symptom duration or severe baseline pain. The weighted mean difference (WMD) for pain relief was 10.2 mm [95% CI: 3.0 to 17.5] and the RR for global improvement was 1.36 [1.16 to 1.60]. Trials which targeted acupuncture points reported negative results, as did trials with wavelengths 820, 830 and 1064 nm. In a subgroup of five trials with 904 nm lasers and one trial with 632 nm wavelength where the lateral elbow tendon insertions were directly irradiated, WMD for pain relief was 17.2 mm [95% CI: 8.5 to 25.9] and 14.0 mm [95% CI: 7.4 to 20.6] respectively, while RR for global pain improvement was only reported for 904 nm at 1.53 [95% CI: 1.28 to 1.83]. LLLT doses in this subgroup ranged between 0.5 and 7.2 Joules. Secondary outcome measures of painfree grip strength, pain pressure threshold, sick leave and follow-up data from 3 to 8 weeks after the end of treatment, showed consistently significant results in favour of the same LLLT subgroup (p < 0.02). No serious side-effects were reported. Conclusion LLLT administered with optimal doses of 904 nm and possibly 632 nm wavelengths directly to the lateral elbow tendon insertions, seem to offer short-term pain relief and less disability in LET, both alone and in conjunction with an exercise regimen. This finding contradicts the conclusions of previous reviews which failed to assess treatment procedures, wavelengths and optimal doses.

A note on the use of the generalized odds ratio in meta-analysis of association studies involving bi- and tri-allelic polymorphisms

Abstract Background The generalized odds ratio (GOR) was recently suggested as a genetic model-free measure for association studies. However, its properties were not extensively investigated. We used Monte Carlo simulations to investigate type-I error rates, power and bias in both effect size and between-study variance estimates of meta-analyses using the GOR as a summary effect, and compared these results to those obtained by usual approaches of model specification. We further applied the GOR in a real meta-analysis of three genome-wide association studies in Alzheimer's disease. Findings For bi-allelic polymorphisms, the GOR performs virtually identical to a standard multiplicative model of analysis (e.g. per-allele odds ratio) for variants acting multiplicatively, but augments slightly the power to detect variants with a dominant mode of action, while reducing the probability to detect recessive variants. Although there were differences among the GOR and usual approaches in terms of bias and type-I error rates, both simulation- and real data-based results provided little indication that these differences will be substantial in practice for meta-analyses involving bi-allelic polymorphisms. However, the use of the GOR may be slightly more powerful for the synthesis of data from tri-allelic variants, particularly when susceptibility alleles are less common in the populations (≤10%). This gain in power may depend on knowledge of the direction of the effects. Conclusions For the synthesis of data from bi-allelic variants, the GOR may be regarded as a multiplicative-like model of analysis. The use of the GOR may be slightly more powerful in the tri-allelic case, particularly when susceptibility alleles are less common in the populations.

Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis

In patients with HIV-1 infection who are starting combination antiretroviral therapy (ART), the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well defined. We did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections, and examined the relation between occurrence and the degree of immunodeficiency. Systematic review identified 54 cohort studies of 13 103 patients starting ART, of whom 1699 developed IRIS. We calculated pooled cumulative incidences with 95% credibility intervals (CrI) by Bayesian methods and did a random-effects metaregression to analyse the relation between CD4 cell count and incidence of IRIS. In patients with previously diagnosed AIDS-defining illnesses, IRIS developed in 37.7% (95% CrI 26.6-49.4) of those with cytomegalovirus retinitis, 19.5% (6.7-44.8) of those with cryptococcal meningitis, 15.7% (9.7-24.5) of those with tuberculosis, 16.7% (2.3-50.7) of those with progressive multifocal leukoencephalopathy, and 6.4% (1.2-24.7) of those with Kaposi's sarcoma, and 12.2% (6.8-19.6) of those with herpes zoster. 16.1% (11.1-22.9) of unselected patients starting ART developed any type of IRIS. 4.5% (2.1-8.6) of patients with any type of IRIS died, 3.2% (0.7-9.2) of those with tuberculosis-associated IRIS died, and 20.8% (5.0-52.7) of those with cryptococcal meningitis died. Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of ART, with a high risk in patients with fewer than 50 cells per microL. Occurrence of IRIS might therefore be reduced by initiation of ART before immunodeficiency becomes advanced.

Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis

Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type. Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships. Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction ¼ 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P ¼ 0.34) or histologic type (P ¼ 0.26). Conclusions: HRT use modifies the BMI-endometrial cancer risk association. Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30.