Heterogeneity In Effect Estimates Research Articles

Design differences and variation in results between randomised trials and non-randomised emulations: meta-analysis of RCT-DUPLICATE data.

To explore how design emulation and population differences relate to variation in results between randomised controlled trials (RCT) and non-randomised real world evidence (RWE) studies, based on the RCT-DUPLICATE initiative (Randomised, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology). Meta-analysis of RCT-DUPLICATE data. Trials included in RCT-DUPLICATE, a demonstration project that emulated 32 randomised controlled trials using three real world data sources: Optum Clinformatics Data Mart, 2004-19; IBM MarketScan, 2003-17; and subsets of Medicare parts A, B, and D, 2009-17. Trials where the primary analysis resulted in a hazard ratio; 29 RCT-RWE study pairs from RCT-DUPLICATE. Differences and variation in effect sizes between the results from randomised controlled trials and real world evidence studies were investigated. Most of the heterogeneity in effect estimates between the RCT-RWE study pairs in this sample could be explained by three emulation differences in the meta-regression model: treatment started in hospital (which does not appear in health insurance claims data), discontinuation of some baseline treatments at randomisation (which would have been an unusual care decision in clinical practice), and delayed onset of drug effects (which would be under-reported in real world clinical practice because of the relatively short persistence of the treatment). Adding the three emulation differences to the meta-regression reduced heterogeneity from 1.9 to almost 1 (absence of heterogeneity). This analysis suggests that a substantial proportion of the observed variation between results from randomised controlled trials and real world evidence studies can be attributed to differences in design emulation.

Abortion Legal Reform and Neonatal Mortality in Mozambique.

Abortion law reforms have been hypothesized to influence reproductive, maternal, and neonatal health services and health outcomes, as well as social inequalities in health. In 2014, Mozambique legalized abortion in specific circumstances. However, due to challenges implementing the law, there is concern that it may have negatively influenced neonatal outcomes. Using a difference-in-differences design, we used birth history data collected via the Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) between 2004 and 2018 to assemble a panel of 476 939 live births across 17 countries including Mozambique. We estimated the effect of the abortion reform on neonatal mortality by comparing Mozambique to a series of control countries that did not change their abortion policies. We also conducted stratified analyses to examine heterogeneity in effect estimates by household wealth, educational attainment, and rural/urban residence. The reform was associated with an additional 5.6 (95% CI = 1.3, 9.9) neonatal deaths per 1,000 live birth. There was evidence of a differential effect of the reform, with a negative effect of the reform on neonatal outcomes for socially disadvantaged women, including those with no schooling, in poorer households, and living in rural areas. Given the delay in implementation, our analyses suggest that abortion reform in Mozambique was associated with an initial increase in neonatal mortality particularly among socially disadvantaged women. This may be due to the delay in effective implementation, including the dissemination of clear guidelines and expansion of safe abortion services. Longer-term follow-up is needed to assess the impact of the reform after 2018, when services were expanded. Abortion legal reform without adequate implementation and enforcement is unlikely to be sufficient to improve abortion access and health outcomes.

Case management interventions in chronic disease reduce anxiety and depressive symptoms: A systematic review and meta-analysis.

There is no systematic insight into the effect of case management on common complications of chronic diseases, including depressive symptoms and symptoms of anxiety. This is a significant knowledge gap, given that people with a chronic disease such as Parkinson Disease or Alzheimer's Disease have identified care coordination as one of their highest priorities. Furthermore, it remains unclear whether the putative beneficial effects of case management would vary by crucial patient characteristics, such as their age, gender, or disease characteristics. Such insights would shift from "one size fits all" healthcare resource allocation to personalized medicine. We systematically examined the effectiveness of case management interventions on two common complications associated PD and other chronic health conditions: Depressive symptoms and symptoms of anxiety. We identified studies published until November 2022 from PubMed and Embase databases using predefined inclusion criteria. For each study, data were extracted independently by two researchers. First, descriptive and qualitative analyses of all included studies were performed, followed by random-effects meta-analyses to assess the impact of case management interventions on anxiety and depressive symptoms. Second, meta-regression was performed to analyze potential modifying effects of demographic characteristics, disease characteristics and case management components. 23 randomized controlled trials and four non-randomized studies reported data on the effect of case management on symptoms of anxiety (8 studies) or depressive symptoms (26 studies). Across meta-analyses, we observed a statistically significant effect of case management on reducing symptoms of anxiety (Standardized Mean Difference [SMD] = - 0.47; 95% confidence interval [CI]: -0.69, -0.32) and depressive symptoms (SMD = - 0.48; CI: -0.71, -0.25). We found large heterogeneity in effect estimates across studies, but this was not explained by patient population or intervention characteristics. Among people with chronic health conditions, case management has beneficial effects on symptoms of depressive symptoms and symptoms of anxiety. Currently, research on case management interventions are rare. Future studies should assess the utility of case management for potentially preventative and common complications, focusing on the optimal content, frequency, and intensity of case management.

Effect of Maternal Obesity on Fetal Macrosomia: Meta-Analysis

Background: Obesity is a condition that shows an imbalance between height and weight. Obesity in women poses a risk to future pregnancies and their pregnancy outcomes. One of the risks of preg¬nancy in obese women is the birth of babies with excess weight or macrosomia. Excess birth weight can increase the risk of death for both mother and baby. This study aims to examine the effect of obesity in pregnant women on child birth using macrosomia. Subjects and Method: Meta-analysis was performed with the PRISMA flowchart using PubMed, Science Direct, and Google Schoolar databases. Keywords used ((maternal obesity OR obesity in pregnancy) AND (macrosomia OR large for gestational)). There were 11 studies with a cohort design published in 2012-2022 that met the inclusion criteria. Analysis was performed using Revman 5.3. Results: There were 11 articles originating from three continents, namely Asia (2 studies from China, 2 from Saudi Arabia, 1 from Taiwan), the Americas (3 from the United States, 1 from Brazil), and the European continent (1 from Poland and 1 from Spanish). The heterogeneity of effect estimates between primary studies showed I² = 95% (p<0.001), so the analysis used the Random Effect Model (REM). Obese pregnant women had a 2.03 times risk of having a baby with macrosomia compared to pregnant women without obesity (aOR=2.03, 95% CI=1.88 to 2.18; p<0.001). Conclusion: Obesity in pregnant women increases the risk of having a baby with macrosomia. Keywords: maternal obesity, macrosomia.

Impact of molecular diagnostic tests on diagnostic and treatment delays in tuberculosis: a systematic review and meta-analysis

BackgroundCountries with high TB burden have expanded access to molecular diagnostic tests. However, their impact on reducing delays in TB diagnosis and treatment has not been assessed. Our primary aim was to summarize the quantitative evidence on the impact of nucleic acid amplification tests (NAAT) on diagnostic and treatment delays compared to that of the standard of care for drug-sensitive and drug-resistant tuberculosis (DS-TB and DR-TB).MethodsWe searched MEDLINE, EMBASE, Web of Science, and the Global Health databases (from their inception to October 12, 2020) and extracted time delay data for each test. We then analysed the diagnostic and treatment initiation delay separately for DS-TB and DR-TB by comparing smear vs Xpert for DS-TB and culture drug sensitivity testing (DST) vs line probe assay (LPA) for DR-TB. We conducted random effects meta-analyses of differences of the medians to quantify the difference in diagnostic and treatment initiation delay, and we investigated heterogeneity in effect estimates based on the period the test was used in, empiric treatment rate, HIV prevalence, healthcare level, and study design. We also evaluated methodological differences in assessing time delays.ResultsA total of 45 studies were included in this review (DS = 26; DR = 20). We found considerable heterogeneity in the definition and reporting of time delays across the studies. For DS-TB, the use of Xpert reduced diagnostic delay by 1.79 days (95% CI − 0.27 to 3.85) and treatment initiation delay by 2.55 days (95% CI 0.54–4.56) in comparison to sputum microscopy. For DR-TB, use of LPAs reduced diagnostic delay by 40.09 days (95% CI 26.82–53.37) and treatment initiation delay by 45.32 days (95% CI 30.27–60.37) in comparison to any culture DST methods.ConclusionsOur findings indicate that the use of World Health Organization recommended diagnostics for TB reduced delays in diagnosing and initiating TB treatment. Future studies evaluating performance and impact of diagnostics should consider reporting time delay estimates based on the standardized reporting framework.

Interactive effects of heat and air pollution on mortality in Europe using small area data – Results of the exhaustion project

Background and Aim: Studies on the interactive short-term health effects of heat and air pollution are limited and mostly carried out in cities thus providing limited evidence at national level and on the effects in suburban and rural areas. Methods: We used daily data on natural, cardiovascular and respiratory mortality, air temperature, particulate matter (PM2.5, PM10) and ozone (O3) for administrative small areas (municipalities) in five regions of Europe (Norway, England and Wales, Germany, Italy, and the Attica Region, Greece) during the warm season. We applied a two-stage design, where area-specific data were analyzed in the first stage with over-dispersed Poisson regression models, and a random-effects meta-analysis was conducted in the second. The interaction between temperature and air pollutants was analysed by a response-surface model with a tensor smoother. The study reports the effects of air temperature for an increase from 75th to 99th percentile by levels of air pollutants (95th percentile=high, 50th=medium, 5th=low). Results: Overall results showed an effect modification by PM2.5 in the relationship between heat and mortality. For an increase in mean temperature, the overall risk of natural mortality increased by 6.6% (95% CI: -1.9%, 15.8%), 10.9% (95% CI: 2.7%, 19.7%), and 14.2% (95% CI: 4.5%, 24.9%) at the low, medium, and high levels of PM2.5, respectively. Stronger heat effects were observed for respiratory mortality with high PM2.5 levels (25.0%; 95%CI: 6.4%, 46.9%). For O3 we found a suggestion of effect modification in the relationship between heat and mortality, with a trend in effect estimates for increasing levels of O3. Among the five regions some heterogeneity in effect estimates and in the impact of effect modification by air pollution was observed. Conclusions: Evidence of effect modification between heat and air pollutants on mortality during the warm period was found, with slightly heterogeneous patterns within regions.

Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates

Background: Although observational studies demonstrate that higher levels of vascular risk factors are associated with an increased risk of dementia, these associations might be explained by confounding or other biases. Mendelian randomization (MR) uses genetic instruments to test causal relationships in observational data. We sought to determine if genetically predicted modifiable risk factors (type 2 diabetes mellitus, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index, and circulating glucose) are associated with dementia by meta-analysing published MR studies. Secondary objectives were to identify heterogeneity in effect estimates across primary MR studies and to compare meta-analysis results with observational studies. Methods: MR studies were identified by systematic search of Web of Science, OVID and Scopus. We selected primary MR studies investigating the modifiable risk factors of interest. Only one study from each cohort per risk factor was included. A quality assessment tool was developed to primarily assess the three assumptions of MR for each MR study. Data were extracted on study characteristics, exposure and outcome, effect estimates per unit increase, and measures of variation. Effect estimates were pooled to generate an overall estimate, I2 and Cochrane Q values using fixed-effect model. Results: We screened 5211 studies and included 12 primary MR studies after applying inclusion and exclusion criteria. Higher genetically predicted body mass index was associated with a higher odds of dementia (OR 1.03 [1.01, 1.05] per 5 kg/m2 increase, one study, p=0.00285). Fewer hypothesized vascular risk factors were supported by estimates from MR studies than estimates from meta-analyses of observational studies. Conclusion: Genetically predicted body mass index was associated with an increase in risk of dementia.

Causal AI with Real World Data: Do Statins Protect from Alzheimer's Disease Onset?

Causal artificial intelligence aims at developing bias-robust models that can be used to intervene on, rather than just be predictive, of risks or outcomes. However, learning interventional models from observational data, including electronic health records (EHR), is challenging due to inherent bias, e.g., protopathic, confounding, collider. When estimating the effects of treatment interventions, classical approaches like propensity score matching are often used, but they pose limitations with large feature sets, nonlinear/nonparallel treatment group assignments, and collider bias. In this work, we used data from a large EHR consortium -OneFlorida- and evaluated causal statistical/machine learning methods for determining the effect of statin treatment on the risk of Alzheimer's disease, a debated clinical research question. We introduced a combination of directed acyclic graph (DAG) learning and comparison with expert's design, with calculation of the generalized adjustment criterion (GAC), to find an optimal set of covariates for estimation of treatment effects -ameliorating collider bias. The DAG/CAC approach was assessed together with traditional propensity score matching, inverse probability weighting, virtual-twin/counterfactual random forests, and deep counterfactual networks. We showed large heterogeneity in effect estimates upon different model configurations. Our results did not exclude a protective effect of statins, where the DAG/GAC point estimate aligned with the maximum credibility estimate, although the 95% credibility interval included a null effect, warranting further studies and replication.

Comparison of associations between mortality and air pollution exposure estimated with a hybrid, a land-use regression and a dispersion model

IntroductionTo characterize air pollution exposure at a fine spatial scale, different exposure assessment methods have been applied. Comparison of associations with health from different exposure methods are scarce. The aim of this study was to evaluate associations of air pollution based on hybrid, land-use regression (LUR) and dispersion models with natural cause and cause-specific mortality. MethodsWe followed a Dutch national cohort of approximately 10.5 million adults aged 29+ years from 2008 until 2012. We used Cox proportional hazard models with age as underlying time scale and adjusted for several potential individual and area-level socio-economic status confounders to evaluate associations of annual average residential NO2, PM2.5 and BC exposure estimates based on two stochastic models (Dutch LUR, European-wide hybrid) and deterministic Dutch dispersion models. ResultsSpatial variability of PM2.5 and BC exposure was smaller for LUR compared to hybrid and dispersion models. NO2 exposure variability was similar for the three methods. Pearson correlations between hybrid, LUR and dispersion modeled NO2 and BC ranged from 0.72 to 0.83; correlations for PM2.5 were slightly lower (0.61–0.72). In general, all three models showed stronger associations of air pollutants with respiratory disease and lung cancer mortality than with natural cause and cardiovascular disease mortality. The strength of the associations differed between the three exposure models. Associations of air pollutants estimated by LUR were generally weaker compared to associations of air pollutants estimated by hybrid and dispersion models. For natural cause mortality, we found a hazard ratio (HR) of 1.030 (95% confidence interval (CI): 1.019, 1.041) per 10 µg/m3 for hybrid modeled NO2, a HR of 1.003 (95% CI: 0.993, 1.013) per 10 µg/m3 for LUR modeled NO2 and a HR of 1.015 (95% CI: 1.005, 1.024) per 10 µg/m3 for dispersion modeled NO2. ConclusionAir pollution was positively associated with natural cause and cause-specific mortality, but the strength of the associations differed between the three exposure models. Our study documents that the selected exposure model may contribute to heterogeneity in effect estimates of associations between air pollution and health.

A stepped-wedge randomised trial on the impact of early ART initiation on HIV-patients' economic outcomes in Eswatini.

Since 2015, the World Health Organisation (WHO) recommends immediate initiation of antiretroviral therapy (ART) for all HIV-positive patients. Epidemiological evidence points to important health benefits of immediate ART initiation; however, the policy’s impact on the economic aspects of patients' lives remains unknown. We conducted a stepped-wedge cluster-randomised controlled trial in Eswatini to determine the causal impact of immediate ART initiation on patients’ individual- and household-level economic outcomes. Fourteen healthcare facilities were non-randomly matched into pairs and then randomly allocated to transition from the standard of care (ART eligibility at CD4 counts of <350 cells/mm3 until September 2016 and <500 cells/mm3 thereafter) to the ‘Early Initiation of ART for All’ (EAAA) intervention at one of seven timepoints. Patients, healthcare personnel, and outcome assessors remained unblinded. Data were collected via standardised paper-based surveys with HIV-positive adults who were neither pregnant nor breastfeeding. Outcomes were patients’ time use, employment status, household expenditures, and household living standards. A total sample of 3019 participants were interviewed over the duration of the study. The mean number of participants approached at each facility per time step varied from 4 to 112 participants. Using mixed-effects negative binomial regressions accounting for time trends and clustering at the level of the healthcare facility, we found no significant difference between study arms for any economic outcome. Specifically, the EAAA intervention had no significant effect on non-resting time use (RR = 1.00 [CI: 0.96, 1.05, p=0.93]) or income-generating time use (RR = 0.94, [CI: 0.73,1.20, p=0.61]). Employment and household expenditures decreased slightly but not significantly in the EAAA group, with risk ratios of 0.93 [CI: 0.82, 1.04, p=0.21] and 0.92 [CI: 0.79, 1.06, p=0.26], respectively. We also found no significant treatment effect on households’ asset ownership and living standards (RR = 0.96, [CI 0.92, 1.00, p=0.253]). Lastly, there was no evidence of heterogeneity in effect estimates by patients’ sex, age, education, timing of HIV diagnosis and ART initiation. Our findings do not provide evidence that should discourage further investments into scaling up immediate ART for all HIV patients. Funded by the Dutch Postcode Lottery in the Netherlands, Alexander von Humboldt-Stiftung (Humboldt-Stiftung), the Embassy of the Kingdom of the Netherlands in South Africa/Mozambique, British Columbia Centre of Excellence in Canada, Doctors Without Borders (MSF USA), National Center for Advancing Translational Sciences of the National Institutes of Health and Joachim Herz Foundation. NCT02909218 and NCT03789448.

Bayesian analysis of the short-term association of NO2 exposure with local burden of asthmatic symptoms in children

Short-term exposure to air pollution has been associated with exacerbation of respiratory diseases such as asthma. Substantial heterogeneity in effect estimates has been observed between previous studies. This study aims to quantify the local burden of daily asthma symptoms in asthmatic children in a medium-sized city. Air pollution exposure was estimated using the nearest sensor in a fine resolution urban air quality sensor network in the city of Eindhoven, the Netherlands. Bayesian estimates of the exposure response function were obtained by updating a priori information from a meta-analysis with data from a panel study using a daily diary. Five children participated in the panel study, resulting in a total of 400 daily diary records. Positive associations between NO2 and lower respiratory symptoms and medication use were observed. The odds ratio for any lower respiratory symptoms was 1.07 (95% C.I. 0.92, 1.28) expressed per 10 μg m−3 for current day NO2 concentration, using data from the panel study only (uninformative prior). Odds ratios for dry cough and phlegm were close to unity. The pattern of associations agreed well with the updated meta-analysis. The meta-analytic random effects summary estimate was 1.05 (1.02, 1.07) for LRS. Credible intervals substantially narrowed when adding prior information from the meta-analysis. The odds ratio for lower respiratory symptoms with an informative prior was 1.06 (0.99, 1.14). Burden of disease maps showed a strong spatial variability in the number of asthmatic symptoms associated with ambient NO2 derived from a regression kriging model. In total, 70 cases of asthmatic symptoms can daily be associated with NO2 exposure in the city of Eindhoven. We conclude that Bayesian estimates are useful in estimation of specific local air pollution effect estimates and subsequent local burden of disease calculations. With the fine resolution air quality network, neighborhood-specific burden of asthmatic symptoms was assessed.

Outcomes of transcatheter aortic valve replacement in bicuspid aortic valve stenosis.

Due to abnormal valve geometry, patients with bicuspid aortic valve (BAV) have been excluded in many transcatheter aortic valve replacement (TAVR) trials resulting in very limited data with regards to its safety and efficacy. We searched electronic databases including Cochrane Database of Systematic Reviews, MEDLINE and EMBASE for all studies including case series, and original reports published before December 2018 that assessed outcomes following TAVR in BAV stenosis. We also included studies that had patients with TAV for comparison. Pooled effect size was calculated with a random-effect model and weighted for the inverse of variance, to compare outcomes post-TAVR between BAV and TAV. The heterogeneity of effect estimates across the studies was assessed using I2. Publication bias was assessed with funnel plots. Statistical analysis was performed using SPSS version 24 (IBM Corp., SPSS Statistics for Windows, Version 24.0. Armonk, NY.). A total of 19 studies describing 1,332 patients with BAV and 3,610 with TAV. There was no significant difference in the30-day mortality between patients with BAV and TAV [odds ratio (OR): 1.18, 95% confidence interval (CI): 0.7-1.7, P=0.41, I2=0]. One-year mortality rate in the BAV population was 13.1% compared to 15.4% in the TAV patients (P=0.75). Patients with BAV had significantly more moderate to severe paravalvular leak (PVL) post TAVR (PVL ≥3) 8.8% vs. 4.2% in TAV patients (OR: 1.478, 95% CI: 1.000-2.184, P=0.050, I2=0. Device success was significantly higher in TAV patients compared to BAV patients 93.5% vs. 87% (OR: 0.63, 95% CI: 0.49-0.86, P=0.003). TAVR in patients with BAV is associated with a high incidence of paravalvular regurgitation with a comparable 30-day mortality rate to TAV patients. The use of newer generation valve prosthesis improved outcomes.

Mass Azithromycin Distribution to Prevent Childhood Mortality: A Pooled Analysis of Cluster-Randomized Trials.

.Mass drug administration (MDA) with azithromycin may reduce under-5 child mortality (U5M) in sub-Saharan Africa. Here, we conducted a pooled analysis of all published cluster-randomized trials evaluating the effect of azithromycin MDA on child mortality. We pooled data from cluster-randomized trials randomizing communities to azithromycin MDA versus control. We calculated mortality rates in the azithromycin and control arms in each study, and by country for multisite studies including multiple countries. We conducted a two-stage individual community data meta-analysis to estimate the effect of azithromycin for prevention of child mortality. Three randomized controlled trials in four countries (Ethiopia, Malawi, Niger, and Tanzania) were identified. The overall pooled mortality rate was 15.9 per 1,000 person-years (95% confidence interval [CI]: 15.5–16.3). The pooled mortality rate was lower in azithromycin-treated communities than in placebo-treated communities (14.7 deaths per 1,000 person-years, 95% CI: 14.2–15.3 versus 17.2 deaths per 1,000 person-years, 95% CI: 16.5–17.8). There was a 14.4% reduction in all-cause child mortality in communities receiving azithromycin MDA (95% CI: 6.3–21.7% reduction, P = 0.0007). All-cause U5M was lower in communities receiving azithromycin MDA than in control communities, suggesting that azithromycin MDA could be a new tool to reduce child mortality in sub-Saharan Africa. However, heterogeneity in effect estimates suggests that the magnitude of the effect may vary in time and space and is currently not predictable.

Relationship between socioeconomic status and gastrointestinal infections in developed countries: A systematic review and meta-analysis.

BackgroundThe association between socioeconomic status (SES) and health is well-documented; however limited evidence on the relationship between SES and gastrointestinal (GI) infections exists, with published studies producing conflicting results. This systematic review aimed to assess the association between SES and GI infection risk, and explore possible sources of heterogeneity in effect estimates reported in the literature.MethodsMEDLINE, Scopus, Web of Science and grey literature were searched from 1980 to October 2015 for studies reporting an association between GI infections and SES in a representative population sample from a member-country of the Organisation for Economic Co-operation and Development. Harvest plots and meta-regression were used to investigate potential sources of heterogeneity such as age; level of SES variable; GI infection measurement; and predominant mode of transmission. The protocol was registered on PROSPERO: CRD42015027231.ResultsIn total, 6021 studies were identified; 102 met the inclusion criteria. Age was identified as the only statistically significant potential effect modifier of the association between SES and GI infection risk. For children, GI infection risk was higher for those of lower SES versus high (RR 1.51, 95% CI;1.26–1.83), but there was no association for adults (RR 0.79, 95% CI;0.58–1.06). In univariate analysis, the increased risk comparing low and high SES groups was significantly higher for pathogens spread by person-to-person transmission, but lower for environmental pathogens, as compared to foodborne pathogens.ConclusionsDisadvantaged children, but not adults, have greater risk of GI infection compared to their more advantaged counterparts. There was high heterogeneity and many studies were of low quality. More high quality studies are needed to investigate the association between SES and GI infection risk, and future research should stratify analyses by age and pathogen type. Gaining further insight into this relationship will help inform policies to reduce inequalities in GI illness in children.

Oncological outcomes of nerve-sparing radical hysterectomy for cervical cancer: a systematic review.

This study aimed to review the oncologic outcomes of nerve-sparing radical hysterectomy (NSRH) in cervical cancer and to compare them with those of standard conventional radical hysterectomy (CRH). A search of the MEDLINE (Ovid), EMBASE (Ovid), and Cochrane Central Register of Controlled Trials (CENTRAL) databases for studies published to March 3, 2014 was performed using the search term "nerve sparing or radical hysterectomy and cervical cancer." The main outcome measure was the recurrence rate after NSRH. The hazard ratio for recurrence was used to compare NSRH and CRH. A total of 21 studies reported data on oncologic outcomes of NSRH. The recurrence rate after NSRH was reported to be 0 to 19.6 %. Of the 21 studies, 10 comparing outcomes between NSRH and CRH were assessed for their eligibility to be included in a meta-analysis. However, the scarcity and heterogeneity of effect estimates in these comparison trials precluded performance of a meta-analysis. The results showed that the evidence addressing the oncologic safety of NSRH over that of CRH in cervical cancer is neither adequate nor statistically relevant. A properly designed, prospective randomized noninferiority trial is needed to assess the oncologic outcomes of NSRH before this surgical approach is adopted as the standard of care for patients with tumors that have unfavorable prognostic features. Until then, NSRH should be considered primarily for patients with small tumors due to the very low risk of parametrial and lymph node involvement, with maximum benefit conferred to the patient from autonomic nerve preservation without any requirement for adjuvant treatment.

Epidemiological time series studies of PM2.5 and daily mortality and hospital admissions: a systematic review and meta-analysis

BackgroundShort-term exposure to outdoor fine particulate matter (particles with a median aerodynamic diameter <2.5 μm (PM2.5)) air pollution has been associated with adverse health effects. Existing literature reviews have been...

A Systematic Review and Meta-Analysis of Risk Factors for Sexual Transmission of HIV in India

BackgroundApproximately 2.4 million people are living with HIV in India. This large disease burden, and potential for epidemic spread in some areas, demands a full understanding of transmission in that country. We wished to quantify the effects of key sexual risk factors for HIV infection for each gender and among high- and low-HIV risk populations in India.MethodologyWe conducted a systematic review of sexual risk factors for HIV infection from 35 published studies. Risk factors analyzed were: male circumcision/religion, Herpes Simplex Virus 2, syphilis, gonorrhoea, genital ulcer, multiple sexual partners and commercial sex. Studies were included if they met predetermined criteria. Data were extracted and checked by two researchers and random-effects meta analysis of effects was conducted. Heterogeneity in effect estimates was examined by I2 statistic. Publication bias was tested by Begg's test and funnel plots. Meta regression was used to assess effect modification by various study attributes.ResultsAll risk factors were significantly associated with HIV status. The factor most strongly associated with HIV for both sexes was HSV-2 infection (ORmen: 5.87; 95%CI: 2.46–14.03; ORwomen: 6.44; 95%CI: 3.22–12.86). The effect of multiple sexual partners was similar among men (OR = 2.46; 95%CI: 1.91–3.17,) and women (OR = 2.02; 95%CI: 1.43–2.87) and when further stratified by HIV-risk group. The association between HSV-2 and HIV prevalence was consistently stronger than other STIs or self-reported genital ulcer. If the strong associations between HSV-2 and HIV were interpreted causally, these results implied that approximately half of the HIV infections observed in our study population were attributable to HSV-2 infection.ConclusionsThe risk factors examined in our analysis should remain targets of HIV prevention programs. Our results confirm that sexual risk factors for HIV infection continue to be an important part of Indian HIV epidemic 26 years after it began.

Variability in the fraction of ambient fine particulate matter found indoors and observed heterogeneity in health effect estimates

Exposure to ambient (outdoor-generated) fine particulate matter (PM(2.5)) occurs predominantly indoors. The variable efficiency with which ambient PM(2.5) penetrates and persists indoors is a source of exposure error in air pollution epidemiology and could contribute to observed temporal and spatial heterogeneity in health effect estimates. We used a mass balance approach to model F for several scenarios across which heterogeneity in effect estimates has been observed: with geographic location of residence, residential roadway proximity, socioeconomic status, and central air-conditioning use. We found F is higher in close proximity to primary combustion sources (e.g. proximity to traffic) and for lower income homes. F is lower when PM(2.5) is enriched in nitrate and with central air-conditioning use. As a result, exposure error resulting from variability in F will be greatest when these factors have high temporal and/or spatial variability. The circumstances for which F is lower in our calculations correspond to circumstances for which lower effect estimates have been observed in epidemiological studies and higher F values correspond to higher effect estimates. Our results suggest that variability in exposure misclassification resulting from variability in F is a possible contributor to heterogeneity in PM-mediated health effect estimates.

P1-08-02: Pre-Diagnosis Body Mass Index and Breast Cancer Prognosis and Survival: Report from the after Breast Cancer Pooling Project.

Abstract Background: A large body of evidence dating back over 30 years suggests that obese women have poorer survival after a breast cancer (BC) diagnosis compared to non-obese women. Despite most studies supporting an association of elevated risk of overall mortality with obesity, the relationship of obesity with risk of BC recurrence, BC mortality and non-BC mortality remains unclear. Furthermore, reports suggest that the association of BMI with BC outcomes may be U or J shaped, prompting the necessity of examining underweight and more severely obese women as independent groups. We conducted a pooled investigation of pre-diagnosis BMI and BC recurrence and survival using data from the After Breast Cancer Pooling Project (ABCPP). Materials and Methods: The ABCPP includes 14,950 BC survivors from four prospective cohorts (three US and one Shanghai, China) diagnosed from 1990–2006 with invasive primary AJCC Stage I-III BC at ages 20–83 years. A random effects meta-analysis was conducted to assess heterogeneity across studies and poolability of data. Delayed entry Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of pre-diagnosis BMI (underweight &amp;lt;18.5 kg/m2, normal 18.5-&amp;lt;25 kg/m2, overweight 25-&amp;lt;30 kg/m2, obese ≥30 kg/m2) with BC recurrence, BC death, non-BC death, and overall death, adjusted for age at diagnosis, stage, race/ethnicity, menopausal status, hormone receptor status, number of positive lymph nodes, treatment, smoking history, and comorbidity (diabetes, hypertension, and/or CVD). Subgroup analyses further divided the obesity group into obese (30-&amp;lt;35 kg/m2), severely obese (35-&amp;lt;40 kg/m2), and morbidly obese (≥40 kg/m2) categories. Results: No heterogeneity in effect estimates by study was found. 2104 deaths (1416 BC-related) and 2320 recurrences were observed after a mean (SD) of 7.66 (3.95) years of follow-up. Both underweight and obese women had a statistically significant increased risk of overall death compared to normal-weight women (underweight HR=1.69; 95% CI: 1.25, 2.28 and obese HR=1.22; 95% CI: 1.08, 1.38; p for nonlinear association&amp;lt;0.01). Similar associations were found for non-BC death. Obese but not underweight was associated with increased risk of BC death (HR=1.17; 95% CI: 1.01, 1.36) and recurrence (HR=1.11; 95% CI: 0.98, 1.26). When examining finer obesity categories, the morbidly obese women had the greatest risk for all outcomes (overall death HR=1.90; 95% CI: 1.48, 2.45; non-BC death HR= 3.27; 95% CI: 2.25, 4.77; BC death HR = 1.47; 95% CI: 1.05, 2.06; recurrence HR = 1.27; 95% CI: 0.95, 1.71). No effect modification was observed by menopausal status, hormone receptor status, chemotherapy, and smoking. In all analyses, overweight women had similar risk of outcomes compared to normal-weight women. Discussion: In this large pooling study of nearly 15,000 BC survivors, we found that the association between BMI and BC outcomes, specifically overall death and non-BC death, was U shaped with both underweight and obese women at greatest risk. Morbidly obese women were at even greater risk compared to other obesity groups. Maintaining a healthy weight throughout adult life may be beneficial for BC prognosis and survival. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-02.

Perinatal and Neonatal Risk Factors for Autism: A Comprehensive Meta-Analysis

Despite extensive epidemiologic research in the past several decades, the cause of autism is unknown. It is believed that the underlying etiology is polygenic, and that an interaction of environmental and genetic factors underlies the risk. Although several studies have reported that certain obstetrical and neonatal complications may be associated with increased risk of autism, the conclusions of these studies vary, in part, because of differences in methodology, diagnostic criteria, and comparison groups. The aim of this study was to provide the first systematic review and meta-analysis of the relationship between perinatal and neonatal factors and the risk of autism. A search of PubMed, Embase, and PsycInfo databases was conducted for epidemiologic articles published through March 2007 that examined the association between perinatal and neonatal factors and autism. A total of 40 studies met criteria for inclusion in the meta-analysis. A random-effects model was used to calculate a summary effect estimate for each exposure. For each of the several risk factors identified with heterogeneity in effect estimates across studies, meta-regression was used to identify measured methodological factors that could explain between-study variability. Over 60 perinatal and neonatal factors were examined in the 40 selected epidemiologic studies. There was an association between many of these factors and risk of autism. The strongest evidence was found for the following factors: abnormal fetal presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, congenital malformation, low 5-minute Apgar score, feeding difficulties, meconium aspiration, neonatal anemia, ABO or Rh incompatibility, and hyperbilirubinemia. Factors with the strongest evidence against a role in autism risk included anesthesia during delivery, assisted vaginal delivery, postterm birth, high birth weight, and head circumference. These findings provide insufficient evidence implicating any one perinatal or neonatal factor in autism etiology, but suggest combined risk from exposure to multiple perinatal and neonatal complications. Variability in methodology may account for the observed heterogeneity of risk factor effects across studies.