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Publication Global, regional, and national mortality trends in older children and young adolescents (5–14 years) from 1990 to 2016: an analysis of empirical data(2018-01-01) Masquelier, Bruno; Hug, Lucia; Sharrow, David; You, Danzhen; Hogan, Daniel; Hill, Kenneth; Liu, Jing; Pedersen, Jon; Alkema, LeontineSummary Background From 1990 to 2016, the mortality of children younger than 5 years decreased by more than half, and there are plentiful data regarding mortality in this age group through which we can track global progress in reducing the under-5 mortality rate. By contrast, little is known on how the mortality risk among older children (5–9 years) and young adolescents (10–14 years) has changed in this time. We aimed to estimate levels and trends in mortality of children aged 5–14 years in 195 countries from 1990 to 2016. Methods In this analysis of empirical data, we expanded the United Nations Inter-agency Group for Child Mortality Estimation database containing data on children younger than 5 years with 5530 data points regarding children aged 5–14 years. Mortality rates from 1990 to 2016 were obtained from nationally representative birth histories, data on household deaths reported in population censuses, and nationwide systems of civil registration and vital statistics. These data were used in a Bayesian B-spline bias-reduction model to generate smoothed trends with 90% uncertainty intervals, to determine the probability of a child aged 5 years dying before reaching age 15 years. Findings Globally, the probability of a child dying between the ages 5 years and 15 years was 7·5 deaths (90% uncertainty interval 7·2–8·3) per 1000 children in 2016, which was less than a fifth of the risk of dying between birth and age 5 years, which was 41 deaths (39–44) per 1000 children. The mortality risk in children aged 5–14 years decreased by 51% (46–54) between 1990 and 2016, despite not being specifically targeted by health interventions. The annual number of deaths in this age group decreased from 1·7 million (1·7 million–1·8 million) to 1 million (0·9 million–1·1 million) in 1990–2016. In 1990–2000, mortality rates in children aged 5–14 years decreased faster than among children aged 0–4 years. However, since 2000, mortality rates in children younger than 5 years have decreased faster than mortality rates in children aged 5–14 years. The annual rate of reduction in mortality among children younger than 5 years has been 4·0% (3·6–4·3) since 2000, versus 2·7% (2·3–3·0) in children aged 5–14 years. Older children and young adolescents in sub-Saharan Africa are disproportionately more likely to die than those in other regions; 55% (51–58) of deaths of children of this age occur in sub-Saharan Africa, despite having only 21% of the global population of children aged 5–14 years. In 2016, 98% (98–99) of all deaths of children aged 5–14 years occurred in low-income and middle-income countries, and seven countries alone accounted for more than half of the total number of deaths of these children. Interpretation Increased efforts are required to accelerate reductions in mortality among older children and to ensure that they benefit from health policies and interventions as much as younger children. Funding UN Children's Fund, Bill & Melinda Gates Foundation, United States Agency for International Development.Publication Vitamin D Status Is Not Associated with Risk of Early Menopause(2018-01-01) Purdue-Smith, Alexandra C.; Whitcomb, Brian W.; Manson, JoAnn E.; Hankinson, Susan E.; Troy, Lisa M.; Rosner, Bernard A.; Bertone-Johnson, Elizabeth R.Background: Early natural menopause, the cessation of ovarian function before age 45 y, is positively associated with cardiovascular disease and other conditions. Dietary vitamin D intake has been inversely associated with early menopause; however, no previous studies have evaluated risk with regard to plasma 25-hydroxyvitamin D [25(OH)D] concentrations. Objective: We prospectively evaluated associations of total and free 25(OH)D and vitamin D–binding protein (VDBP) concentrations and the risk of early menopause in a case-control study nested within the Nurses’ Health Study II (NHS2). We also considered associations of 25(OH)D and VDBP with anti-Müllerian hormone (AMH) concentrations. Methods: The NHS2 is a prospective study in 116,430 nurses, aged 25–42 y at baseline (1989). Premenopausal plasma blood samples were collected between 1996 and 1999, from which total 25(OH)D and VDBP concentrations were measured and free 25(OH)D concentrations were calculated. Cases experienced menopause between blood collection and age 45 y (n = 328) and were matched 1:1 by age and other factors to controls who experienced menopause after age 48 y (n = 328). Conditional logistic regression models were used to estimate ORs and 95% CIs for early menopause according to each biomarker. Generalized linear models were used to estimate AMH geometric means according to each biomarker. Results: After adjusting for smoking and other factors, total and free 25(OH)D were not associated with early menopause. Quartile 4 compared with quartile 1 ORs were 1.04 (95% CI: 0.60, 1.81) for total 25(OH)D and 0.70 (95% CI: 0.41, 1.20) for free 25(OH)D. 25(OH)D was unrelated to AMH concentrations. VDBP was positively associated with early menopause; the OR comparing the highest with the lowest quartile of VDBP was 1.80 (95% CI: 1.09, 2.98). Conclusions: Our findings suggest that total and free 25(OH)D are not importantly related to the risk of early menopause. VDBP may be associated with increased risk, but replication is warranted.Publication The Effect of Cluster Size Variability on Statistical Power in Cluster-Randomized Trials(2015-01-01) Lauer, Stephen A.; Kleinman, Ken P.; Reich, Nicholas G.The frequency of cluster-randomized trials (CRTs) in peer-reviewed literature has increased exponentially over the past two decades. CRTs are a valuable tool for studying interventions that cannot be effectively implemented or randomized at the individual level. However, some aspects of the design and analysis of data from CRTs are more complex than those for individually randomized controlled trials. One of the key components to designing a successful CRT is calculating the proper sample size (i.e. number of clusters) needed to attain an acceptable level of statistical power. In order to do this, a researcher must make assumptions about the value of several variables, including a fixed mean cluster size. In practice, cluster size can often vary dramatically. Few studies account for the effect of cluster size variation when assessing the statistical power for a given trial. We conducted a simulation study to investigate how the statistical power of CRTs changes with variable cluster sizes. In general, we observed that increases in cluster size variability lead to a decrease in power.Publication The importance of friends and family to recreational gambling, at-risk gambling, and problem gambling(2018-01-01) Mazar, Alissa; Williams, Robert J.; Stanek, Edward J.; Zorn, Martha; Volberg, Rachel A.Background The variables correlated with problem gambling are routinely assessed and fairly well established. However, problem gamblers were all ‘at-risk’ and ‘recreational’ gamblers at some point. Thus, it is instructive from a prevention perspective to also understand the variables which discriminate between recreational gambling and at-risk gambling and whether they are similar or different to the ones correlated with problem gambling. This is the purpose of the present study. Method Between September 2013 to May 2014, a representative sample of 9,523 Massachusetts adults was administered a comprehensive survey of their past year gambling behavior and problem gambling symptomatology. Based on responses to the Problem and Pathological Gambling Measure, respondents were categorized as Non-Gamblers (2,523), Recreational Gamblers (6,271), At-Risk Gamblers (600), or Problem/Pathological Gamblers (129). With the reference category of Recreational Gambler, a series of binary logistic regressions were conducted to identify the demographic, health, and gambling related variables that differentiated Recreational Gamblers from Non-Gamblers, At-Risk-Gamblers, and Problem/Pathological Gamblers. Results The strongest discriminator of being a Non-Gambler rather than a Recreational Gambler was having a lower portion of friends and family that were regular gamblers. Compared to Recreational Gamblers, At-Risk Gamblers were more likely to: gamble at casinos; play the instant and daily lottery; be male; gamble online; and be born outside the United States. Compared to Recreational Gamblers, Problem and Pathological Gamblers were more likely to: play the daily lottery; be Black; gamble at casinos; be male; gamble online; and play the instant lottery. Importantly, having a greater portion of friends and family who were regular gamblers was the second strongest correlate of being both an At-Risk Gambler and Problem/Pathological Gambler. Conclusions These analyses offer an examination of the similarities and differences between gambling subtypes. An important finding throughout the analyses is that the gambling involvement of family and friends is strongly related to Recreational Gambling, At-Risk Gambling, and Problem/Pathological Gambling. This suggests that targeting the social networks of heavily involved Recreational Gamblers and At-Risk Gamblers (in addition to Problem/Pathological Gamblers) could be an important focus of efforts in problem gambling prevention.Publication Comparison of combination methods to create calibrated ensemble forecasts for seasonal influenza in the U.S.(2023-01-01) Wattanachit, Nutcha; Ray, Evan L.; McAndrew, Thomas C.; Reich, Nicholas G.The characteristics of influenza seasons vary substantially from year to year, posing challenges for public health preparation and response. Influenza forecasting is used to inform seasonal outbreak response, which can in turn potentially reduce the impact of an epidemic. The United States Centers for Disease Control and Prevention, in collaboration with external researchers, has run an annual prospective influenza forecasting exercise, known as the FluSight challenge. Uniting theoretical results from the forecasting literature with domain-specific forecasts from influenza outbreaks, we applied parametric forecast combination methods that simultaneously optimize model weights and calibrate the ensemble via a beta transformation and made adjustments to the methods to reduce their complexity. We used the beta-transformed linear pool, the finite beta mixture model, and their equal weight adaptations to produce ensemble forecasts retrospectively for the 2016/2017, 2017/2018, and 2018/2019 influenza seasons in the U.S. We compared their performance to methods that were used in the FluSight challenge to produce the FluSight Network ensemble, namely the equally weighted linear pool and the linear pool. Ensemble forecasts produced from methods with a beta transformation were shown to outperform those from the equally weighted linear pool and the linear pool for all week-ahead targets across in the test seasons based on average log scores. We observed improvements in overall accuracy despite the beta-transformed linear pool or beta mixture methods' modest under-prediction across all targets and seasons. Combination techniques that explicitly adjust for known calibration issues in linear pooling should be considered to improve probabilistic scores in outbreak settings.Publication Childhood and adulthood passive and active smoking, and the ABO group as risk factors for pancreatic cancer in women(2023-01-01) Vedie, Anne-Laure; Laouali, Nasser; Gelot, Amandine; Severi, Gianluca; Boutron-Ruault, Marie-Christine; Rebours, VincianeObjectives Active smoking and the A blood group are associated with pancreatic adenocarcinoma (PC) risk. However, potential interactions between those risk factors and the role of passive smoking have been little investigated. We aimed to explore specific and joint associations of passive and active smoking, and effect modification by the ABO blood group in French women. Methods The study included 96,594 women from the E3N prospective cohort, mean age: 49 years (SD 6.7). Information on active and passive smoking was reported at inclusion and throughout follow-up. Cases were classified according to the International Classification of Diseases 10. Associations with passive and active smoking and effect modification by the ABO blood group were investigated with multivariable Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results During a 24-year median follow-up, 346 incident PC cases were identified. Current smoking compared with never and former smoking (HR 1.51 [95% CI 1.08–2.10]), and passive smoking in childhood compared with no childhood exposure (HR 1.47 [95% CI 1.08–2.00]) were associated with increased PC risk, but not passive exposure in adulthood (HR 1.16 [95% CI 0.91–1.47]). Exposure to both passive smoking in childhood and current smoking was associated with a stronger risk (HR 2.80 [95% CI 1.42–5.52]) than exposure to both current smoking and passive smoking only in adulthood (HR 1.68 [95% CI 1.10–2.57]) compared with neither passive nor active smoking. Associations between active smoking and PC risk were strongest in the O or B groups, while associations with passive smoking were strongest in the A or AB blood groups, but the interaction terms were not statistically significant. Conclusions Both current smoking and passive smoking in childhood were associated with PC risk, with a maximal risk of current smokers exposed to passive smoking during childhood. Possible interactions between blood groups and active or passive smoking must be investigated in a larger series.Publication A cross-ancestry genome-wide meta-analysis, fine-mapping, and gene prioritization approach to characterize the genetic architecture of adiponectin(2023-01-01) Spracklen, Casssandra N.Publication A Simple Test of Class-Level Genetics Association Can Reveal Novel Cardiometabolic Trait Loci(2016-01-01) Qian, Jing; Nunez, Sara; Reed, Eric; Reilly, Muredach P.; Foulkes, Andrea S.Background Characterizing the genetic determinants of complex diseases can be further augmented by incorporating knowledge of underlying structure or classifications of the genome, such as newly developed mappings of protein-coding genes, epigenetic marks, enhancer elements and non-coding RNAs. Methods We apply a simple class-level testing framework, termed Genetic Class Association Testing (GenCAT), to identify protein-coding gene association with 14 cardiometabolic (CMD) related traits across 6 publicly available genome wide association (GWA) meta-analysis data resources. GenCAT uses SNP-level meta-analysis test statistics across all SNPs within a class of elements, as well as the size of the class and its unique correlation structure, to determine if the class is statistically meaningful. The novelty of findings is evaluated through investigation of regional signals. A subset of findings are validated using recently updated, larger meta-analysis resources. A simulation study is presented to characterize overall performance with respect to power, control of family-wise error and computational efficiency. All analysis is performed using the GenCAT package, R version 3.2.1. Results We demonstrate that class-level testing complements the common first stage minP approach that involves individual SNP-level testing followed by post-hoc ascribing of statistically significant SNPs to genes and loci. GenCAT suggests 54 protein-coding genes at 41 distinct loci for the 13 CMD traits investigated in the discovery analysis, that are beyond the discoveries of minP alone. An additional application to biological pathways demonstrates flexibility in defining genetic classes. Conclusions We conclude that it would be prudent to include class-level testing as standard practice in GWA analysis. GenCAT, for example, can be used as a simple, complementary and efficient strategy for class-level testing that leverages existing data resources, requires only summary level data in the form of test statistics, and adds significant value with respect to its potential for identifying multiple novel and clinically relevant trait associations.Publication Racial and Geographic Variation in Effects of Maternal Education and Neighborhood-Level Measures of Socioeconomic Status on Gestational Age at Birth: Findings From the ECHO Cohorts(2021-01-01) Dunlop, Anne L.; Essalmi, Alicynne Glazier; Alvalos, Lyndsay; Breton, Carrie; Camargo, Carlos A.; Cowell, Whitney J.; Dabelea, Dana; Dager, Stephen R.; Duarte, Cristiane; Kleinman, KenPreterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate's degree, vocational or technical training [reference category]; bachelor's degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor's degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor's degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.Publication Vibrio cholerae in rural and urban Bangladesh, findings from hospital-based surveillance, 2000–2021(2023-01-01) Das, Rina; Nasrin, Sabiha; Palit, Parag; Sobi, Rukaeya Amin; Sultana, Al-Afroza; Khan, Soroar Hossain; Haque, Md. Ahshanul; Nuzhat, Sharika; Ahmed, Tahmeed; Faruque, A. S. G.; Chisti, Mohammod JobayerWith more than 100,000 cases estimated each year, Bangladesh is one of the countries with the highest number of people at risk for cholera. Moreover, Bangladesh is formulating a countrywide cholera-control plan to satisfy the GTFCC (The Global Task Force on Cholera Control) Roadmap's goals. With a particular focus on cholera trends, variance in baseline and clinical characteristics of cholera cases, and trends in antibiotic susceptibility among clinical isolates of Vibrio cholerae, we used data from facility-based surveillance systems from icddr,b’s Dhaka, and Matlab Hospitals from years 2000 to 2021. Female patients comprised 3,553 (43%) in urban and 1,099 (51.6%) in rural sites. Of the cases and most patients 5,236 (63.7%) in urban and 1,208 (56.7%) in the rural site were aged 15 years and more. More than 50% of the families belonged to the poor and lower-middle-class; in 2009 (24.4%) were in urban and in 1,791 (84.2%) were in rural sites. In the urban site, 2,446 (30%) of households used untreated drinking water, and 702 (9%) of families disposed of waste in their courtyard. In the multiple logistic regression analysis, the risk of cholera has significantly increased due to waste disposal in the courtyard and the boiling of water has a protective effect against cholera. Rotavirus (9.7%) was the most prevalent co-pathogen among the under-5 children in both sites. In urban sites, the percentage of V. cholerae along with co-existing ETEC and Campylobacter is changing in the last 20 years; Campylobacter (8.36%) and Enterotoxigenic Escherichia coli (ETEC) (7.15%) were the second and third most prevalent co-pathogens. Shigella (1.64%) was the second most common co-pathogen in the rural site. Azithromycin susceptibility increased slowly from 265 (8%) in 2006–2010 to 1485 (47.8%) in 2016–2021, and erythromycin susceptibility dropped substantially over 20 years period from 2,155 (98.4%) to 21 (0.9%). Tetracycline susceptibility decreased in the urban site from 2051 (45.9%) to 186 (4.2%) and ciprofloxacin susceptibility decreased from 2,581 (31.6%) to 1,360 (16.6%) until 2015, then increased 1,009 (22.6%) and 1,490 (18.2%) in 2016–2021, respectively. Since 2016, doxycycline showed 902 (100%) susceptibility. Clinicians need access to up-to-date information on antimicrobial susceptibility for treating hospitalized patients. To achieve the WHO-backed objective of eliminating cholera by 2030, the health systems need to be put under a proper surveillance system that may help to improve water and sanitation practices and deploy oral cholera vaccines strategically.Publication Improving Probabilistic Infectious Disease Forecasting Through Coherence(2021-01-01) Gibson, Graham Casey; Moran, Kelly R.; Reich, Nicholas G.; Osthus, DaveAuthor summary Seasonal influenza causes a significant public health burden nationwide. Accurate influenza forecasting may help public health officials allocate resources and plan responses to emerging outbreaks. The U.S. Centers for Disease Control and Prevention (CDC) reports influenza data at multiple geographical units, including regionally and nationally, where the national data are by construction a weighted sum of the regional data. In an effort to improve influenza forecast accuracy across all models submitted to the CDC's annual flu forecasting challenge, we examined the effect of imposing this geographical constraint on the set of independent forecasts, made publicly available by the CDC. We developed a novel method to transform forecast densities to obey the geographical constraint that respects the correlation structure between geographical units. This method showed consistent improvement across 79% of models and that held when stratified by targets and test seasons. Our method can be applied to other forecasting systems both within and outside an infectious disease context that have a geographical hierarchy. With an estimated $10.4 billion in medical costs and 31.4 million outpatient visits each year, influenza poses a serious burden of disease in the United States. To provide insights and advance warning into the spread of influenza, the U.S. Centers for Disease Control and Prevention (CDC) runs a challenge for forecasting weighted influenza-like illness (wILI) at the national and regional level. Many models produce independent forecasts for each geographical unit, ignoring the constraint that the national wILI is a weighted sum of regional wILI, where the weights correspond to the population size of the region. We propose a novel algorithm that transforms a set of independent forecast distributions to obey this constraint, which we refer to as probabilistically coherent. Enforcing probabilistic coherence led to an increase in forecast skill for 79% of the models we tested over multiple flu seasons, highlighting the importance of respecting the forecasting system's geographical hierarchy.Publication Modeling of Future COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Rates and Nonpharmaceutical Intervention Scenarios — United States, April–September 2021(2021-01-01) Borchering, Rebecca K.; Viboud, Cécile; Howerton, Emily; Smith, Claire P.; Truelove, Shaun; Runge, Michael C.; Reich, Nicholas G.; Contamin, Lucie; Levander, John; Salerno, JessicaPublication HIV Incidence After Pre-Exposure Prophylaxis Initiation Among Women and Men at Elevated HIV Risk: A Population-Based Study in Rural Kenya and Uganda(2021-01-01) Koss, Catherine A.; Havlir, Diane V.; Ayieko, James; Kwarisiima, Dalsone; Kabami, Jane; Chamie, Gabriel; Atukunda, Mucunguzi; Mwinike, Yusuf; Mwangwa, Florence; Balzer, Laura B.Author summary Why was this study done? Despite major gains in HIV testing and treatment, there were 1.7 million new HIV infections worldwide in 2019, of which nearly 60% occurred in sub-Saharan Africa. Daily oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is highly effective for HIV prevention and could substantially reduce new HIV infections if offered alongside access to HIV testing and treatment. Little is known about the incidence of new HIV infections among PrEP users in settings with generalized HIV epidemics, particularly when offered broadly across communities where access to HIV testing and treatment have already been scaled up. What did the researchers do and find? In 16 communities in rural Kenya and Uganda, we conducted community-wide HIV testing and offered universal access to PrEP with an inclusive approach to eligibility (for persons in serodifferent partnerships, those identified by an HIV risk prediction tool, or those who self-identified as being at risk of HIV). We offered rapid PrEP start and a flexible care delivery model with follow-up visits at health facilities or community-based sites for HIV testing and PrEP refills. Of 74,541 persons who tested negative for HIV, 15,632 (21%) were assessed to be at elevated HIV risk, of whom 5,447 (35%) started PrEP. Overall, 79% of persons who initiated PrEP engaged in the program for follow-up visits. Among PrEP initiators in the 16 study communities, there were 25 seroconversions over 7,150 person-years of follow-up. HIV incidence was 0.35 per 100 person-years (95% confidence interval [CI] 0.22-0.49). In 8 communities, we compared HIV incidence among PrEP initiators to persons with similar characteristics (matched controls) from the year before PrEP was available. Compared to matched controls, HIV incidence was 74% lower among PrEP initiators overall; 76% lower among women who initiated PrEP; and 40% lower among men who initiated PrEP, although this result among men did not reach statistical significance. What do these findings mean? Providing universal access to PrEP in the context of community-wide HIV testing in rural Kenya and Uganda was associated with lower HIV incidence among persons who initiated PrEP compared to matched recent controls. We found lower HIV incidence after PrEP initiation among women, for whom rates of new HIV infections are higher than in men, including in recent prevention studies without PrEP. These results suggest that PrEP may help to close the gap in new infections between men and women. Universal access to HIV testing, treatment, and prevention, including rapid provision of PrEP with flexible service delivery, could reduce HIV incidence in generalized epidemic settings. Background Oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, but data are limited on HIV incidence among PrEP users in generalized epidemic settings, particularly outside of selected risk groups. We performed a population-based PrEP study in rural Kenya and Uganda and sought to evaluate both changes in HIV incidence and clinical and virologic outcomes following seroconversion on PrEP. Methods and findings During population-level HIV testing of individuals >= 15 years in 16 communities in the Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603), we offered universal access to PrEP with enhanced counseling for persons at elevated HIV risk (based on serodifferent partnership, machine learning-based risk score, or self-identified HIV risk). We offered rapid or same-day PrEP initiation and flexible service delivery with follow-up visits at facilities or community-based sites at 4, 12, and every 12 weeks up to week 144. Among participants with incident HIV infection after PrEP initiation, we offered same-day antiretroviral therapy (ART) initiation and analyzed HIV RNA, tenofovir hair concentrations, drug resistance, and viral suppression (<1,000 c/ml based on available assays) after ART start. Using Poisson regression with cluster-robust standard errors, we compared HIV incidence among PrEP initiators to incidence among propensity score-matched recent historical controls (from the year before PrEP availability) in 8 of the 16 communities, adjusted for risk group. Among 74,541 individuals who tested negative for HIV, 15,632/74,541 (21%) were assessed to be at elevated HIV risk; 5,447/15,632 (35%) initiated PrEP (49% female; 29% 15-24 years; 19% in serodifferent partnerships), of whom 79% engaged in >= 1 follow-up visit and 61% self-reported PrEP adherence at >= 1 visit. Over 7,150 person-years of follow-up, HIV incidence was 0.35 per 100 person-years (95% confidence interval [CI] 0.22-0.49) among PrEP initiators. Among matched controls, HIV incidence was 0.92 per 100 person-years (95% CI 0.49-1.41), corresponding to 74% lower incidence among PrEP initiators compared to matched controls (adjusted incidence rate ratio [aIRR] 0.26, 95% CI 0.09-0.75; p = 0.013). Among women, HIV incidence was 76% lower among PrEP initiators versus matched controls (aIRR 0.24, 95% CI 0.07-0.79; p = 0.019); among men, HIV incidence was 40% lower, but not significantly so (aIRR 0.60, 95% CI 0.12-3.05; p = 0.54). Of 25 participants with incident HIV infection (68% women), 7/25 (28%) reported taking PrEP <= 30 days before HIV diagnosis, and 24/25 (96%) started ART. Of those with repeat HIV RNA after ART start, 18/19 (95%) had <1,000 c/ml. One participant with viral non-suppression was found to have transmitted viral resistance, as well as emtricitabine resistance possibly related to PrEP use. Limitations include the lack of contemporaneous controls to assess HIV incidence without PrEP and that plasma samples were not archived to assess for baseline acute infection. Conclusions Population-level offer of PrEP with rapid start and flexible service delivery was associated with 74% lower HIV incidence among PrEP initiators compared to matched recent controls prior to PrEP availability. HIV infections were significantly lower among women who started PrEP. Universal HIV testing with linkage to treatment and prevention, including PrEP, is a promising approach to accelerate reductions in new infections in generalized epidemic settings.Publication Projecting Sex Imbalances at Birth at Global, Regional and National Levels From 2021 to 2100: Scenario-Based Bayesian Probabilistic Projections of the Sex Ratio at Birth and Missing Female Births Based on 3.26 Billion Birth Records(2021-01-01) Chao, Fengqing; Gerland, Patrick; Cook, Alex Richard; Guilmoto, Christophe Z.; Alkema, LeontineIntroduction Skewed levels of the sex ratio at birth (SRB) due to sex-selective abortions have been observed in several countries since the 1970s. They will lead to long-term sex imbalances in more than one-third of the world's population with yet unknown social and economic impacts on affected countries. Understanding the potential evolution of sex imbalances at birth is therefore essential for anticipating and planning for changing sex structures across the world. Methods We produced probabilistic SRB projections from 2021 to 2100 based on different scenarios of sex ratio transition and assessed their implications in terms of missing female births at global, regional and national levels. Based on a comprehensive SRB database with 3.26 billion birth records, we project the skewed SRB and missing female births with a Bayesian hierarchical time series mixture model. The SRB projections under reference scenario S1 assumed SRB transitions only for countries with strong statistical evidence of SRB inflation, and the more extreme scenario S2 assumed a sex ratio transition for countries at risk of SRB inflation but with no or limited evidence of ongoing inflation. Results Under scenario S1, we projected 5.7 (95% uncertainty interval (1.2; 15.3)) million additional missing female births to occur by 2100. Countries affected will be those already affected in the past by imbalanced SRB, such as China and India. If all countries at risk of SRB inflation experience a sex ratio transition as in scenario S2, the projected missing female births increase to 22.1 (12.2; 39.8) million with a sizeable contribution of sub-Saharan Africa. Conclusion The scenario-based projections provide important illustrations of the potential burden of future prenatal sex discrimination and the need to monitor SRBs in countries with son preference. Policy planning will be needed in the years to come to minimise future prenatal sex discrimination and its impact on social structures.Publication Evaluating Epidemic Forecasts in an Interval Format(2021-01-01) Bracher, Johannes; Ray, Evan L.; Gneiting, Tilmann; Reich, Nicholas G.For practical reasons, many forecasts of case, hospitalization, and death counts in the context of the current Coronavirus Disease 2019 (COVID-19) pandemic are issued in the form of central predictive intervals at various levels. This is also the case for the forecasts collected in the COVID-19 Forecast Hub (https://covid19forecasthub.org/). Forecast evaluation metrics like the logarithmic score, which has been applied in several infectious disease forecasting challenges, are then not available as they require full predictive distributions. This article provides an overview of how established methods for the evaluation of quantile and interval forecasts can be applied to epidemic forecasts in this format. Specifically, we discuss the computation and interpretation of the weighted interval score, which is a proper score that approximates the continuous ranked probability score. It can be interpreted as a generalization of the absolute error to probabilistic forecasts and allows for a decomposition into a measure of sharpness and penalties for over- and underprediction. Author summary During the COVID-19 pandemic, model-based probabilistic forecasts of case, hospitalization, and death numbers can help to improve situational awareness and guide public health interventions. The COVID-19 Forecast Hub (https://covid19forecasthub.org/) collects such forecasts from numerous national and international groups. Systematic and statistically sound evaluation of forecasts is an important prerequisite to revise and improve models and to combine different forecasts into ensemble predictions. We provide an intuitive introduction to scoring methods, which are suitable for the interval/quantile-based format used in the Forecast Hub, and compare them to other commonly used performance measures.Publication Characteristics of HIV Seroconverters in the Setting of Universal Test and Treat: Results From the SEARCH Trial in Rural Uganda and Kenya(2021-01-01) Nyabuti, Marilyn N.; Petersen, Maya L.; Bukusi, Elizabeth A.; Kamya, Moses R.; Mwangwa, Florence; Kabami, Jane; Sang, Norton; Charlebois, Edwin D.; Balzer, Laura B.Background Additional progress towards HIV epidemic control requires understanding who remains at risk of HIV infection in the context of high uptake of universal testing and treatment (UTT). We sought to characterize seroconverters and risk factors in the SEARCH UTT trial (NCT01864603), which achieved high uptake of universal HIV testing and ART coverage in 32 communities of adults (>= 15 years) in rural Uganda and Kenya. Methods In a pooled cohort of 117,114 individuals with baseline HIV negative test results, we described those who seroconverted within 3 years, calculated gender-specific HIV incidence rates, evaluated adjusted risk ratios (aRR) for seroconversion using multivariable targeted maximum likelihood estimation, and assessed potential infection sources based on self-report. Results Of 704 seroconverters, 63% were women. Young (15-24 years) men comprised a larger proportion of seroconverters in Western Uganda (18%) than Eastern Uganda (6%) or Kenya (10%). After adjustment for other risk factors, men who were mobile [>= 1 month of prior year living outside community] (aRR:1.68; 95%CI:1.09,2.60) or who HIV tested at home vs. health fair (aRR:2.44; 95%CI:1.89,3.23) were more likely to seroconvert. Women who were aged <= 24 years (aRR:1.91; 95%CI:1.27,2.90), mobile (aRR:1.49; 95%CI:1.04,2.11), or reported a prior HIV test (aRR:1.34; 95%CI:1.06,1.70), or alcohol use (aRR:2.07; 95%CI:1.34,3.22) were more likely to seroconvert. Among survey responders (N = 607, 86%), suspected infection source was more likely for women than men to be >= 10 years older (28% versus 8%) or a spouse (51% vs. 31%) and less likely to be transactional sex (10% versus 16%). Conclusion In the context of universal testing and treatment, additional strategies tailored to regional variability are needed to address HIV infection risks of young women, alcohol users, mobile populations, and those engaged in transactional sex to further reduce HIV incidence rates.Publication Spatio-Temporal Associations Between Deforestation and Malaria Incidence in Lao PDR(2021-01-01) Rerolle, Francois; Dantzer, Emily; Lover, Andrew A.; Marshall, John M.; Hongvanthong, Bouasy; Sturrock, Hugh J. W.; Bennett, AdamAs countries in the Greater Mekong Sub-region (GMS) increasingly focus their malaria control and elimination efforts on reducing forest-related transmission, greater understanding of the relationship between deforestation and malaria incidence will be essential for programs to assess and meet their 2030 elimination goals. Leveraging village-level health facility surveillance data and forest cover data in a spatio-temporal modeling framework, we found evidence that deforestation is associated with short-term increases, but long-term decreases confirmed malaria case incidence in Lao People's Democratic Republic (Lao PDR). We identified strong associations with deforestation measured within 30 km of villages but not with deforestation in the near (10 km) and immediate (1 km) vicinity. Results appear driven by deforestation in densely forested areas and were more pronounced for infections with Plasmodium falciparum (P. falciparum) than for Plasmodium vivax (P. vivax). These findings highlight the influence of forest activities on malaria transmission in the GMS.Publication A Gender Perspective on Gambling Clusters in Sweden using Longitudinal Data(2016-01-01) Romild, Ulla; Svensson, Jessika; Volberg, RachelAIMS - This study describes five groups of gamblers and changes in their gambling involvement and gambling problems over four years with a particular focus on whether gambling problems among men and women develop differently within the five groups. DESIGN - The study sample is a subset of participants from the Swedish Longitudinal Gambling Study (Swelogs). Six different clusters of past-year gambling, based on frequency of participation in the nine most common forms of gambling in Sweden (lotteries, horses, number games, sports games, bingo, poker, slot machines, casino games or TV contests) were identified in Two-Way Cluster Analysis after the first wave of data collection in 2008/09. There were 2,508 individuals identified in EP1 (n=5,012) who then also participated in waves EP2 and EP3 and were selected for the present analysis. METHODS - Statistical analysis was done in SPSS 22.0 using Pearson’s Chi-Square test of Independence (or Fisher’s Exact test when the requirements or expected frequency were not met for Pearson’s Test), Mann-Whitney U-test and logistic regression. P-values below 0.05 were regarded as significant. RESULTS - Gambling remains gendered in Sweden. Even though the clusters are based on gambling activities, there are differences between men and women within the clusters as regards the gambling participation patterns. CONCLUSIONS - Men and women gamble differently, but they may still be equals in their total experience of gambling and in relation to how their gambling problems develop. All differences need to be taken into consideration when preventive actions or messages are created.Publication Type I Error Control for Cluster Randomized Trials Under Varying Small Sample Structures(2021-01-01) Nugent, Joshua R.; Kleinman, Ken P.BackgroundLinear mixed models (LMM) are a common approach to analyzing data from cluster randomized trials (CRTs). Inference on parameters can be performed via Wald tests or likelihood ratio tests (LRT), but both approaches may give incorrect Type I error rates in common finite sample settings. The impact of different combinations of cluster size, number of clusters, intraclass correlation coefficient (ICC), and analysis approach on Type I error rates has not been well studied. Reviews of published CRTs find that small sample sizes are not uncommon, so the performance of different inferential approaches in these settings can guide data analysts to the best choices.MethodsUsing a random-intercept LMM stucture, we use simulations to study Type I error rates with the LRT and Wald test with different degrees of freedom (DF) choices across different combinations of cluster size, number of clusters, and ICC.ResultsOur simulations show that the LRT can be anti-conservative when the ICC is large and the number of clusters is small, with the effect most pronouced when the cluster size is relatively large. Wald tests with the between-within DF method or the Satterthwaite DF approximation maintain Type I error control at the stated level, though they are conservative when the number of clusters, the cluster size, and the ICC are small.ConclusionsDepending on the structure of the CRT, analysts should choose a hypothesis testing approach that will maintain the appropriate Type I error rate for their data. Wald tests with the Satterthwaite DF approximation work well in many circumstances, but in other cases the LRT may have Type I error rates closer to the nominal level.Publication Global, Regional, and National Mortality Trends in Youth Aged 15-24 Years Between 1990 and 2019: a Systemic Analysis(2021-01-01) Masquelier, Bruno; Hug, Lucia; Sharrow, David; You, Danzhen; Mathers, Colin; Gerland, Patrick; Alkema, LeontineBackground The global health community is devoting considerable attention to adolescents and young people, but risk of death in this population is poorly measured. We aimed to reconstruct global, regional, and national mortality trends for youths aged 15-24 years between 1990 and 2019. Methods In this systematic analysis, we used all publicly available data on mortality in the age group 15-24 years for 195 countries, as compiled by the UN Inter-agency Group for Child Mortality Estimation. We used nationally representative vital registration data, estimated the completeness of death registration, and extracted mortality rates from surveys with sibling histories, household deaths reported in censuses, and sample registration systems. We used a Bayesian B-spline bias-reduction model to generate trends in (10)q(15), the probability that an adolescent aged 15 years would die before reaching age 25 years. This model treats observations of the (10)q(15) probability as the product of the actual risk of death and an error multiplier that varies depending on the data source. The main outcome that we assessed was the levels of and trends in youth mortality and the global and regional mortality rates from 1990 to 2019. Findings Globally, the probability of an individual dying between age 15 years and 24 years was 11.2 deaths (90% uncertainty interval [UI] 10.7-12.5) per 1000 youths aged 15 in 2019, which is about 2.5 times less than infant mortality (28.2 deaths [27.2-30.0] by age 1 year per 1000 live births) but is higher than the risk of dying from age 1 to 5 (9.7 deaths [9.1-11.1] per 1000 children aged 1 year). The probability of dying between age 15 years and 24 years declined by 1.4% per year (90% UI 1.1-1.8) between 1990 and 2019, from 17.1 deaths (16.5-18.9) per 1000 in 1990; by contrast with this total decrease of 34% (27-41), under-5 mortality declined by 59% (56-61) in this period. The annual number of deaths declined from 1.7 million (90% UI 1.7-1.9) in 1990 to 1.4 million (1.3-1.5) in 2019. In sub-Saharan Africa, the number of deaths increased by 20.8% from 1990 to 2019. Although 18.3% of the population aged 15-24 years were living in sub-Saharan Africa in 2019, the region accounted for 37.9% (90% UI 34.8-41.9) of all worldwide deaths in youth. Interpretation It is urgent to accelerate progress in reducing youth mortality. Efforts are particularly needed in sub-Saharan Africa, where the burden of mortality is increasingly concentrated. In the future, a growing number of countries will see youth mortality exceeding under-5 mortality if current trends continue. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.