Defining and estimating effects in cluster randomized trials: A methods comparison.

Across research disciplines, cluster randomized trials (CRTs) are commonly implemented to evaluate interventions delivered to groups of participants, such as communities and clinics. Despite advances in the design and analysis of CRTs, several challenges remain. First, there are many possible ways to specify the causal effect of interest (eg, at the individual-level or at the cluster-level). Second, the theoretical and practical performance of common methods for CRT analysis remain poorly understood. Here, we present a general framework to formally define an array of causal effects in terms of summary measures of counterfactual outcomes. Next, we provide a comprehensive overview of CRT estimators, including the t-test, generalized estimating equations (GEE), augmented-GEE, and targeted maximum likelihood estimation (TMLE). Using finite sample simulations, we illustrate the practical performance of these estimators for different causal effects and when, as commonly occurs, there are limited numbers of clusters of different sizes. Finally, our application to data from the Preterm Birth Initiative (PTBi) study demonstrates the real-world impact of varying cluster sizes and targeting effects at the cluster-level or at the individual-level. Specifically, the relative effect of the PTBi intervention was 0.81 at the cluster-level, corresponding to a 19% reduction in outcome incidence, and was 0.66 at the individual-level, corresponding to a 34% reduction in outcome risk. Given its flexibility to estimate a variety of user-specified effects and ability to adaptively adjust for covariates for precision gains while maintaining Type-I error control, we conclude TMLE is a promising tool for CRT analysis.

Predictors of Seeking Care for Influenza-Like Illness in a Novel Digital Study.

Background: Previous research has estimated that >50% of individuals experiencing influenza-like illness (ILI) do not seek health care. Understanding factors influencing care-seeking behavior for viral respiratory infections may help inform policies to improve access to care and protect public health. We used person-generated health data (PGHD) to identify factors associated with seeking care for ILI. Methods: Two observational studies (FluStudy2020, ISP) were conducted during the United States 2019-2020 influenza season. Participants self-reported ILI symptoms using the online Evidation platform. A log-binomial regression model was used to identify factors associated with seeking care. Results: Of 1667 participants in FluStudy2020 and 47 480 participants in ISP eligible for analysis, 518 (31.1%) and 11 426 (24.1%), respectively, sought health care. Participants were mostly female (92.2% FluStudy2020, 80.6% ISP) and aged 18-49 years (89.6% FluStudy2020, 89.8% ISP). In FluStudy2020, factors associated with seeking care included having health insurance (risk ratio [RR], 2.14; 95% CI, 1.30-3.54), more severe respiratory symptoms (RR, 1.53; 95% CI, 1.37-1.71), and comorbidities (RR, 1.37; 95% CI, 1.20-1.58). In ISP, the strongest predictor of seeking care was high symptom number (RR for 6/7 symptoms, 2.14; 95% CI, 1.93-2.38). Conclusions: Using PGHD, we confirmed low rates of health care-seeking behavior for ILI and show that having health insurance, comorbidities, and a high symptom burden were associated with seeking health care. Reducing barriers in access to care for viral respiratory infections may lead to better disease management and contribute to protecting public health.

Assessing the impact of group antenatal care on gestational length in Rwanda: A cluster-randomized trial.

BACKGROUND: Research on group antenatal care in low- and middle-income contexts suggests high acceptability and preliminary implementation success. METHODS: We studied the effect of group antenatal care on gestational age at birth among women in Rwanda, hypothesizing that participation would increase mean gestational length. For this unblinded cluster randomized trial, 36 health centers were pair-matched and randomized; half continued individual antenatal care (control), half implemented group antenatal care (intervention). Women who initiated antenatal care between May 2017 and December 2018 were invited to participate, and included in analyses if they presented before 24 weeks gestation, attended at least two visits, and their birth outcome was obtained. We used a generalized estimating equations model for analysis. FINDINGS: In total, 4091 women in 18 control clusters and 4752 women in 18 intervention clusters were included in the analysis. On average, women attended three total antenatal care visits. Gestational length was equivalent in the intervention and control groups (39.3 weeks (SD 1.6) and 39.3 weeks (SD 1.5)). There were no significant differences between groups in secondary outcomes except that more women in control sites attended postnatal care visits (40.1% versus 29.7%, p = 0.003) and more women in intervention sites attended at least three total antenatal care visits (80.7% versus 71.7%, p = 0.003). No harms were observed. INTERPRETATION: Group antenatal care did not result in a difference in gestational length between groups. This may be due to the low intervention dose. We suggest studies of both the effectiveness and costs of higher doses of group antenatal care among women at higher risk of preterm birth. We observed threats to group care due to facility staff shortages; we recommend studies in which antenatal care providers are exclusively allocated to group antenatal care during visits. TRIAL REGISTRATION: ClinicalTrials.gov NCT03154177.

Super learner analysis of real-time electronically monitored adherence to antiretroviral therapy under constrained optimization and comparison to non-differentiated care approaches for persons living with HIV in rural Uganda.

INTRODUCTION: Real-time electronic adherence monitoring (EAM) systems could inform on-going risk assessment for HIV viraemia and be used to personalize viral load testing schedules. We evaluated the potential of real-time EAM (transferred via cellular signal) and standard EAM (downloaded via USB cable) in rural Uganda to inform individually differentiated viral load testing strategies by applying machine learning approaches. METHODS: We evaluated an observational cohort of persons living with HIV and treated with antiretroviral therapy (ART) who were monitored longitudinally with standard EAM from 2005 to 2011 and real-time EAM from 2011 to 2015. Super learner, an ensemble machine learning method, was used to develop a tool for targeting viral load testing to detect viraemia (>1000 copies/ml) based on clinical (CD4 count, ART regimen), viral load and demographic data, together with EAM-based adherence. Using sample-splitting (cross-validation), we evaluated area under the receiver operating characteristic curve (cvAUC), potential for EAM data to selectively defer viral load tests while minimizing delays in viraemia detection, and performance compared to WHO-recommended testing schedules. RESULTS: In total, 443 persons (1801 person-years) and 485 persons (930 person-years) contributed to standard and real-time EAM analyses respectively. In the 2011 to 2015 dataset, addition of real-time EAM (cvAUC: 0.88; 95% CI: 0.83, 0.93) significantly improved prediction compared to clinical/demographic data alone (cvAUC: 0.78; 95% CI: 0.72, 0.86; p = 0.03). In the 2005 to 2011 dataset, addition of standard EAM (cvAUC: 0.77; 95% CI: 0.72, 0.81) did not significantly improve prediction compared to clinical/demographic data alone (cvAUC: 0.70; 95% CI: 0.64, 0.76; p = 0.08). A hypothetical testing strategy using real-time EAM to guide deferral of viral load tests would have reduced the number of tests by 32% while detecting 87% of viraemia cases without delay. By comparison, the WHO-recommended testing schedule would have reduced the number of tests by 69%, but resulted in delayed detection of viraemia a mean of 74 days for 84% of individuals with viraemia. Similar rules derived from standard EAM also resulted in potential testing frequency reductions. CONCLUSIONS: Our machine learning approach demonstrates potential for combining EAM data with other clinical measures to develop a selective testing rule that reduces number of viral load tests ordered, while still identifying those at highest risk for viraemia.

Group antenatal care versus standard antenatal care and effect on mean gestational age at birth in Rwanda: protocol for a cluster randomized controlled trial.

Background: Group antenatal care has demonstrated promise as a service delivery model that may result in improved outcomes compared to standard antenatal care in socio-demographic populations at disparately high risk for poor perinatal outcomes. Intrigued by results from the United States showing lower preterm birth rates among high-risk women who participate in group antenatal care, partners working together as the Preterm Birth Initiative - Rwanda designed a trial to assess the impact of group antenatal care on gestational age at birth. Methods: This study is a pair-matched cluster randomized controlled trial with four arms. Pairs randomized to group or standard care were further matched with other pairs into quadruples, within which one pair was assigned to implement basic obstetric ultrasound at the health center and early pregnancy testing at the community. At facilities randomized to group care, this will follow the opt-out model of service delivery and individual visits will always be available for those who need or prefer them. The primary outcome of interest is mean gestational age at birth among women who presented for antenatal care before 24 completed weeks of pregnancy and attended more than one antenatal care visit. Secondary outcomes of interest include attendance at antenatal and postnatal care, preterm birth rates, satisfaction of mothers and providers, and feasibility. A convenience sample of women will be recruited to participate in a longitudinal survey in which they will report such indicators as self-reported health-related behaviors and depressive symptoms. Providers will be surveyed about satisfaction and stress. Discussion: This is the largest cluster randomized controlled trial of group antenatal and postnatal care ever conducted, and the first in a low- or middle-income country to examine the effect of this model on gestational age at birth. Trial registration: This study is registered on ClinicalTrials.gov as NCT03154177 May 16, 2017.

A general approach for combining diverse rare variant association tests provides improved robustness across a wider range of genetic architectures.

The widespread availability of genome sequencing data made possible by way of next-generation technologies has yielded a flood of different gene-based rare variant association tests. Most of these tests have been published because they have superior power for particular genetic architectures. However, for applied researchers it is challenging to know which test to choose in practice when little is known a priori about genetic architecture. Recently, tests have been proposed which combine two particular individual tests (one burden and one variance components) to minimize power loss while improving robustness to a wider range of genetic architectures. In our analysis we propose an expansion of these approaches, yielding a general method that works for combining any number of individual tests. We demonstrate that running multiple different tests on the same data set and using a Bonferroni correction for multiple testing is never better than combining tests using our general method. We also find that using a test statistic that is highly robust to the inclusion of non-causal variants (joint-infinity) together with a previously published combined test (sequence kernel adaptive test-optimal) provides improved robustness to a wide range of genetic architectures and should be considered for use in practice. Software for this approach is supplied. We support the increased use of combined tests in practice - as well as further exploration of novel combined testing approaches using the general framework provided here - to maximize robustness of rare variant testing strategies against a wide range of genetic architectures.

Evaluating the impact of genotype errors on rare variant tests of association.

The new class of rare variant tests has usually been evaluated assuming perfect genotype information. In reality, rare variant genotypes may be incorrect, and so rare variant tests should be robust to imperfect data. Errors and uncertainty in SNP genotyping are already known to dramatically impact statistical power for single marker tests on common variants and, in some cases, inflate the type I error rate. Recent results show that uncertainty in genotype calls derived from sequencing reads are dependent on several factors, including read depth, calling algorithm, number of alleles present in the sample, and the frequency at which an allele segregates in the population. We have recently proposed a general framework for the evaluation and investigation of rare variant tests of association, classifying most rare variant tests into one of two broad categories (length or joint tests). We use this framework to relate factors affecting genotype uncertainty to the power and type I error rate of rare variant tests. We find that non-differential genotype errors (an error process that occurs independent of phenotype) decrease power, with larger decreases for extremely rare variants, and for the common homozygote to heterozygote error. Differential genotype errors (an error process that is associated with phenotype status), lead to inflated type I error rates which are more likely to occur at sites with more common homozygote to heterozygote errors than vice versa. Finally, our work suggests that certain rare variant tests and study designs may be more robust to the inclusion of genotype errors. Further work is needed to directly integrate genotype calling algorithm decisions, study costs and test statistic choices to provide comprehensive design and analysis advice which appropriately accounts for the impact of genotype errors.

Identificación de lesiones en los tejidos blandos de la cavidad bucal en adolescentes con privacion de libertad en el odontopediátrico de carapa: Septiembre 2005- abril 2006 venezuela

El Odontopediátra es el responsable de tratar niños, niñas y adolescentes, el cual debe tener presente la posibilidad de encontrar condiciones patológicas a nivel de la cavidad bucal de esta población. El propósito de este estudio fue realizar un levantamiento epidemiológico, de las lesiones patológicas presentes en tejidos blandos de la población adolescente recluida en las entidades para el cumplimiento de la medida socio educativa de privación de libertad y detención preventiva del área metropolitana de Caracas y determinar la relación de estas con las condiciones de supervivencia dentro de las entidades tales como stress, violencia, hacinamiento, malos hábitos, alimentación inadecuada, etc., durante el período Septiembre 2005 - Abril 2006. El presente trabajo se realizó en una población total de 96 pacientes distribuidos en cuatro entidades para el cumplimiento de la medida socio educativa de privación de libertad y detención preventiva, de los cuales fueron estudiados 88 pacientes entre 12 y 19 años de edad, de estos 69 pacientes (91%) presentaron 122 lesiones y 19 pacientes (9%) no presentó lesiones; el género masculino fue el más prevalente con 92,75% y el femenino el 7,25%. Las lesiones más frecuentes fueron la Queilitis Actínica con un 17%, Leucoplasia con 13%, Morsiscatum Bucarum y Fibroma Traumático con 12% cada uno, también se observaron lesiones como Nevus, Mucocele, Úlcera Traumática entre otras. La edad de mayor prevalencia fue entre 16 y 17 años con 68% y la localización anatómica más frecuente fue el Labio Superior en un 49% seguido por carrillo 19%, reborde 14%, paladar, encía y lengua 6% cada una. La etnia mestiza fue la de mayor prevalencia con 44%. El hábito con mayor frecuencia que se encontró fue Queilofagia con 44% y la condición de supervivencia en cuanto a su relación con las lesiones patológicas presentes encontramos que la de mayor prevalencia fue la Ansiedad y Stress con 92%, luego Hacinamiento 6% y Violencia con 2%. Con éste estudio se evidencia la incidencia de lesiones premalignas como es la Leucoplasia en una población adolescente; situación preocupante por demás por la capacidad de transformación neoplásica de sus tejidos y aún más si se relaciona con hábitos como el fumar, alcohol y facticias (lesiones autoinducidas), que pudieran potencializar cambios celulares a nivel de la cavidad bucal de esta población.

The Odontopediatre is the person in charge of treating children and teenagers, who must bear in mind the possibility of finding pathological conditions at the mouth cavity’s levels in a population. The purpose of this study was to discover an epidemiological population at the Odontopediatric Center of Carapa in Caracas, Venezuela. The teenager population at the center was preventive imprisoned to fulfilled social-educative measures in the Caracas metropolitan area. Several pathological injuries were found in their soft tissues. These injuries determine the relation of the living conditions at the center such as stress, violence, bad habits and inadequate nourishment, etc; during September 2005-April 2006 period. The present study carried out a total population of 96 patients, distributed in 4 entities. Around 88 out of these 96 patients were between 12 to 19 years of age. About 69 of these patients (91%) presented 122 injuries and the other 19 patients (9%) did not present any injuries. The masculine genre was the most affected with a 92.75% of injuries. The most frequent injuries were the actinic queilitis with 17%, leukoplakia with 13%, morsiscatum Bucarum and traumatic fibroma with a 12% each. There were also found other types of injuries as Nevus, Mucocele and traumatic sores among others. The most prevalence age was between 16 and 17 years of age with a 68% and the most frequent anatomical location was the lips with 49% followed by buccal mucosa19%, rim 14% and the palate, gingiva, tongue with a 2% respectively. This study demonstrates the incident of pre-malign injuries in a teen population as Leukoplakia. It is an aggravating situation due to the neo-plastic transformation capacity of tissues if they are directly related to bad habits such as smoking and alcohol consumption. These habits could promote cellular changes to the mouth cavity levels of teen population.

Levantamiento epidemiológico de lesiones patológicas en los tejidos blandos de la cavidad bucal de los niños y adolescente del centro odontopediátrico de carapa, parroquia antímano, caracas, distrito capital Venezuela Período mayo - noviembre 2005 / Epidemiological Survey of pathological lesions in the soft tissues of the oral cavity of children and adolescents odontopediátrico of carapa center, parish Antímano, Caracas, Venezuela

El Odontopediátra es el responsable de tratar niños y adolescentes, el cual debe tener presente la posibilidad de encontrar condiciones patológicas a nivel de la cavidad bucal de esta población. El propósito de este estudio fue realizar un levantamiento epidemiológico de lesiones patológicas en tejidos blandos en niños y adolescentes en una región urbana de la ciudad de Caracas - Venezuela, en el Centro Odontopediátrico de Carapa, Parroquia Antímano, en un período de Mayo - Noviembre del 2005. El presente trabajo se realizó en una población de 245 pacientes entre 2 y 17 años de edad, de estos 69 pacientes (28,16 por ciento) presentaron 82 lesiones lo cual equivale al 1,18 por ciento de lesiones patológicas en tejidos blandos; el género masculino fue el más prevalente 56,52 por ciento. Las lesiones más frecuentes fueron el Morsiscatum Buccarum y la Leucoplasia con 15,87 por ciento, seguido por el Fibroma Traumático con 12,19 por ciento, Candidiasis y Glositis Migratoria Benigna el 9,75 por ciento, Úlcera Traumática 8,53 por ciento, Queilitis Actínica y Herpes Recurrente 6,09 por ciento, Mucocele 4,87 por ciento, Quiste de Erupción, Impétigo, Estomatitis Nicotínica y Estomatitis Subprotésica 2,43 por ciento y Úlcera Aftosa Recurrente 1,21 por ciento. La edad de mayor prevalencia fue entre 16 y 17 años 49,27 por ciento y la localización anatómica más frecuente fue Carrillo y Reborde 28 por ciento seguido por labio 25 por ciento, lengua el 16 por ciento. La etnia mestiza fue la de mayor prevalencia con 53,33 por ciento. Con éste estudio se evidencia la incidencia de lesiones premalignas como es la Leucoplasia en una población adolescente; situación preocupante por demás por la capacidad de transformación neoplásica de sus tejidos y aún más si se relaciona con hábitos como el fumar, alcohol y facticias, que pudieran potencializar cambios celulares a nivel de la cavidad bucal de esta población

The Odontopediatra is the person in charge to treat children and adolescents, which must have present the possibility of finding patologicas conditions at level of the buccal cavity of this population. The proposito of this study was to make a epidemiologico rise of patologicas injuries in soft weaves of children and adolescents in an urbana region of the city of Caracas - Venezuela, in the Center Odontopediátrico de Carapa, Antimano Parish, in a period of May - November of the 2005. The present work of realizoen a population of 245 patients between 2 and 17 years of age, of which 69 (28,16 percent) presented/displayed 82 injuries which is equivalent to 1.18 percent of patologicas injuries in soft weaves; I generate masculine was prevalente 56,52 percent; the frequent injuries but were the Morsiscatum Buccarum and the Leucoplasia with 15.87 percent, followed by the Fibroma Traumatic with 12.19 percent, Candidiasis and Benign Migratory Glositis 9.75 percent, Traumatic Ulcer 8.53 percent, Queilitis Actinica and Recurrent Herpes 6.09 percent, Mucoceles 4.87 percent, Cyst of Eruption, Impetigo, Estomatitis Nicotínica and Estomatitis Subprotésica 2.43 percent and Recurrent Aftosa Ulcer 1,21 percent; the age of greater prevalence was between 16 and 17 years 49,27 percent and the most frequent location was Cheek and Rim 28 percent followed by lip 25 percent, language 16 percent. The racially mixed race was the one of greater prevalence with 53,33 percent. With this study the incidence of injuries is demonstrated you previtiate like Leucoplasia in an adolescent population; situation that is worrisome by the capacity of transformation of weaves and still more if it is related to habits like smoking, alcohol and facticias, that could potencializar cellular changes at level of the buccal cavity of this population

Long-term evaluation of a sequential batch reactor (SBR) treating dairy wastewater for carbon removal.

Many dairy industries have been using SBR wastewater treatment plants because they allow optimal working condition to be reached. However, to take advantage of SBR capabilities, strong process automation is needed. The aim of this work is to study the factors that influence SBR performance to improve modelling and control. To better understand the whole process we studied the kinetic modelling, the carbon removal mechanism and the relation between reactor performance, aerobic heterotrophic activity and bacterial population dynamics (by terminal restriction fragment length polymorphisms of 16S rDNA, T-RFLP). The heterotrophic activity values presented high variability during some periods; however, this was not reflected on the reactor performance. As sludge health indicator, the average activity in a period was better than individual values. Although all the carbon removal mechanisms are still unclear for this process, they seemed to be influenced by non-respirometric ways (storage, biosorption, accumulation, etc.). The variability of heterotrophic activity could be correlated with the bacterial population diversity over time. Despite the high variability of the activity, a simple kinetic model (pseudo ASM1) based on apparent constant parameters was developed and calibrated. Such modellisation provided a good tool for control purposes.