Biostatistical Analysis of the Schistosomiasis Control Initiative Programme on Schistosoma Prevalence, Intensity and Associated Morbidity

Background: Schistosomiasis remains one of the most prevalent parasitic diseases in developing countries. Goal and objectives: The potential relationship between Schistosoma mansoni and anaemia, was examined using Schistosomiasis Control Initiative (SCI) data on Ugandan children and a randomized clinical trial implemented by colleagues from the London School of Hygiene and Tropical Medicine (LSHTM) in Western Kenya. The impact of large-scale administration of chemotherapy on Schistosoma haematobium infection and associated morbidity was also evaluated using SCI data on Burkinabe children. Evaluation and validation of field applicable tools, such as ultrasound, for the cost-effective diagnosis of schistosomiasis morbidity using SCI baseline data from Malian children was another aim of this thesis. Furthermore, in combination with the ultrasound scans, microscopic examination of urine for detection of S. haematobium eggs, dipsticks for detection of haematuria, tests for circulating antigens and serology tests were examined for the cost-effective assessment of S. haematobium prevalence in an adult’s dataset from Ghana. Methods: Biostatistical analysis of afore mentioned data was applied. Principal findings: Results from SCI and LSHTM studies suggest that anaemia is associated with schistosomiasis in African children, and that such anaemia shows a significant improvement following chemotherapy. Results from the SCI study in Burkina Faso suggested that even a single round of mass chemotherapy can have a substantial impact on S. haematobium infection and its associated morbidity in children. Microscopy and haematuria dipsticks were suggested as sensitive and specific indicators of prevalence of S. haematobium infection in Ghanaian adults. Furthermore, ultrasound global scores were demonstrated to be valuable markers in children for morbidity caused by S. haematobium infection, but ultrasonographic examination is not a reasonable substitute for microscopy or dipsticks for determining the prevalence of this infection. Significance: Finally, the key findings from all the studies presented, emphasizing how these relate to one another, are discussed

Pathways from maternal depression to young adult offspring depression: an exploratory longitudinal mediation analysis.

Maternal depression in the peri-natal period is associated with increased risk for young adult depression in offspring. This study explored mediation of these links via trajectories of child conduct and emotional problems (Strengths and Difficulties Questionnaire) from ages 4-16 years old in data from the Avon Longitudinal Study of Parents and Children cohort (n = 13373). Through gender-specific structural equation models, a composite measure of exposure to early maternal depression (Edinburgh Postnatal Depression Scale), predicted young adult depression at age 18 (Revised Clinical Interview Schedule - distal outcome). Mediational effects were then estimated by testing which parts of joint piecewise latent trajectory models for child/adolescent conduct and emotional problems were associated with both exposure and distal outcome. For girls, only conduct problems in early childhood were consistently indicated to mediate effects of early maternal depression on risk of young adulthood depression. Some evidence for a pathway via changing levels of childhood and adolescent emotional difficulties was also suggested. For boys, by contrast, the differing models gave less consistent findings providing some evidence for a small time-specific indirect effect via early childhood conduct problems. In addition to its practice implications the current methodological application offers considerable potential in exploratory longitudinal developmental mediation studies. © 2016 The Authors International Journal of Methods in Psychiatric Research Published by John Wiley & Sons Ltd

A strengthening evidence-base for mass deworming, but questions remain.

Soil-transmitted helminths, a group of three intestinal parasitic worms, are estimated to affect about a billion people worldwide, predominantly in low-income settings. The world's largest deworming programme is the lymphatic filariasis elimination programme, which combines community-wide treatment with drugs that target soil-transmitted helminths. As these programmes are scaled back because of successful control of lymphatic filariasis, the question of whether and how to continue or expand deworming for soil-transmitted helminths, usually delivered through school-based deworming programmes, remains to be answered

Validation of a new test for Schistosoma haematobium based on detection of Dra1 DNA fragments in urine: evaluation through latent class analysis.

BACKGROUND: Diagnosis of urogenital schistosomiasis in chronically infected adults is challenging but important, especially because long term infection of the bladder and urinary tract can have dire consequences. We evaluated three tests for viable infection: detection of parasite specific DNA Dra1 fragments, haematuria and presence of parasite eggs for sensitivity (Se) and specificity (Sp). METHODS: Over 400 urine specimens collected from adult volunteers in an endemic area in Western Nigeria were assessed for haematuria then filtered in the field, the filter papers dried and later examined for eggs and DNA. The results were stratified according to sex and age and subjected to Latent Class analysis. CONCLUSIONS: Presence of Dra1 in males (Se=100%; Sp=100%) exceeded haematuria (Se=87.6%: Sp=34.7%) and detection of eggs (Se=70.1%; Sp=100%). In females presence of Dra1 was Se=100%: Sp=100%, exceeding haematuria (Se=86.7%: Sp=77.0%) and eggs (Se=70.1%; Sp=100%). Dra1 became undetectable 2 weeks after praziquantel treatment. We conclude detection of Dra1 fragment is a definitive test for the presence of Schistosoma haematobium infection

Associations of smoking and alcohol consumption with healthy ageing: a systematic review and meta-analysis of longitudinal studies.

OBJECTIVES: The number of older people is growing across the world; however, quantitative synthesis of studies examining the impact of lifestyle factors on the ageing process is rare. We conducted a systematic review and meta-analysis of longitudinal studies to synthesise the associations of smoking and alcohol consumption with healthy ageing (HA). METHODS: Major electronic databases were searched from inception to March 2017 (prospectively registered systematic reviews registration number CRD42016038130). Studies were assessed for methodological quality. Random-effect meta-analysis was performed to calculate pooled ORs and 95% CI. RESULTS: In total, we identified 28 studies (n=184 543); 27 studies reported results on smoking, 22 on alcohol consumption. 23 studies reported a significant positive association of never or former smoking with HA and 4 non-significant. 12 studies reported a significant positive association of alcohol consumption with HA, 9 no association and 1 negative. Meta-analysis revealed increased pooled OR of HA for never smokers compared with current smokers (2.36, 95% CI 2.03 to 2.75), never smokers compared with former smokers (1.32, 95% CI 1.23 to 1.41), former or never smokers compared with current smokers (1.72, 95% CI 1.20 to 2.47), never smokers compared with past or current smokers (1.29, 95% CI 1.16 to 1.43); drinkers compared with non-drinkers (1.28, 95% CI 1.08 to 1.52), light drinkers compared with non-drinkers (1.12, 95% CI 1.03 to 1.22), moderate drinkers compared with non-drinkers (1.35, 95% CI 0.93 to 1.97) and high drinkers compared with non-drinkers (1.25, 95% CI 1.09 to 1.44). There was considerable heterogeneity in the definition and measurement of HA and alcohol consumption. CONCLUSIONS: There is consistent evidence from longitudinal studies that smoking is negatively associated with HA. The associations of alcohol consumption with HA are equivocal. Future research should focus on the implementation of a single metric of HA, on the use of consistent drinking assessment among studies and on a full-range of confounding adjustment. Our research also highlighted the limited research on ageing in low-and-middle-income countries

Healthy ageing and the prediction of mortality and incidence dependence in low- and middle- income countries: a 10/66 population-based cohort study.

BACKGROUND: In the absence of a consensus on definition and measurement of healthy ageing, we created a healthy ageing index tallying with the functional ability framework provided by the World Health Organization. To create this index, we employed items of functional ability and intrinsic capacity. The current study aims to establish the predictive validity and discrimination properties of this healthy ageing index in settings in Latin American, part of the 10/66 cohort. METHODS: Population-based cohort studies including 12,865 people ≥65 years old in catchment areas of Cuba, Dominican Republic, Venezuela, Mexico and Peru. We employed latent variable modelling to estimate the healthy ageing scores of each participant. We grouped participants according to the quintiles of the healthy ageing score distribution. Cox's proportional hazard models for mortality and sub-hazard (competing risks) models for incident dependence (i.e. needing care) were calculated per area after a median of 3.9 years and 3.7 years, respectively. Results were pooled together via fixed-effects meta-analysis. Our findings were compared with those obtained from self-rated health. RESULTS: Participants with lowest levels, compared to participants with highest level of healthy ageing, had increased risk of mortality and incident dependence, even after adjusting for sociodemographic and health conditions (HR: 3.25, 95%CI: 2.63-4.02; sub-HR: 5.21, 95%CI: 4.02-6.75). Healthy ageing scores compared to self-rated health had higher population attributable fractions (PAFs) for mortality (43.6% vs 19.3%) and incident dependence (58.6% vs 17.0%), and better discriminative power (Harrell's c-statistic: mortality 0.74 vs 0.72; incident dependence 0.76 vs 0.70). CONCLUSION: These results provide evidence that our healthy ageing index could be a valuable tool for prevention strategies as it demonstrated predictive and discriminative properties. Further research in other cultural settings will assist moving from a theoretical conceptualisation of healthy ageing to a more practical one

Development of a healthy ageing index in Latin American countries - a 10/66 dementia research group population-based study.

BACKGROUND: Our population is ageing and in 2050 more than one out of five people will be 60 years or older; 80% of whom will be living in a low-and-middle income country. Living longer does not entail living healthier; however, there is not a widely accepted measure of healthy ageing hampering policy and research. The World Health Organization defines healthy ageing as the process of developing and maintaining functional ability that will enable well-being in older age. We aimed to create a healthy ageing index (HAI) in a subset of six low-and-middle income countries, part of the 10/66 study, by using items of functional ability and intrinsic capacity. METHODS: The study sample included residents 65-years old and over (n = 12,865) from catchment area sites in Cuba, Dominican Republic, Peru, Venezuela, Mexico and Puerto Rico. Items were collected by interviewing participants or key informants between 2003 and 2010. Two-stage factor analysis was employed and we compared one-factor, second-order and bifactor models. The psychometric properties of the index, including reliability, replicability, unidimensionality and concurrent convergent validity as well as measurement invariance per ethnic group and gender were further examined in the best fit model. RESULTS: The bifactor model displayed superior model fit statistics supporting that a general factor underlies the various items but other subdomain factors are also needed. The HAI indicated excellent reliability (ω = 0.96, ωΗ = 0.84), replicability (H = 0.96), some support for unidimensionality (Explained Common Variance = 0.65) and some concurrent convergent validity with self-rated health. Scalar measurement invariance per ethnic group and gender was supported. CONCLUSIONS: A HAI with excellent psychometric properties was created by using items of functional ability and intrinsic capacity in a subset of six low-and-middle income countries. Further research is needed to explore sub-population differences and to validate this index to other cultural settings

Healthy ageing and the prediction of mortality and incidence dependence in low- and middle- income countries: a 10/66 population-based cohort study

Background: In the absence of a consensus on definition and measurement of healthy ageing, we created a healthy ageing index tallying with the functional ability framework provided by the World Health Organization. To create this index, we employed items of functional ability and intrinsic capacity. The current study aims to establish the predictive validity and discrimination properties of this healthy ageing index in settings in Latin American, part of the 10/66 cohort. Methods: Population-based cohort studies including 12,865 people ≥65 years old in catchment areas of Cuba, Dominican Republic, Venezuela, Mexico and Peru. We employed latent variable modelling to estimate the healthy ageing scores of each participant. We grouped participants according to the quintiles of the healthy ageing score distribution. Cox's proportional hazard models for mortality and sub-hazard (competing risks) models for incident dependence (i.e. needing care) were calculated per area after a median of 3.9 years and 3.7 years, respectively. Results were pooled together via fixed-effects meta-analysis. Our findings were compared with those obtained from self-rated health. Results: Participants with lowest levels, compared to participants with highest level of healthy ageing, had increased risk of mortality and incident dependence, even after adjusting for sociodemographic and health conditions (HR: 3.25, 95%CI: 2.63-4.02; sub-HR: 5.21, 95%CI: 4.02-6.75). Healthy ageing scores compared to self-rated health had higher population attributable fractions (PAFs) for mortality (43.6% vs 19.3%) and incident dependence (58.6% vs 17.0%), and better discriminative power (Harrell's c-statistic: mortality 0.74 vs 0.72; incident dependence 0.76 vs 0.70). Conclusion: These results provide evidence that our healthy ageing index could be a valuable tool for prevention strategies as it demonstrated predictive and discriminative properties. Further research in other cultural settings will assist moving from a theoretical conceptualisation of healthy ageing to a more practical one

Stillbirths and neonatal deaths among 18 942 women with postpartum hemorrhage: Analysis of perinatal outcomes in the WOMAN trial.

OBJECTIVE: To describe the rates and risk factors for stillbirth and pre-discharge neonatal mortality (PDNM), and impact on quality of life (QoL) among women with postpartum hemorrhage (PPH). METHODS: A secondary analysis was conducted of the WOMAN trial, which evaluated the use of tranexamic acid for PPH and collected infant outcome data to assess drug safety. The analysis was restricted to singletons (n=18 942). Overall and country-level rates of stillbirth and PDNM were calculated. Multilevel logistic regression models examined the association of stillbirth and PDNM with selected risks, and the association of mother's QoL at discharge after stillbirth or PDNM. RESULTS: For women with PPH, the rate of stillbirths was 104.42 per 1000 births (n=1978) and the rate of PDNM was 15.56 per 1000 live births (n=264). Cesarean delivery, increasing blood loss, maternal complications, and maternal death were strongly associated with these adverse outcomes. Women with stillbirth and PDNM were significantly more likely to report poorer QoL. CONCLUSION: Women with PPH experience an extremely high rate of stillbirth and slightly elevated PDNM, which is associated with markers of the severity of their condition and impacts on their QoL

Evaluating hybrid controls methodology in early-phase oncology trials: a simulation study based on the MORPHEUS-UC trial

Phase Ib/II oncology trials, despite their small sample sizes, aim to provide information for optimal internal company decision-making concerning novel drug development. Hybrid controls (a combination of the current control arm and controls from one or more sources of historical trial data [HTD]) can be used to increase the statistical precision. Here we assess combining two sources of Roche HTD to construct a hybrid control in targeted therapy for decision-making via an extensive simulation study. Our simulations are based on the real data of one of the experimental arms and the control arm of the MORPHEUS-UC Phase Ib/II study and two Roche HTD for atezolizumab monotherapy. We consider potential complications such as model misspecification, unmeasured confounding, different sample sizes of current treatment groups, and heterogeneity among the three trials. We evaluate two frequentist methods (with both Cox and Weibull accelerated failure time [AFT] models) and three different priors in Bayesian dynamic borrowing (with a Weibull AFT model), and modifications within each of those, when estimating the effect of treatment on survival outcomes and measures of effect such as marginal hazard ratios. We assess the performance of these methods in different settings and potential of generalizations to supplement decisions in early-phase oncology trials. The results show that the proposed joint frequentist methods and noninformative priors within Bayesian dynamic borrowing with no adjustment on covariates are preferred, especially when treatment effects across the three trials are heterogeneous. For generalization of hybrid control methods in such settings we recommend more simulation studies.Comment: 34 pages, 3 figures, 5 tables. To be appear in Pharmaceutical Statistic