Multinomial logistic model for coinfection diagnosis between arbovirus and malaria in Kedougou

In tropical regions, populations continue to suffer morbidity and mortality from malaria and arboviral diseases. In Kedougou (Senegal), these illnesses are all endemic due to the climate and its geographical position. The co-circulation of malaria parasites and arboviruses can explain the observation of coinfected cases. Indeed there is strong resemblance in symptoms between these diseases making problematic targeted medical care of coinfected cases. This is due to the fact that the origin of illness is not obviously known. Some cases could be immunized against one or the other of the pathogens, immunity typically acquired with factors like age and exposure as usual for endemic area. Then, coinfection needs to be better diagnosed. Using data collected from patients in Kedougou region, from 2009 to 2013, we adjusted a multinomial logistic model and selected relevant variables in explaining coinfection status. We observed specific sets of variables explaining each of the diseases exclusively and the coinfection. We tested the independence between arboviral and malaria infections and derived coinfection probabilities from the model fitting. In case of a coinfection probability greater than a threshold value to be calibrated on the data, duration of illness above 3 days and age above 10 years-old are mostly indicative of arboviral disease while body temperature higher than 40{\textdegree}C and presence of nausea or vomiting symptoms during the rainy season are mostly indicative of malaria disease

Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in general populations are related to ASD and common sleep problems like insomnia traits in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as sleep disturbances in children with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection (SSC) and MSSNG database, as well as 7509 individuals from two unselected populations (IMAGEN and Generation Scotland). Sleep duration and insomnia symptoms were parent reported for SSC probands. We identified 335 and 616 rare CNVs encompassing circadian and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (not duplications) were associated with ASD in both cohorts. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Circadian genes did not influence sleep duration or insomnia traits in ASD. Insomnia risk genes intolerant to haploinsufficiency increased risk for insomnia when duplicated. CNVs encompassing circadian and insomnia risk genes increase ASD liability with little to no observable impacts on sleep disturbances

Feasibility and safety of integrating mass drug administration for helminth control with seasonal malaria chemoprevention among Senegalese children: a randomized controlled, observer-blind trial

BACKGROUND: The overlap in the epidemiology of malaria and helminths has been identified as a potential area to exploit for the development of an integrated control strategy that may help to achieve elimination of malaria and helminths. A randomized, controlled, observer-blind trial was conducted to assess the feasibility and safety of combining mass drug administration (MDA) for schistosomiasis and soil transmitted helminths (STH) with seasonal malaria chemoprevention (SMC) among children living in Senegal. METHODS: Female and male children aged 1-14 years were randomized 1:1:1, to receive Vitamin A and Zinc on Day 0, followed by SMC drugs (sulfadoxine-pyrimethamine and amodiaquine) on Days 1-3 (control group); or praziquantel and Vitamin A on Day 0, followed by SMC drugs on Days 1-3 (treatment group 1); or albendazole and praziquantel on Day 0, followed by SMC drugs on Days 1-3 (treatment group 2). Safety assessment was performed by collecting adverse events from all children for six subsequent days following administration of the study drugs. Pre- and post-intervention, blood samples were collected for determination of haemoglobin concentration, malaria microscopy, and PCR assays. Stool samples were analyzed using Kato-Katz, Merthiolate-iodine-formalin and PCR methods. Urine filtration, PCR and circulating cathodic antigen tests were also performed. RESULTS: From 9 to 22 June 2022, 627 children aged 1-14 years were randomized into the three groups described above. Mild, transient vomiting was observed in 12.6% (26/206) of children in treatment group 2, in 10.6% (22/207) in group 1, and in 4.2% (9/214) in the control group (p = 0.005). Pre-intervention, the geometric mean value of Plasmodium falciparum parasite density was highest among children who received albendazole, praziquantel with SMC drugs. Post-intervention, the parasite density was highest among children who received SMC drugs only. Children who received praziquantel and SMC drugs had a lower risk of developing severe anaemia than their counterparts who received SMC drugs alone (OR = 0.81, 95% CI 0.13-5.00, p = 0.63). CONCLUSIONS: Integration of MDA for helminths with SMC drugs was safe and feasible among Senegalese children. These findings support further evaluation of the integrated control model. TRIAL REGISTRATION: The study is registered at Clinical Trial.gov NCT05354258

Mixture model and generalized linear models, application to co-infection data (arbovirus & malaria)

Nous nous intéressons, dans cette thèse, à l'étude des modèles de mélange et des modèles linéaires généralisés, avec une application aux données de co-infection entre les arbovirus et les parasites du paludisme. Après une première partie consacrée à l'étude de la co-infection par un modèle logistique multinomial, nous proposons dans une deuxième partie l'étude des mélanges de modèles linéaires généralisés. La méthode proposée pour estimer les paramètres du mélange est une combinaison d'une méthode des moments et d'une méthode spectrale. Nous proposons à la fin une dernière partie consacrée aux mélanges de valeurs extrêmes en présence de censure. La méthode d'estimation proposée dans cette partie se fait en deux étapes basées sur la maximisation d'une vraisemblance.We are interested, in this thesis, to the study of mixture models and generalized linear models, with an application to co-infection data between arboviruses and malaria parasites. After a first part dedicated to the study of co-infection using a multinomial logistic model, we propose in a second part to study the mixtures of generalized linear models. The proposed method to estimate the parameters of the mixture is a combination of a moment method and a spectral method. Finally, we propose a final section for studing extreme value mixtures under random censoring. The estimation method proposed in this section is done in two steps based on the maximization of a likelihood

Modèle de mélange et modèles linéaires généralisés, application aux données de co-infection (arbovirus & paludisme)

We are interested, in this thesis, to the study of mixture models and generalized linear models, with an application to co-infection data between arboviruses and malaria parasites. After a first part dedicated to the study of co-infection using a multinomial logistic model, we propose in a second part to study the mixtures of generalized linear models. The proposed method to estimate the parameters of the mixture is a combination of a moment method and a spectral method. Finally, we propose a final section for studing extreme value mixtures under random censoring. The estimation method proposed in this section is done in two steps based on the maximization of a likelihood.Nous nous intéressons, dans cette thèse, à l'étude des modèles de mélange et des modèles linéaires généralisés, avec une application aux données de co-infection entre les arbovirus et les parasites du paludisme. Après une première partie consacrée à l'étude de la co-infection par un modèle logistique multinomial, nous proposons dans une deuxième partie l'étude des mélanges de modèles linéaires généralisés. La méthode proposée pour estimer les paramètres du mélange est une combinaison d'une méthode des moments et d'une méthode spectrale. Nous proposons à la fin une dernière partie consacrée aux mélanges de valeurs extrêmes en présence de censure. La méthode d'estimation proposée dans cette partie se fait en deux étapes basées sur la maximisation d'une vraisemblance

Prevalence of malaria-helminth co-infections among children living in a setting of high coverage of standard interventions for malaria and helminths: Two population-based studies in Senegal

BackgroundConcurrent infections of Plasmodium falciparum with Soil Transmitted Helminths (STH) and Schistosoma spp are still a major public health problem among children living in Sub-Saharan Africa. We conducted two prospective studies among children living in urban and rural settings of Senegal, where control programmes for malaria, STH and schistosomiasis have been sustained, to determine the prevalence of malaria-helminth co-infection.MethodsWe enrolled 910 children aged 1–14 years from Saraya and Diourbel districts of Senegal in June and November 2021, respectively. We collected finger-prick blood samples from the children for malaria parasite detection using microscopy and PCR methods. Stool samples were also collected and Kato-Katz and PCR methods were used to detect STH and S. mansoni; and Merthiolate-iodine-formalin (MIF) test for other intestinal protozoans. Urine samples were analyzed using a filtration test, Point of Care Circulating Cathodic Antigens (POC-CCA) and PCR methods for detection of S. haematobium. Statistical analyses were performed to compare the continuous and categorical variables across the two study sites and age groups, as well as using the adjusted Odds ratios (aOR) to explore risk factors for malaria-helminth co-infections.ResultsThe overall prevalence of polyparasitism with P. falciparum, STH, S. haematobium and S. mansoni among children in the two study sites was 2.2% (20/910) while prevalence of P. falciparum-S. haematobium co-infection was 1.1% (10/910); P. falciparum-S. mansoni 0.7% (6/910) and P. falciparum with any intestinal protozoan 2.4% (22/910). Co-infection was slightly higher among 5–14 year old children (17/629, 2.7%; 95% CI: 1.43–3.97) than 1–4 years (3/281, 1.1%; 95% CI: −0.12–2.32) and, in boys (13/567, 2.3%; 95% CI: 1.27–3.96) than girls (7/343, 2.1%; 95% CI: 0.52–3.48). Children aged 5–14 years (aOR = 3.37; 95% CI: 0.82–13.77, p = 0.09), who were boys (aOR = 1.44; 95% CI: 0.48–4.36, p = 0.51) and lived in Saraya (aOR = 1.27; 95% CI: 0.24–6.69, p = 0.77) had a higher risk of malaria-helminth co-infection than other age group, in girls and those who lived in Diourbel. Living in houses with spaces between the walls and roofs as well as frequent contacts with water during swimming were statistically significant risk factors for malaria-helminth co-infection.ConclusionsThe prevalence of malaria-helminth co-infection is low in two districts in Senegal, possibly due to sustained implementation of effective control measures for malaria and NTDs. These findings could help to develop and implement strategies that would lead to elimination of malaria and helminths in the study areas.</jats:sec

Effect sizes of deletions and duplications on autism risk across the genome

International audienceObjective:Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, levels of autism risk conferred by most rare CNVs remain unknown. The authors recently developed statistical models to estimate the effect size on IQ of all CNVs, including undocumented ones. In this study, the authors extended this model to autism susceptibility.Methods:The authors identified CNVs in two autism populations (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models were used to test nine quantitative variables associated with genes encompassed in CNVs to explain their effects on IQ, autism susceptibility, and behavioral domains.Results:The “probability of being loss-of-function intolerant” (pLI) best explains the effect of CNVs on IQ and autism risk. Deleting 1 point of pLI decreases IQ by 2.6 points in autism and unselected populations. The effect of duplications on IQ is threefold smaller. Autism susceptibility increases when deleting or duplicating any point of pLI. This is true for individuals with high or low IQ and after removing de novo and known recurrent neuropsychiatric CNVs. When CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behavior, and phonological memory, whereas both equally affect motor skills.Conclusions:Autism risk conferred by duplications is less influenced by IQ compared with deletions. The model applied in this study, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk and IQ loss. These models will help to interpret CNVs identified in the clinic