Characterising information gains and losses when collecting multiple epidemic model outputs.

BACKGROUND: Collaborative comparisons and combinations of epidemic models are used as policy-relevant evidence during epidemic outbreaks. In the process of collecting multiple model projections, such collaborations may gain or lose relevant information. Typically, modellers contribute a probabilistic summary at each time-step. We compared this to directly collecting simulated trajectories. We aimed to explore information on key epidemic quantities; ensemble uncertainty; and performance against data, investigating potential to continuously gain information from a single cross-sectional collection of model results. METHODS: We compared projections from the European COVID-19 Scenario Modelling Hub. Five teams modelled incidence in Belgium, the Netherlands, and Spain. We compared July 2022 projections by incidence, peaks, and cumulative totals. We created a probabilistic ensemble drawn from all trajectories, and compared to ensembles from a median across each model's quantiles, or a linear opinion pool. We measured the predictive accuracy of individual trajectories against observations, using this in a weighted ensemble. We repeated this sequentially against increasing weeks of observed data. We evaluated these ensembles to reflect performance with varying observed data. RESULTS: By collecting modelled trajectories, we showed policy-relevant epidemic characteristics. Trajectories contained a right-skewed distribution well represented by an ensemble of trajectories or a linear opinion pool, but not models' quantile intervals. Ensembles weighted by performance typically retained the range of plausible incidence over time, and in some cases narrowed this by excluding some epidemic shapes. CONCLUSIONS: We observed several information gains from collecting modelled trajectories rather than quantile distributions, including potential for continuously updated information from a single model collection. The value of information gains and losses may vary with each collaborative effort's aims, depending on the needs of projection users. Understanding the differing information potential of methods to collect model projections can support the accuracy, sustainability, and communication of collaborative infectious disease modelling efforts.

Who acquires infection from whom? A sensitivity analysis of transmission dynamics during the early phase of the COVID-19 pandemic in Belgium.

Age-related heterogeneity in a host population, whether due to how individuals mix and contact each other, the nature of host-pathogen interactions defining epidemiological parameters, or demographics, is crucial in studying infectious disease dynamics. Compartmental models represent a popular approach to address the problem, dividing the population of interest into a discrete and finite number of states depending on, for example, individuals' age and stage of infection. We study the corresponding linearised system whose operator, in the context of a discrete-time model, equates to a square matrix known as the next generation matrix. Performing formal perturbation analysis of the entries of the aforementioned matrix, we derive indices to quantify the age-specific variation of its dominant eigenvalue (i.e., the reproduction number) and explore the relevant epidemiological information we can derive from the eigenstructure of the matrix. The resulting method enables the assessment of the impact of age-related population heterogeneity on virus transmission. In particular, starting from an age-structured SEIR model, we demonstrate the use of this approach for COVID-19 dynamics in Belgium. We analyse the early stages of the SARS-CoV-2 spread, with particular attention to the pre-pandemic framework and the lockdown lifting phase initiated as of May 2020. Our results, influenced by our assumption on age-specific susceptibility and infectiousness, support the hypothesis that transmission was only influenced to a small extent by children in the age group [0,18) and adults over 60 years of age during the early phases of the pandemic and up to the end of July 2020.

Use of Genetically Modified Organism (GMO)-Containing Food Products in Children.

Families increasingly raise questions about the use of genetically modified organism (GMO)-containing food products. These products are widely found in the US food supply but originate from a narrow list of crops. Although GMO technology could be used to increase the micronutrient content of foods, this does not occur in the United States; instead, GMO technology has been used to make crops resistant to chemical herbicides. As a result, herbicide use has increased exponentially. The World Health Organization's International Agency on Research for Cancer has determined that glyphosate, an herbicide widely used in producing GMO food crops, is a probable human carcinogen. Measurable quantities of glyphosate are detected in some GMO foods. Families who wish to minimize GMO food products can do so by focusing on a dietary pattern of primarily whole, plant-based foods while minimizing ultra-processed foods. Pediatricians play a vital role in their efforts to minimize fear-based messaging and support families through shared decision-making. Pediatrician awareness of GMO labeling can guide individualized conversations, particularly that non-GMO labeling does not indicate organic status and that increased cost of some non-GMO foods, especially if also organic, may limit this choice for many families.

Disparities in the non-laboratory INTERHEART risk score and its components in selected countries of Europe and sub-Saharan Africa: analysis from the SPICES multi-country project.

Aims: Accurate prediction of a person's risk of cardiovascular disease (CVD) is vital to initiate appropriate intervention. The non-laboratory INTERHEART risk score (NL-IHRS) is among the tools to estimate future risk of CVD. However, measurement disparities of the tool across contexts are not well documented. Thus, we investigated variation in NL-IHRS and components in selected sub-Saharan African and European countries. Methods and results: We used data from a multi-country study involving 9309 participants, i.e. 4941 in Europe, 3371 in South Africa, and 997 in Uganda. Disparities in total NL-IHRS score, specific subcomponents, subcategories, and their contribution to the total score were investigated. The variation in the adjusted total and component scores was compared across contexts using analysis of variance. The adjusted mean NL-IHRS was higher in South Africa (10.2) and Europe (10.0) compared to Uganda (8.2), and the difference was statistically significant (P < 0.001). The prevalence and per cent contribution of diabetes mellitus and high blood pressure were lowest in Uganda. Score contribution of non-modifiable factors was lower in Uganda and South Africa, entailing 11.5% and 8.0% of the total score, respectively. Contribution of behavioural factors to the total score was highest in both sub-Saharan African countries. In particular, adjusted scores related to unhealthy dietary patterns were highest in South Africa (3.21) compared to Uganda (1.66) and Europe (1.09). Whereas, contribution of metabolic factors was highest in Europe (30.6%) compared with Uganda (20.8%) and South Africa (22.6%). Conclusion: The total risk score, subcomponents, categories, and their contribution to total score greatly vary across contexts, which could be due to disparities in risk burden and/or self-reporting bias in resource-limited settings. Therefore, primary preventive initiatives should identify risk factor burden across contexts and intervention activities need to be customized accordingly. Furthermore, contextualizing the risk assessment tool and evaluating its usefulness in different settings are recommended.

Older Infant-Young Child "Formulas".

The category of "formulas" directed at older infants and toddlers 6 to 36 months of age has increased in prominence over the last years but is characterized by lack of standardization in nomenclature and composition as well as questionable marketing practices. There has been uncertainty and misperception regarding some of the roles of these beverages in ensuring adequate childhood nutrition. The aim of this clinical report is to review the context, evidence, and rationale for older infant-young child formulas, followed by recommendations.

The direct disease burden of COVID-19 in Belgium in 2020 and 2021.

BACKGROUND: Burden of disease estimates have become important population health metrics over the past decade to measure losses in health. In Belgium, the disease burden caused by COVID-19 has not yet been estimated, although COVID-19 has emerged as one of the most important diseases. Therefore, the current study aims to estimate the direct COVID-19 burden in Belgium, observed despite policy interventions, during 2020 and 2021, and compare it to the burden from other causes. METHODS: Disability-adjusted life years (DALYs) are the sum of Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) due to disease. DALYs allow comparing the burden of disease between countries, diseases, and over time. We used the European Burden of Disease Network consensus disease model for COVID-19 to estimate DALYs related to COVID-19. Estimates of person-years for (a) acute non-fatal disease states were calculated from a compartmental model, using Belgian seroprevalence, social contact, hospital, and intensive care admission data, (b) deaths were sourced from the national COVID-19 mortality surveillance, and (c) chronic post-acute disease states were derived from a Belgian cohort study. RESULTS: In 2020, the total number of COVID-19 related DALYs was estimated at 253,577 [252,541 - 254,739], which is higher than in 2021, when it was 139,281 [136,704 - 142,306]. The observed COVID-19 burden was largely borne by the elderly, and over 90% of the burden was attributable to premature mortality (i.e., YLLs). In younger people, morbidity (i.e., YLD) contributed relatively more to the DALYs, especially in 2021, when vaccination was rolled out. Morbidity was mainly attributable to long-lasting post-acute symptoms. CONCLUSION: COVID-19 had a substantial impact on population health in Belgium, especially in 2020, when COVID-19 would have been the main cause of disease burden if all other causes had maintained their 2019 level.

A Bayesian approach to estimate the probability of resistance to bedaquiline in the presence of a genomic variant.

BACKGROUND: Bedaquiline is a core drug for treatment of rifampicin-resistant tuberculosis. Few genomic variants have been statistically associated with bedaquiline resistance. Alternative approaches for determining the genotypic-phenotypic association are needed to guide clinical care. METHODS: Using published phenotype data for variants in Rv0678, atpE, pepQ and Rv1979c genes in 756 Mycobacterium tuberculosis isolates and survey data of the opinion of 33 experts, we applied Bayesian methods to estimate the posterior probability of bedaquiline resistance and corresponding 95% credible intervals. RESULTS: Experts agreed on the role of Rv0678, and atpE, were uncertain about the role of pepQ and Rv1979c variants and overestimated the probability of bedaquiline resistance for most variant types, resulting in lower posterior probabilities compared to prior estimates. The posterior median probability of bedaquiline resistance was low for synonymous mutations in atpE (0.1%) and Rv0678 (3.3%), high for missense mutations in atpE (60.8%) and nonsense mutations in Rv0678 (55.1%), relatively low for missense (31.5%) mutations and frameshift (30.0%) in Rv0678 and low for missense mutations in pepQ (2.6%) and Rv1979c (2.9%), but 95% credible intervals were wide. CONCLUSIONS: Bayesian probability estimates of bedaquiline resistance given the presence of a specific mutation could be useful for clinical decision-making as it presents interpretable probabilities compared to standard odds ratios. For a newly emerging variant, the probability of resistance for the variant type and gene can still be used to guide clinical decision-making. Future studies should investigate the feasibility of using Bayesian probabilities for bedaquiline resistance in clinical practice.

The impact of national and international travel on spatio-temporal transmission of SARS-CoV-2 in Belgium in 2021.

BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread over the world and caused tremendous impacts on global health. Understanding the mechanism responsible for the spread of this pathogen and the impact of specific factors, such as human mobility, will help authorities to tailor interventions for future SARS-CoV-2 waves or newly emerging airborne infections. In this study, we aim to analyze the spatio-temporal transmission of SARS-CoV-2 in Belgium at municipality level between January and December 2021 and explore the effect of different levels of human travel on disease incidence through the use of counterfactual scenarios. METHODS: We applied the endemic-epidemic modelling framework, in which the disease incidence decomposes into endemic, autoregressive and neighbourhood components. The spatial dependencies among areas are adjusted based on actual connectivity through mobile network data. We also took into account other important factors such as international mobility, vaccination coverage, population size and the stringency of restriction measures. RESULTS: The results demonstrate the aggravating effect of international travel on the incidence, and simulated counterfactual scenarios further stress the alleviating impact of a reduction in national and international travel on epidemic growth. It is also clear that local transmission contributed the most during 2021, and municipalities with a larger population tended to attract a higher number of cases from neighboring areas. CONCLUSIONS: Although transmission between municipalities was observed, local transmission was dominant. We highlight the positive association between the mobility data and the infection spread over time. Our study provides insight to assist health authorities in decision-making, particularly when the disease is airborne and therefore likely influenced by human movement.

Prenatal Weight Change Trajectories and Perinatal Outcomes among Twin Gestations.

OBJECTIVE: Despite an increase in twin pregnancies in recent decades, the Institute of Medicine twin weight gain recommendations remain provisional and provide no guidance for the pattern or timing of weight change. We sought to characterize gestational weight change trajectory patterns and examine associations with birth outcomes in a cohort of twin pregnancies. STUDY DESIGN: Prenatal and delivery records were examined for 320 twin pregnancies from a maternal-fetal medicine practice in Austin, TX 2011-2019. Prenatal weights for those with >1 measured weight in the first trimester and ≥3 prenatal weights were included in analyses. Trajectories were estimated to 32 weeks (mean delivery: 33.7 ± 3.3 weeks) using flexible latent class mixed models with low-rank thin-plate splines. Associations between trajectory classes and infant outcomes were analyzed using multivariable Poisson or linear regression. RESULTS: Weight change from prepregnancy to delivery was 15.4 ± 6.3 kg for people with an underweight body mass index, 15.4 ± 5.8 kg for healthy weight, 14.7 ± 6.9 kg for overweight, and 12.5 ± 6.4 kg for obesity. Three trajectory classes were identified: low (Class 1), moderate (Class 2), or high gain (Class 3). Class 1 (24.7%) maintained weight for 15 weeks and then gained an estimated 6.6 kg at 32 weeks. Class 2 (60.9%) exhibited steady gain with 13.5 kg predicted total gain, and Class 3 (14.4%) showed rapid gain across pregnancy with 21.3 kg predicted gain. Compared to Class 1, Class 3 was associated with higher birth weight z-score (ß = 0.63, 95% confidence interval [CI]: 0.31,0.96), increased risk for large for gestational age (IRR = 5.60, 95% CI: 1.59, 19.67), and birth <32 weeks (IRR = 2.44, 95%CI: 1.10, 5.4) that was attenuated in sensitivity analyses. Class 2 was associated with moderately elevated birth weight z-score (ß = 0.24, 95%CI: 0.00, 0.48, p = 0.050). CONCLUSION: Gestational weight change followed a low, moderate, or high trajectory; both moderate and high gain patterns were associated with increased infant size outcomes. Optimal patterns of weight change that balance risk during the prenatal, perinatal, and neonatal periods require further investigation, particularly in high-risk twin pregnancies. KEY POINTS: · A majority gained weight below IOM twin recommendations.. · Three patterns of GWC across pregnancy were identified.. · Moderate or high GWC was associated with infant size..

Within-host modeling to measure dynamics of antibody responses after natural infection or vaccination: A systematic review.

BACKGROUND: Within-host models describe the dynamics of immune cells when encountering a pathogen, and how these dynamics can lead to an individual-specific immune response. This systematic review aims to summarize which within-host methodology has been used to study and quantify antibody kinetics after infection or vaccination. In particular, we focus on data-driven and theory-driven mechanistic models. MATERIALS: PubMed and Web of Science databases were used to identify eligible papers published until May 2022. Eligible publications included those studying mathematical models that measure antibody kinetics as the primary outcome (ranging from phenomenological to mechanistic models). RESULTS: We identified 78 eligible publications, of which 8 relied on an Ordinary Differential Equations (ODEs)-based modelling approach to describe antibody kinetics after vaccination, and 12 studies used such models in the context of humoral immunity induced by natural infection. Mechanistic modeling studies were summarized in terms of type of study, sample size, measurements collected, antibody half-life, compartments and parameters included, inferential or analytical method, and model selection. CONCLUSIONS: Despite the importance of investigating antibody kinetics and underlying mechanisms of (waning of) the humoral immunity, few publications explicitly account for this in a mathematical model. In particular, most research focuses on phenomenological rather than mechanistic models. The limited information on the age groups or other risk factors that might impact antibody kinetics, as well as a lack of experimental or observational data remain important concerns regarding the interpretation of mathematical modeling results. We reviewed the similarities between the kinetics following vaccination and infection, emphasising that it may be worth translating some features from one setting to another. However, we also stress that some biological mechanisms need to be distinguished. We found that data-driven mechanistic models tend to be more simplistic, and theory-driven approaches lack representative data to validate model results.

Infant burn injuries related to water heating for powdered infant formula preparation.

Background: Guidance for preparing powdered infant formula (PIF) helps to ensure it meets the nutritional needs of infants and is safe to consume. Among safety concerns is Cronobacter sakazakii contamination which can lead to serious infections and death. PIF preparation guidance varies; there is a lack of consensus on whether there is a need to boil water to inactivate potential Cronobacter and for how long to let the water cool before reconstitution. We sought to quantify the burden of burn injuries among infants related to water heating for PIF preparation. Estimating this burden may help inform preparation recommendations. Methods: Burn injuries among infants <18 months of age were identified from 2017 to 2019 National Electronic Injury Surveillance System data collected from sampled hospital emergency departments. Injuries were classified as related to PIF water heating, potentially related to PIF water heating but with undetermined causation, related to other infant feeding aspects, or unrelated to infant formula or breast milk feeding. Unweighted case counts for each injury classification were determined. Results: Across sampled emergency departments, 7 PIF water heating injuries were seen among the 44,395 injuries reported for infants <18 months. No reported PIF water heating injuries were fatal, but 3 required hospitalization. Another 238 injuries potentially related to PIF water heating but with undetermined causation were also seen. Conclusion: Preparation guidance should consider both the potential risk for Cronobacter infection and the potential risk for burns.

Dietary outcomes of community-based CVD preventive interventions: a systematic review and meta-analysis.

OBJECTIVE: We aimed to synthesise available evidence on the effects of community-based interventions in improving various dietary outcome measures. DESIGN: Systematic review and meta-analysis. SETTING: We searched databases including Medline, EMBASE, PSYCINFO, CINAHL and the Cochrane registry for studies reported between January 2000 and June 2022. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tools for each study type. For some of the outcomes, we pooled the effect size using a random-effects meta-analysis. PARTICIPANTS: A total of fifty-one studies, thirty-three randomised and eighteen non-randomised, involving 100 746 participants were included. RESULTS: Overall, thirty-seven studies found a statistically significant difference in at least one dietary outcome measure favouring the intervention group, whereas fourteen studies found no statistically significant difference. Our meta-analyses indicated that, compared with controls, interventions were effective in decreasing daily energy intake (MJ/d) (mean difference (MD): -0·25; 95 % CI: -0·37, -0·14), fat % of energy (MD: -1·01; 95 % CI: -1·76, -0·25) and saturated fat % of energy (MD: -1·54; 95 % CI: -2·01, -1·07). Furthermore, the interventions were effective in improving fibre intake (g/d) (MD: 1·08; 95 % CI: 0·39, 1·77). Effective interventions use various strategies including tailored individual lifestyle coaching, health education, health promotion activities, community engagement activities and/or structural changes. CONCLUSION: This review shows the potential of improving dietary patterns through community-based CVD preventive interventions. Thus, development and implementation of context-specific preventive interventions could help to minimise dietary risk factors, which in turn decrease morbidity and mortality due to CVD and other non-communicable diseases.

Estimation of skeletal muscle mass in 4-year-old children using the D3-creatine dilution method.

BACKGROUND: Given limited experience in applying the creatine-(methyl-D3) (D3Cr) dilution method to measure skeletal muscle mass (SMM) in young children, the feasibility of deployment in a fielding setting and performance of the method was assessed in a cohort of 4-year-old children in Dhaka, Bangladesh. METHODS: Following D3Cr oral dose (10 mg) administration, single fasting urine samples were collected at 2-4 days (n = 100). Twenty-four-hour post-dose collections and serial spot urine samples on days 2, 3 and 4 were obtained in a subset of participants (n = 10). Urinary creatine, creatinine, D3Cr and D3-creatinine enrichment were analyzed by liquid chromatography-tandem mass spectrometry. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry and grip strength was measured by a hand-held dynamometer. RESULTS: SMM was measured successfully in 91% of participants, and there were no adverse events. Mean ± SD SMM was greater than ALM (4.5 ± 0.4 and 3.2 ± 0.6 kg, respectively). Precision of SMM was low (intraclass correlation = 0.20; 95% CI: 0.02, 0.75; n = 10). Grip strength was not associated with SMM in multivariable analysis (0.004 kg per 100 g of SMM; 95% CI: -0.031, 0.038; n = 91). CONCLUSIONS: The D3Cr dilution method was feasible in a community setting. However, high within-child variability in SMM estimates suggests the need for further optimization of this approach. IMPACT: The D3-creatine (D3Cr) stable isotope dilution method was considered a feasible method for the estimation of skeletal muscle mass (SMM) in young children in a community setting and was well accepted among participants. SMM was weakly associated with both dual-energy x-ray absorptiometry-derived values of appendicular lean mass and grip strength. High within-child variability in estimated values of SMM suggests that further optimization of the D3Cr stable isotope dilution method is required prior to implementation in community research settings.

Modeling antibody dynamics following herpes zoster indicates that higher varicella-zoster virus viremia generates more VZV-specific antibodies.

Introduction: Studying antibody dynamics following re-exposure to infection and/or vaccination is crucial for a better understanding of fundamental immunological processes, vaccine development, and health policy research. Methods: We adopted a nonlinear mixed modeling approach based on ordinary differential equations (ODE) to characterize varicella-zoster virus specific antibody dynamics during and after clinical herpes zoster. Our ODEs models convert underlying immunological processes into mathematical formulations, allowing for testable data analysis. In order to cope with inter- and intra-individual variability, mixed models include population-averaged parameters (fixed effects) and individual-specific parameters (random effects). We explored the use of various ODE-based nonlinear mixed models to describe longitudinally collected markers of immunological response in 61 herpes zoster patients. Results: Starting from a general formulation of such models, we study different plausible processes underlying observed antibody titer concentrations over time, including various individual-specific parameters. Among the converged models, the best fitting and most parsimonious model implies that once Varicella-zoster virus (VZV) reactivation is clinically apparent (i.e., Herpes-zoster (HZ) can be diagnosed), short-living and long-living antibody secreting cells (SASC and LASC, respectively) will not expand anymore. Additionally, we investigated the relationship between age and viral load on SASC using a covariate model to gain a deeper understanding of the population's characteristics. Conclusion: The results of this study provide crucial and unique insights that can aid in improving our understanding of VZV antibody dynamics and in making more accurate projections regarding the potential impact of vaccines.

Perspective: Is It Time to Revise the Current Nutrient Requirements for Infant Formulas Principally Established in 1980?

Because of the production of nutrient-deficient infant formulas (IFs), the United States Congress passed regulations on the composition and production of IF, referred to as the Infant Formula Act (IFA), in 1980, which was amended in 1986. More detailed FDA rules have been created since then, specifying the ranges or minimum intakes of nutrients and providing details for the safe production and evaluation of infant formulas. Although generally effective in ensuring safe IF, recent events have made it clear that a re-evaluation of aspects of all the nutrient composition regulations for IF is needed, including consideration of adding requirements related to bioactive nutrients not mentioned in the IFA. We propose that, as principal examples, the requirement for iron content needs to be re-evaluated and that DHA and AA should be considered for addition to the nutrient requirements after scientific review by a panel such as those established by the National Academies of Sciences, Engineering, and Medicine. Additionally, there is no specific requirement in current FDA regulations for the energy density of IF, and this should be added alongside potential revisions of the protein requirement. It would also be ideal to have specific FDA rules on nutrient intakes for premature infants as these are exempted from the specific nutrient regulations of the amended IFA.

Evolution of human papilloma virus prevalence in a highly vaccinated region in Belgium: a retrospective cohort study in Flemish women (2010-2019).

OBJECTIVE: In order to lower the incidence of cervical cancer, vaccines against high-risk types of the human papilloma virus (hrHPV) were approved and brought on the market in 2007, with a partial reimbursement for Belgian citizens younger than 18 years old. Since 2010, a school-based vaccination program ensures a high vaccination coverage in young women. In this study, the impact of the Belgian vaccination program on the prevalence of HPV 16/18 is studied, together with the evolution of the prevalence of other hrHPV types and precancerous lesions. METHODS: Results of HPV typing and cytology in papanicolaou-smears from women aged 20-23 years taken between 2010 and 2019 were used. An older, nonvaccinated group of women of 40-45 years old served as a control group. RESULTS: A significant decrease in prevalence of HPV types 16 and 18 was found in the 20-23-years-old women, whereas no decrease was found in the age group 40-45. Alongside this decrease, a significant decrease in prevalence of subtypes 6, 11 and 31 was observed, whereas type 31 is not included in the administered vaccines. Remarkably, there was no decrease in prevalence of cytological abnormalities in the study group during this study. There was even an increase in prevalence of high-risk types 53, 58 and 67. CONCLUSION: These findings emphasise the need to maintain the screening programs, even in areas with high vaccination coverage.

Modelling longitudinal binary outcomes with outcome dependent observation times: an application to a malaria cohort study.

BACKGROUND : In spite of the global reduction of 21% in malaria incidence between 2010 and 2015, the disease still threatens many lives of children and pregnant mothers in African countries. A correct assessment and evaluation of the impact of malaria control strategies still remains quintessential in order to eliminate the disease and its burden. Malaria follow-up studies typically involve routine visits at pre-scheduled time points and/or clinical visits whenever individuals experience malaria-like symptoms. In the latter case, infection triggers outcome assessment, thereby leading to outcome-dependent sampling (ODS). Commonly used methods to analyze such longitudinal data ignore ODS and potentially lead to biased estimates of malaria-specific transmission parameters, hence, inducing an incorrect assessment and evaluation of malaria control strategies. METHODS : In this paper, a new method is proposed to handle ODS by use of a joint model for the longitudinal binary outcome measured at routine visits and the clinical event times. The methodology is applied to malaria parasitaemia data from a cohort of [Formula: see text] Ugandan children aged 0.5-10 years from 3 regions (Walukuba-300 children, Kihihi-355 children and Nagongera-333 children) with varying transmission intensities (entomological inoculation rate equal to 2.8, 32 and 310 infectious bites per unit year, respectively) collected between 2011-2014. RESULTS : The results indicate that malaria parasite prevalence and force of infection (FOI) increase with age in the region of high malaria intensity with highest FOI in age group 5-10 years. For the region of medium intensity, the prevalence slightly increases with age and the FOI for the routine process is highest in age group 5-10 years, yet for the clinical infections, the FOI gradually decreases with increasing age. For the region with low intensity, both the prevalence and FOI peak at the age of 1 year after which the former remains constant with age yet the latter suddenly decreases with age for the clinically observed infections. CONCLUSION : Malaria parasite prevalence and FOI increase with age in the region of high malaria intensity. In all study sites, both the prevalence and FOI are highest among previously asymptomatic children and lowest among their symptomatic counterparts. Using a simulation study inspired by the malaria data at hand, the proposed methodology shows to have the smallest bias, especially when consecutive positive malaria parasitaemia presence results within a time period of 35 days were considered to be due to the same infection.

Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment (SMARTT): a study protocol for a phase IV pragmatic randomized controlled patient management strategy trial.

BACKGROUND: Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into individualized treatment regimen composition. METHODS: This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective. DISCUSSION: This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.