Stuck in a corner: Anthropogenic noise threatens narwhals in their once pristine Arctic habitat.

Niche-conservative species are especially susceptible to changes in their environment, and detecting the negative effects of new stressors in their habitats is vital for safeguarding of these species. In the Arctic, human disturbance including marine traffic and exploration of resources is increasing rapidly due to climate change-induced reduction of sea ice. Here, we show that the narwhal, Monodon monoceros, is extremely sensitive to human-made noise. Narwhals avoided deep diving (> 350 m) with simultaneous reduction of foraging and increased shallow diving activity as a response to either ship sound alone or ship sound with concurrent seismic airgun pulses. Normal behavior decreased by 50 to 75% at distances where received sound levels were below background noise. Narwhals were equally responsive to both disturbance types, hence demonstrating their acute sensitivity to ship sound. This sensitivity coupled with their special behavioral-ecological strategy including a narrow ecological niche and high site fidelity makes them thus especially vulnerable to human impacts in the Arctic.

Remote Monitoring of Positive Airway Pressure Data: Challenges, Pitfalls, and Strategies to Consider for Optimal Data Science Applications.

Over recent years, positive airway pressure (PAP) remote monitoring has transformed the management of OSA and produced a large amount of data. Accumulated PAP data provide valuable and objective information regarding patient treatment adherence and efficiency. However, the majority of studies that have analyzed longitudinal PAP remote monitoring have summarized data trajectories in static and simplistic metrics for PAP adherence and the residual apnea-hypopnea index by the use of mean or median values. The aims of this article are to suggest directions for improving data cleaning and processing and to address major concerns for the following data science applications: (1) conditions for residual apnea-hypopnea index reliability, (2) lack of standardization of indicators provided by different PAP models, (3) missing values, and (4) consideration of treatment interruptions. To allow fair comparison among studies and to avoid biases in computation, PAP data processing and management should be conducted rigorously with these points in mind. PAP remote monitoring data contain a wealth of information that currently is underused in the field of sleep research. Improving the quality and standardizing data handling could facilitate data sharing among specialists worldwide and enable artificial intelligence strategies to be applied in the field of sleep apnea.

Dataset of numerically-generated interfaces of Newtonian jets in CIJ regime.

The so-called Rayleigh-Plateau instability of fluid jets has been widely studied and is extensively used in the Continuous InkJet (CIJ) printing process. The present dataset contains the numerically-generated interfaces of Newtonian fluids jets in CIJ jetting conditions for low to moderately high stimulation amplitudes. We used Basilisk, an open-source Computational Fluid Dynamics (CFD) software specialized in multiphase flow to compute thousands of jets of fluids for Reynolds numbers ranging from 100 to 1000. The dataset gives raw data of CFD simulations liquid-air interfaces, for each Reynolds - stimulation amplitude pair. The present 10 GB dataset contains ≈ 110000 interfaces which allows to use novel machine learning and deep-learning approaches to explore jet morphologies evolution that can't be addressed with the classical Rayleigh's theory.

Narwhals react to ship noise and airgun pulses embedded in background noise.

Anthropogenic activities are increasing in the Arctic, posing a threat to niche-conservative species with high seasonal site fidelity, such as the narwhal Monodon monoceros. In this controlled sound exposure study, six narwhals were live-captured and instrumented with animal-borne tags providing movement and behavioural data, and exposed to concurrent ship noise and airgun pulses. All narwhals reacted to sound exposure with reduced buzzing rates, where the response was dependent on the magnitude of exposure defined as 1/distance to ship. Buzzing rate was halved at 12 km from the ship, and whales ceased foraging at 7-8 km. Effects of exposure could be detected at distances > 40 km from the ship.At only a few kilometres from the ship, the received high-frequency cetacean weighted sound exposure levels were below background noise indicating extreme sensitivity of narwhals towards sound disturbance and demonstrating their ability to detect signals embedded in background noise. The narwhal's reactions to sustained disturbance may have a plethora of consequences both at individual and population levels. The observed reactions of the whales demonstrate their auditory sensitivity but also emphasize, that anthropogenic activities in pristine narwhal habitats needs to be managed carefully if healthy narwhal populations are to be maintained.

Continuous positive airway pressure adherence trajectories in sleep apnea: Clustering with summed discrete Fréchet and dynamic time warping dissimilarities.

BACKGROUND: Obstructive sleep apnea (OSA) is a chronic disease characterized by recurrent pharyngeal collapses during sleep. In most severe cases, continuous positive airway pressure (CPAP) consists in keeping the airways open by administering mild air pressure. This treatment faces adherence issues. OBJECTIVES: Eight hundred and forty-eight subjects were equipped with CPAP prescribed at the Grenoble University Hospital between 2016 and 2018. Their daily CPAP uses have been recorded during the first 3 months. Our aim is to cluster these adherence time series. With hierarchical agglomerative clustering, we focused on the choices of the dissimilarity measure and the internal cluster validation index (CVI). METHODS: The Euclidean distance, the dynamic time warping (DTW) and the generalized summed discrete Fréchet dissimilarity were implemented with three linkage strategies ("average," "complete," and "Ward"). The performances of each method (dissimilarity and linkage) were evaluated on a simulation study through the adjusted Rand index (ARI). The Ward linkage with DTW dissimilarity provided the best ARI. Then six different internal CVIs (Silhouette, Calinski Harabasz, Davies Bouldin, Modified Davies Bouldin, Dunn, and COP) were compared on their ability to choose the best number of clusters. The Dunn index beat the others. RESULTS: CPAP data were clustered with the Ward linkage, the DTW dissimilarity and the Dunn index. It identified six clusters, from a cluster of patients (N = 29 subjects) whose stopped the therapy early on to a cluster (N = 105) with increasing adherence over time. Other clusters were extremely good users (N = 151), good users (N = 150), moderate users (N = 235), and poor adherers (N = 178).

Parameter estimation and treatment optimization in a stochastic model for immunotherapy of cancer.

Adoptive Cell Transfer therapy of cancer is currently in full development and mathematical modeling is playing a critical role in this area. We study a stochastic model developed by Baar et al. (2015) for modeling immunotherapy against melanoma skin cancer. First, we estimate the parameters of the deterministic limit of the model based on biological data of tumor growth in mice. A Nonlinear Mixed Effects Model is estimated by the Stochastic Approximation Expectation Maximization algorithm. With the estimated parameters, we return to the stochastic model and calculate the probability of complete T cells exhaustion. We show that for some relevant parameter values, an early relapse is due to stochastic fluctuations (complete T cells exhaustion) with a non negligible probability. Then, focusing on the relapse related to the T cell exhaustion, we propose to optimize the treatment plan (treatment doses and restimulation times) by minimizing the T cell exhaustion probability in the parameter estimation ranges.

Long-term effects of cochlear implantation on the intelligibility of speech in French-speaking children.

Our study compares the intelligibility of French-speaking children with a cochlear implant (N = 13) and age-matched children with typical hearing (N = 13) in a narrative task. This contrasts with previous studies in which speech intelligibility of children with cochlear implants is most often tested using repetition or reading tasks. Languages other than English are seldom considered. Their productions were graded by naive and expert listeners. The results show that (1) children with CIs have lower intelligibility, (2) early implantation is a predictor of good intelligibility, and (3) late implantation after two years of age does not prevent the children from eventually reaching good intelligibility.

Statistical Methodology for the Analysis of Repeated Duration Data in Behavioral Studies.

Purpose: Repeated duration data are frequently used in behavioral studies. Classical linear or log-linear mixed models are often inadequate to analyze such data, because they usually consist of nonnegative and skew-distributed variables. Therefore, we recommend use of a statistical methodology specific to duration data. Method: We propose a methodology based on Cox mixed models and written under the R language. This semiparametric model is indeed flexible enough to fit duration data. To compare log-linear and Cox mixed models in terms of goodness-of-fit on real data sets, we also provide a procedure based on simulations and quantile-quantile plots. Results: We present two examples from a data set of speech and gesture interactions, which illustrate the limitations of linear and log-linear mixed models, as compared to Cox models. The linear models are not validated on our data, whereas Cox models are. Moreover, in the second example, the Cox model exhibits a significant effect that the linear model does not. Conclusions: We provide methods to select the best-fitting models for repeated duration data and to compare statistical methodologies. In this study, we show that Cox models are best suited to the analysis of our data set.

Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies.

The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose-toxicity and dose-efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children.

A Comparative Study of the Precision of Carstens and Northern Digital Instruments Electromagnetic Articulographs.

Purpose: This study compares the precision of the electromagnetic articulographs used in speech research: Northern Digital Instruments' Wave and Carstens' AG200, AG500, and AG501 systems. Method: The fluctuation of distances between 3 pairs of sensors attached to a manually rotated device that can position them inside the measurement volumes was determined. For each device, 2 precision estimates made on the basis of the 95% quantile range of these distances (QR95) were defined: The local QR95 was computed for bins around specific rotation angles, and the global QR95 was computed for all angles pooled. Results: For all devices, although the local precision lies around 0.1 cm, the global precision is much more worrisome, ranging from 0.03 cm to 2.18 cm, and displays large variations as a function of the position of the sensors in the measurement volume. No influence of the rotational speed was found. The AG501 produced-by far-the lowest errors, in particular concerning the global precision. Conclusions: The local precision can be considered suitable for speech articulatory measurements, but the variations of the global precision need to be taken into account by the knowledge of the spatial distribution of errors. A guideline for good practice in EMA recording is proposed for each system.

Analysis of temozolomide resistance in low-grade gliomas using a mechanistic mathematical model.

Understanding how tumors develop resistance to chemotherapy is a major issue in oncology. When treated with temozolomide (TMZ), an oral alkylating chemotherapy drug, most low-grade gliomas (LGG) show an initial volume decrease but this effect is rarely long lasting. In addition, it has been suggested that TMZ may drive tumor progression in a subset of patients as a result of acquired resistance. Using longitudinal tumor size measurements from 121 patients, the aim of this study was to develop a semi-mechanistic mathematical model to determine whether resistance of LGG to TMZ was more likely to result from primary and/or from chemotherapy-induced acquired resistance that may contribute to tumor progression. We applied the model to a series of patients treated upfront with TMZ (n = 109) or PCV (procarbazine, CCNU, vincristine) chemotherapy (n = 12) and used a population mixture approach to classify patients according to the mechanism of resistance most likely to explain individual tumor growth dynamics. Our modeling results predicted acquired resistance in 51% of LGG treated with TMZ. In agreement with the different biological effects of nitrosoureas, none of the patients treated with PCV were classified in the acquired resistance group. Consistent with the mutational analysis of recurrent LGG, analysis of growth dynamics using mathematical modeling suggested that in a subset of patients, TMZ might paradoxically contribute to tumor progression as a result of chemotherapy-induced resistance. Identification of patients at risk of developing acquired resistance is warranted to better define the role of TMZ in LGG.

Physiological and acoustic characteristics of the male music theatre voice.

Six male music theatre singers were recorded in three different voice qualities: legit and two types of belt ("chesty" and "twangy"), on two vowels ([e] and [ɔ]), at four increasing pitches in the upper limit of each singer's belt range (∼250-440 Hz). The audio signal, the electroglottographic (EGG) signal, and the vocal tract impedance were all measured simultaneously. Voice samples were analyzed and then evaluated perceptually by 16 expert listeners. The three qualities were produced with significant differences at the physiological, acoustical, and perceptual levels: Singers produced belt qualities with a higher EGG contact quotient (CQEGG) and greater contacting speed quotient (Qcs), greater sound pressure level (SPL), and energy above 1 kHz (alpha ratio), and with higher frequencies of the first two vocal tract resonances (fR1, fR2), especially in the upper pitch range when compared to legit. Singers produced the chesty belt quality with higher CQEGG, Qcs, and SPL values and lower alpha ratios over the whole belt range, and with higher fR1 at the higher pitch range when compared to twangy belt. Consistent tuning of fR1 to the second voice harmonic (2f0) was observed in all three qualities and for both vowels. Expert listeners tended to identify all qualities based on the same acoustical and physiological variations as those observed in the singers' intended qualities.

Incidence of venous thromboembolism in France: a retrospective analysis of a national insurance claims database.

BACKGROUND: Data estimating the annual incidence of venous thromboembolism (VTE) in France, taking into account both hospital and community settings, are very lacking. This study aimed to estimate the annual incidence of VTE (pulmonary embolism (PE) and deep vein thrombosis (DVT)) in France in 2011 in "real world" population. METHODS: This was a longitudinal insurance claims study of the incidence of VTE in France over 2 years (2010 and 2011). The data analysis was performed using the EGB (Echantillon Généraliste des Bénéficiaires) database, a randomly selected sample of the French national insurance database (CNAMTS) which covers 77 % of the population. All adult patients experiencing a VTE event during the study period were analysed. Recurrence rate of VTE and all-cause mortality rate were also estimated over a 12-month follow-up period. RESULTS: The estimated annual incidence of VTE in France was 184.0 per 100 000 subjects, corresponding to a total of 119 670 events countrywide. The estimated incidence of DVT and PE were respectively 119.8 and 64.2 per 100 000 subjects. Annual recurrence of VTE was reported in 5.5 % (n = 99) patients, with a significantly higher recurrence rate in patients with PE than those with DVT (p = 0.02). Overall, 6.2 % (n = 112) of patients had died over the 12-month follow-up (respectively 10.2 and 7.7 % of patients with DVT and PE). DISCUSSION: To our knowledge, this analysis is the first to estimate the annual incidence of VTE in France using exhaustive data from the EGB database. This has allowed the incidence of DVT in the community to be documented, which to date has not been characterised. Previous studies in France have been limited to the hospital setting and have yielded incidence rates comparable to ours. CONCLUSIONS: This analysis is the first to estimate the annual incidence of VTE in France using exhaustive data from the EGB database. This study showed that the incidence and the burden of the disease remains elevated.

Burden of stroke and other cardiovascular complications in patients with atrial fibrillation hospitalized in France.

AIMS: Atrial fibrillation (AF) is associated with numerous cardiovascular complications. We sought to estimate the annual burden of cardiovascular complications in AF patients in French hospitals. METHODS AND RESULTS: All AF patients hospitalized in France in 2012 were identified from the national public/private hospital database. Comorbid conditions and medical histories were documented using medical records dating back 5 years. Reasons for hospitalization, type of admission (emergency or otherwise), length of stay, rehabilitation transfers, and death at discharge were identified and costs of acute and rehabilitation care determined (2012 Euros). In total, 533 044 AF patients (mean age ± SD 78.0 ± 11.4 years, 47.1% women) were hospitalized in 2012 for any reason. Hospitalizations were cardiovascular-related in 267 681 patients [22.5% cardiac dysrhythmia, 18.3% heart failure, 7.1% vascular/ischaemic diseases, 6.9% stroke/transient ischaemic attack (TIA)/systemic embolism (SE), and 1.3% haemorrhages]. Patients with stroke/TIA/SE had higher rates of emergency admission (68.1%), transfer to rehabilitation unit (28.1%), and death at discharge (13.7%) than those with other cardiovascular complications, with the exception of haemorrhages, where emergency admission rates were similar. They also had longer mean lengths of stay (12.6 ± 13.2 days for acute care and 46.8 ± 42.5 days for rehabilitation). The annual total cost (acute care and rehabilitation) for all hospitalized cardiovascular events was €1.94 billion, of which heart failure represented €805 million, vascular/ischaemic diseases €386 million, stroke €362 million, cardiac dysrhythmia €341 million, and haemorrhage €48 million. CONCLUSION: Half a million patients with AF were hospitalized in France in 2012. Cardiovascular-related hospitalizations involved half of these admissions, for a global burden of almost €2 billion, equivalent to 2.6% of total expenditure in French hospitals. Among these hospitalizations stroke/TIA/SE represented costly, but potentially preventable, complications.

Designing a Pediatric Study for an Antimalarial Drug by Using Information from Adults.

The objectives of this study were to design a pharmacokinetic (PK) study by using information about adults and evaluate the robustness of the recommended design through a case study of mefloquine. PK data about adults and children were available from two different randomized studies of the treatment of malaria with the same artesunate-mefloquine combination regimen. A recommended design for pediatric studies of mefloquine was optimized on the basis of an extrapolated model built from adult data through the following approach. (i) An adult PK model was built, and parameters were estimated by using the stochastic approximation expectation-maximization algorithm. (ii) Pediatric PK parameters were then obtained by adding allometry and maturation to the adult model. (iii) A D-optimal design for children was obtained with PFIM by assuming the extrapolated design. Finally, the robustness of the recommended design was evaluated in terms of the relative bias and relative standard errors (RSE) of the parameters in a simulation study with four different models and was compared to the empirical design used for the pediatric study. Combining PK modeling, extrapolation, and design optimization led to a design for children with five sampling times. PK parameters were well estimated by this design with few RSE. Although the extrapolated model did not predict the observed mefloquine concentrations in children very accurately, it allowed precise and unbiased estimates across various model assumptions, contrary to the empirical design. Using information from adult studies combined with allometry and maturation can help provide robust designs for pediatric studies.

Cause of death in patients with atrial fibrillation admitted to French hospitals in 2012: a nationwide database study.

OBJECTIVE: Most patients with atrial fibrillation (AF) have risk factors and coexisting conditions that increase their mortality risk. We performed a cause-of-death analysis to identify predictors of mortality in hospitalised patients with AF in France. METHODS AND RESULTS: In this retrospective, population-based cross-sectional study, the Programme de médicalisation des systèmes d'information was used to identify 533 044 adults with a diagnosis of AF or atrial flutter hospitalised for any reason in France from January through December 2012. Stepwise multivariable analyses were performed to identify determinants of mortality. The mean age was 78.0±11.4 years, 47.1% were women, and the mean CHA2DS2-VASc score was 4.0±1.8. During hospitalisation, 9.4% (n=50 165) of the patients died, 34% due to a cardiovascular event, most often heart failure (16.6%), stroke/transient ischaemic attack/systemic embolism (9.8%) or vascular or ischaemic disease (4.0%). The strongest predictors of overall death were age ≥75 years (OR 2.57, 95% CI 2.47 to 2.68), renal failure (OR 1.85, 95% CI 1.81 to 1.89), cancer (OR 1.81, 95% CI 1.78 to 1.85) and lung disease (OR 1.58, 95% CI 1.55 to 1.62). CONCLUSIONS: Cardiovascular events were the most common cause of death, occurring in one-third of patients, in this comprehensive study of hospitalised patients with AF. Despite the high risk of stroke in this population, only 10% died from stroke/transient ischaemic attack/systemic embolism. The strongest predictors of overall death were non-cardiovascular. Physicians should be encouraged to focus on preventable serious and disabling cardiovascular events (such as stroke) as well as on potentially fatal non-cardiovascular comorbidities.

Routine OGTT: a robust model including incretin effect for precise identification of insulin sensitivity and secretion in a single individual.

In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10(-5)±9.36×10(-5) min(-1)pM(-1)), IFG (5.30×10(-5)±5.18×10(-5)) and combined IGT, IFG+IGT and T2DM (2.09×10(-5)±1.95×10(-5), 2.38×10(-5)±2.28×10(-5) and 2.38×10(-5)±2.09×10(-5) respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically diverse subject groups. The SIMO model may therefore be of value for the quantification of glucose homeostasis from clinical OGTT data.

A review on estimation of stochastic differential equations for pharmacokinetic/pharmacodynamic models.

This paper is a survey of existing estimation methods for pharmacokinetic/pharmacodynamic (PK/PD) models based on stochastic differential equations (SDEs). Most parametric estimation methods proposed for SDEs require high frequency data and are often poorly suited for PK/PD data which are usually sparse. Moreover, PK/PD experiments generally include not a single individual but a group of subjects, leading to a population estimation approach. This review concentrates on estimation methods which have been applied to PK/PD data, for SDEs observed with and without measurement noise, with a standard or a population approach. Besides, the adopted methodologies highly differ depending on the existence or not of an explicit transition density of the SDE solution.

Day-specific probabilities of conception in fertile cycles resulting in spontaneous pregnancies.

STUDY QUESTION: When, within the female cycle, does conception occur in spontaneously fertile cycles? SUMMARY ANSWER: This study provides reference values of day-specific probabilities of date of conception in ongoing pregnancies. The maximum probability of being within a 5-day fertile window was reached on Day 12 following the last menstrual period (LMP). WHAT IS KNOWN ALREADY: The true date of conception is not observable and may only be estimated. Accuracy of these estimates impacts on obstetric management of ongoing pregnancies. Timing of ovulation and fertility has been extensively studied in prospective studies of non-pregnant fertile women using error-prone proxies, such as hormonal changes, body-basal temperature and ultrasound, yielding day-specific probabilities of conception and fertile windows. In pregnant women, date of conception may be retrospectively estimated from early pregnancy fetal measurement by ultrasound. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of consecutive pregnancies in women referred for routine first-trimester screening, over a 3-year period (2009-2011) in a single ultrasound center (n = 6323). PARTICIPANTS/MATERIALS, SETTING, METHODS: Within the overall population, 5830 cases with a certain date of last menses were selected for analysis. The date of conception was estimated using a crown-rump length biometry and an equation derived from IVF/ICSI pregnancies. Day-specific probabilities of conception were estimated across several covariates, including age, cycle characteristics and ethnicity, using deconvolution methods to account for measurement error. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the day-specific probability of conception sharply rises at 7 days after the LMP, reaching its maximum at 15 days and returning to zero by 25 days. Older women tend to conceive earlier within their cycle, as did women with regular cycles and white and black women compared with Asian ethnicity. The probability of being within the fertile window was 2% probability at Day 4, a maximum probability of 58% at Day 12 and a 5% probability by Day 21 of the cycle. LIMITATIONS, REASONS FOR CAUTION: Although conception is believed to occur within hours following ovulation, a discrepancy is theoretically possible. However, when comparing our results to those of prospective studies, no such difference was found. The equation used for estimating the date of pregnancy was estimated in IVF/ICSI pregnancies, which could lead to potential bias in spontaneous pregnancies. However, in our population, the observed bias was negligible. Non-fertile cycles and early pregnancy losses are necessarily overlooked because of the nature of our data. WIDER IMPLICATIONS OF THE FINDINGS: Because of the wider access to retrospective data and the potential bias in prospective studies of ovulation monitoring, this study should broaden the perspectives of future epidemiologic research in fertility and pregnancy monitoring. STUDY FUNDING/COMPETING INTERESTS: None.

Multiple treatment comparisons in a series of anti-malarial trials with an ordinal primary outcome and repeated treatment evaluations.

BACKGROUND: Artemisinin-based combination therapies (ACT) are widely used in African countries, including Cameroon. Between 2005 and 2007, five randomized studies comparing different treatment arms among artesunate-amodiaquine and other ACT were conducted in Cameroonian children aged two to 60 months who had uncomplicated Plasmodium falciparum malaria. In these studies, the categorical criterion proposed by the World Health Organization (WHO) to assess the relative effectiveness of anti-malarial drugs was repeatedly evaluated on Days 14, 21 and 28 after treatment initiation. The aim of the present study was to compare the effects of different treatments on this repeated ordinal outcome, hence using the fully available information. METHODS: The quantitative synthesis was based on individual patient data. Due to the incomplete block design concerning treatment arms between different trials, a mixed treatment comparison (MTC) meta-analysis approach was adopted. The repeated ordinal outcome was modelled through a latent variable, as a proportional odds mixed model with trial, period and treatment arms as covariates. The model was further complexified to account for the variance heterogeneity, and the individual log-residual variance was modelled as a linear mixed model, as well. The effects of individual covariates at inclusion, such as parasitaemia, fever, gender and weight, were also tested. Model parameters were estimated using a Bayesian approach via the WinBUGS software. After selecting the best model using Deviance Information Criterion (DIC), mixed treatment comparisons were based on the estimated treatment effects. RESULTS: Modeling the residual variance improved the model ability to adjust the data. The results showed that, compared to artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DHPP) was significantly more efficacious. Artesunate-chlorproguanil-dapsone (ASCD) was less efficacious than artesunate-sulphadoxine-pyrimethamine (ASSP), artemether-lumefantrine (AMLM) and DHPP, the difference with the latter being significant. No difference in efficacy was found between ASAQ and AMLM. CONCLUSIONS: Bayesian mixed treatment comparisons of a network of connected randomized trials with repeated measurements of the primary categorical outcome allowed to take into account both the individual- and between- studies sources of heterogeneity. The results of the present study complete the previous quantitative review based on a binary outcome at a fixed time point, suggesting that DHPP represents an alternative for the treatment of uncomplicated P. falciparum malaria in Cameroonian children.