Metabolomic signatures in elite cyclists: differential characterization of a seeming normal endocrine status regarding three serum hormones.

INTRODUCTION: Serum phenotyping of elite cyclists regarding cortisol, IGF1 and testosterone is a way to detect endocrine disruptions possibly explained by exercise overload, non-balanced diet or by doping. This latter disruption-driven approach is supported by fundamental physiology although without any evidence of any metabolic markers. OBJECTIVES: Serum samples were distributed through Low, High or Normal endocrine classes according to hormone concentration. A 1H NMR metabolomic study of 655 serum obtained in the context of the longitudinal medical follow-up of 253 subjects was performed to discriminate the three classes for every endocrine phenotype. METHODS: An original processing algorithm was built which combined a partial-least squares-based orthogonal correction of metabolomic signals and a shrinkage discriminant analysis (SDA) to get satisfying classifications. An extended validation procedure was used to plan in larger size cohorts a minimal size to get a global prediction rate (GPR), i.e. the product of the three class prediction rates, higher than 99.9%. RESULTS: Considering the 200 most SDA-informative variables, a sigmoidal fitting of the GPR gave estimates of a minimal sample size to 929, 2346 and 1408 for cortisol, IGF1 and testosterone, respectively. Analysis of outliers from cortisol and testosterone Normal classes outside the 97.5%-confidence limit of score prediction revealed possibly (i) an inadequate protein intake for outliers or (ii) an intake of dietary ergogenics, glycine or glutamine, which might explain the significant presence of heterogeneous metabolic profiles in a supposedly normal cyclists subgroup. CONCLUSION: In a next validation metabolomics study of a so-sized cohort, anthropological, clinical and dietary metadata should be recorded in priority at the blood collection time to confirm these functional hypotheses.

Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study.

OBJECTIVE: Women with ovarian cancer have poor survival rates, which have proven difficult to improve; therefore primary prevention is important. The levonorgestrel-releasing intrauterine system (LNG-IUS) prevents endometrial cancer, and recent studies suggested that it may also prevent ovarian cancer, but with a concurrent increased risk of breast cancer. We compared adjusted risks of ovarian, endometrial, and breast cancer in ever users and never users of LNG-IUS. METHODS: Our study cohort consisted of 104,318 women from the Norwegian Women and Cancer Study, 9144 of whom were ever users and 95,174 of whom were never users of LNG-IUS. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated with Poisson regression using robust error estimates. RESULTS: Median age at inclusion was 52years and mean follow-up time was 12.5 (standard deviation 3.7) years, for a total of 1,305,435 person-years. Among ever users of LNG-IUS there were 18 cases of epithelial ovarian cancer, 15 cases of endometrial cancer, and 297 cases of breast cancer. When ever users were compared to never users of LNG-IUS, the multivariable RR of ovarian, endometrial, and breast cancer was 0.53 (95% CI: 0.32, 0.88), 0.22 (0.13, 0.40), and 1.03 (0.91, 1.17), respectively. CONCLUSION: In this population-based prospective cohort study, ever users of LNG-IUS had a strongly reduced risk of ovarian and endometrial cancer compared to never users, with no increased risk of breast cancer.

Ovulatory status and menstrual cycle duration assessed by self-collection of urine on pH strips in a population-based sample of French women not using hormonal contraception.

BACKGROUND: Assessing menstrual cycle function in the general population using a non-invasive method is challenging, both in non-industrialized and industrialized countries. SUBJECTS AND METHODS: The Observatory of Fecundity in France (Obseff) recruited on a nationwide basis a random sample of 943 women aged 18-44 years with unprotected intercourse. A sub-study was set up to assess the characteristics of a menstrual cycle by using a non-invasive method adapted to the general population. Voluntary women were sent a collection kit by the post and requested to collect urine samples on pH strips, together with daily recording of reproductive-related information during a full menstrual cycle. A total of 48 women collected urine every day, whereas 160 women collected urine every other day. Immunoassays were used to measure pregnanediol-3-α-glucuronide, estrone-3-glucuronide and creatinine. Ovulation occurrence and follicular phase duration were estimated using ovulation detection algorithms, compared to a gold standard consisting of three external experts in reproductive medicine. RESULTS: Every other day urine collection gave consistent results in terms of ovulation detection with every day collection (intraclass coefficient of correlation, 0.84, 95% confidence interval, 0.76-0.98). The proportion of anovulatory menstrual cycles was 8%. The characteristics of the ovulatory cycles were length 28 (26-34), follicular phase 16 (12-23), luteal phase 13 (10-16) days median (10th-90th percentiles). DISCUSSION-CONCLUSION: Assessing menstrual cycle characteristics based on urine sample spot only collected every other day in population-based studies through a non-invasive, well accepted and cost-limited procedure not requiring any direct contact with the survey team appears feasible and accurate.

A new statistical method for curve group analysis of longitudinal gene expression data illustrated for breast cancer in the NOWAC postgenome cohort as a proof of principle.

BACKGROUND: The understanding of changes in temporal processes related to human carcinogenesis is limited. One approach for prospective functional genomic studies is to compile trajectories of differential expression of genes, based on measurements from many case-control pairs. We propose a new statistical method that does not assume any parametric shape for the gene trajectories. METHODS: The trajectory of a gene is defined as the curve representing the changes in gene expression levels in the blood as a function of time to cancer diagnosis. In a nested case-control design it consists of differences in gene expression levels between cases and controls. Genes can be grouped into curve groups, each curve group corresponding to genes with a similar development over time. The proposed new statistical approach is based on a set of hypothesis testing that can determine whether or not there is development in gene expression levels over time, and whether this development varies among different strata. Curve group analysis may reveal significant differences in gene expression levels over time among the different strata considered. This new method was applied as a "proof of concept" to breast cancer in the Norwegian Women and Cancer (NOWAC) postgenome cohort, using blood samples collected prospectively that were specifically preserved for transcriptomic analyses (PAX tube). Cohort members diagnosed with invasive breast cancer through 2009 were identified through linkage to the Cancer Registry of Norway, and for each case a random control from the postgenome cohort was also selected, matched by birth year and time of blood sampling, to create a case-control pair. After exclusions, 441 case-control pairs were available for analyses, in which we considered strata of lymph node status at time of diagnosis and time of diagnosis with respect to breast cancer screening visits. RESULTS: The development of gene expression levels in the NOWAC postgenome cohort varied in the last years before breast cancer diagnosis, and this development differed by lymph node status and participation in the Norwegian Breast Cancer Screening Program. The differences among the investigated strata appeared larger in the year before breast cancer diagnosis compared to earlier years. CONCLUSIONS: This approach shows good properties in term of statistical power and type 1 error under minimal assumptions. When applied to a real data set it was able to discriminate between groups of genes with non-linear similar patterns before diagnosis.

Biosocial correlates of age at menarche in a British cohort.

BACKGROUND: A large number of biosocial variables have been shown to associate with age at menarche, but the results are inconsistent and differentiate not only between countries but within countries as well. AIM: This study examined age at menarche in a British national cohort in relation to 21 biosocial and anthropometric variables. SUBJECTS AND METHODS: The analyses were based on 4483 girls from the British National Child Development Study (NCDS). RESULTS: The majority of girls reached menarche between 12-14 years of age. Girls from smaller families, those living in the East and South East, South West, West Midlands and Wales regions, in tied housing and uncrowded conditions, not sharing a bedroom, not having free school meals, whose families lived in households without financial problems had started menstruating earlier than their peers from families with lower socioeconomic status. However, when all the significant variables were analysed together significant associations remained only for mother's age at menarche, height and weight at 7 years, family size and tenure. CONCLUSIONS: The results of this study support the hypotheses that intra-uterine growth and conditions in early life as well as socio-economic background are associated with the timing of menarche and that greater childhood growth and better SES are related to earlier menarche.

Is human mating for height associated with fertility? Results from a British National Cohort Study.

OBJECTIVES: Very few studies have investigated whether spousal similarity for height is related to fertility. This study examined the relationship between mating for height and fertility after correction for spousal age, social class, education, and region. METHODS: The data used were collected as part of the British National Child Development Study and 6,535 husband-wife pairs for whom data were available on measured height, spousal age, education, social class, region, and the number of children were studied. RESULTS: Fertility varied between the regions with the highest fertility in Scotland. Fertility tended to increase from more to less educated and from higher to lower social classes in both sexes. These relationships remained significant after correction for mean age. A negative association between husband's height in relation to fertility was noted as well as the negative and the quadratic term for wife's height. Both the linear as well as the quadratic effects of parental height difference were significantly related to fertility, but after removing the effects of mean age, age difference and mean height these effects disappeared. Analysis of region, mean age, social class, education, height, and differences in age, social class, education, and height together revealed that 32.4% of variation in fertility was explained but only mean age, mean social class and mean height and difference in social class remained significant. CONCLUSIONS: The results did not provide any evidence that differential fertility was associated with spousal height difference after taking into account age, social class, education and region.

Prostate cancer outcomes in France: treatments, adverse effects and two-year mortality.

BACKGROUND: This very large population-based study investigated outcomes after a diagnosis of prostate cancer (PCa) in terms of mortality rates, treatments and adverse effects. METHODS: Among the 11 million men aged 40 years and over covered by the general national health insurance scheme, those with newly managed PCa in 2009 were followed for two years based on data from the national health insurance information system (SNIIRAM). Patients were identified using hospitalisation diagnoses and specific refunds related to PCa and PCa treatments. Adverse effects of PCa treatments were identified by using hospital diagnoses, specific procedures and drug refunds. RESULTS: The age-standardised two-year all-cause mortality rate among the 43,460 men included in the study was 8.4%, twice that of all men aged 40 years and over. Among the 36,734 two-year survivors, 38% had undergone prostatectomy, 36% had been treated by hormone therapy, 29% by radiotherapy, 3% by brachytherapy and 20% were not treated. The frequency of treatment-related adverse effects varied according to age and type of treatment. Among men between 50 and 69 years of age treated by prostatectomy alone, 61% were treated for erectile dysfunction and 24% were treated for urinary disorders. The frequency of treatment for these disorders decreased during the second year compared to the first year (erectile dysfunction: 41% vs 53%, urinary disorders: 9% vs 20%). The frequencies of these treatments among men treated by external beam radiotherapy alone were 7% and 14%, respectively. Among men between 50 and 69 years with treated PCa, 46% received treatments for erectile dysfunction and 22% for urinary disorders. For controls without PCa but treated surgically for benign prostatic hyperplasia, these frequencies were 1.5% and 6.0%, respectively. CONCLUSIONS: We report high survival rates two years after a diagnosis of PCa, but a high frequency of PCa treatment-related adverse effects. These frequencies remain underestimated, as they are based on treatments for erectile dysfunction and urinary disorders and do not reflect all functional outcomes. These results should help urologists and general practitioners to inform their patients about outcomes at the time of screening and diagnosis, and especially about potential treatment-related adverse effects.

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.

Overdiagnosis of breast cancer in the Norwegian Breast Cancer Screening Program estimated by the Norwegian Women and Cancer cohort study.

BACKGROUND: There is increasing ambiguity towards national mammographic screening programs due to varying publicized estimates of overdiagnosis, i.e., breast cancer that would not have been diagnosed in the women's lifetime outside screening. This analysis compares the cumulative incidence of breast cancer in screened and unscreened women in Norway from the start of the fully implemented Norwegian Breast Cancer Screening Program (NBCSP) in 2005. METHODS: Subjects were 53 363 women in the Norwegian Women and Cancer (NOWAC) study, aged 52-79 years, with follow-up through 2010. Mammogram and breast cancer risk factor information were taken from the most recent questionnaire (2002-07) before the start of individual follow-up. The analysis differentiated screening into incidence (52-69 years) and post screening (70-79 years). Relative risks (RR) were estimated by Poisson regression. RESULTS: The analysis failed to detect a significantly increased cumulative incidence rate in screened versus other women 52-79 years. RR of breast cancer among women outside the NBCSP, the "control group", was non-significantly reduced by 7% (RR=0∙93; 95% confidence interval 0∙79 to 1∙10) compared to those in the program. The RR was attenuated when adjusted for risk factors; RRadj=0∙97 (0∙82 to 1∙15). The control group consisted of two subpopulations, those who only had a mammogram outside the program (RRadj =1∙04; 0∙86 to 1∙26) and those who never had a mammogram (RRadj=0∙77; 0∙59 to 1∙01). These groups differed significantly with respect to risk factors for breast cancer, partly as a consequence of the prescription rules for hormone therapy which indicate a mammogram. CONCLUSIONS: In the fully implemented NBCSP, no significant difference was found in cumulative incidence rates of breast cancer between NOWAC women screened and not screened. Naïve comparisons of screened and unscreened women may be affected by important differences in risk factors. The current challenge for the screening program is to improve the diagnostics used at prevalence screenings (ages 50-51).

Categorization and Analysis of Primary Care mHealth Apps Related to Breast Health and Breast Cancer: Systematic Search in App Stores and Content Analysis.

BACKGROUND: Breast cancer is the most common cause of cancer mortality among women globally. The use of mobile health tools such as apps and games is increasing rapidly, even in low- and middle-income countries, to promote early diagnosis and to manage care and support of survivors and patients. OBJECTIVE: The primary objective of this review was to categorize selected mobile health apps related to breast health and prevention of breast cancer, based on features such as breast self-examination (BSE) training and reminders, and to analyze their current dissemination. An ancillary objective was to highlight the limitations of existing tools and suggest ways to improve them. METHODS: We defined strict inclusion and exclusion criteria, which required apps to have titles or descriptions that suggest that they were designed for the general public, and not for patients with breast cancer or health workers. Apps that focused on awareness and primary care via self-check were included, while those that focused on topics such as alternative treatments and medical news were excluded. Apps that were not specifically related to breast cancer were also excluded. Apps (in any language) that appeared in the search with keywords were included. The database consisted of apps from AppAgg and Google Play Store. Only 85 apps met the inclusion criteria. Selected apps were categorized on the basis of their alleged interactive features. Descriptive statistics were obtained, and available language options, the number of downloads, and the cost of the apps were the main parameters reviewed. RESULTS: The selected apps were categorized on the basis of the following features: education, BSE training, reminders, and recording. Of the 85 selected apps, 72 (84.7%) focused on disseminating breast cancer information. BSE training was provided by only 47% (n=40) of the apps, and very few had reminder (n=26, 30.5%) and recording (n=11, 12.9%) features. The median number of downloads was the highest for apps with recording features (>1000 downloads) than those with education, BSE training, reminder, and recording features (>5000 downloads). Most of these apps (n=74, 83.5%) were monolingual, and around 80.3% (n=49) of these apps were in English. Almost all the apps on Google Play Store were free of charge. CONCLUSIONS: Although there exist several apps on Google Play Store to promote awareness about breast health and cancer, the usefulness of most of them appears debatable. To provide a complete breast health package to the users, such apps must have all of the following features: reminders or notifications and symptom recording and tracking. There is still an urgent need to scientifically evaluate existing apps in the target populations in order to make them more functional and user-friendly.

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.

Regularized bidimensional estimation of the hazard rate.

In epidemiological or demographic studies, with variable age at onset, a typical quantity of interest is the incidence of a disease (for example the cancer incidence). In these studies, the individuals are usually highly heterogeneous in terms of dates of birth (the cohort) and with respect to the calendar time (the period) and appropriate estimation methods are needed. In this article a new estimation method is presented which extends classical age-period-cohort analysis by allowing interactions between age, period and cohort effects. We introduce a bidimensional regularized estimate of the hazard rate where a penalty is introduced on the likelihood of the model. This penalty can be designed either to smooth the hazard rate or to enforce consecutive values of the hazard to be equal, leading to a parsimonious representation of the hazard rate. In the latter case, we make use of an iterative penalized likelihood scheme to approximate the L0 norm, which makes the computation tractable. The method is evaluated on simulated data and applied on breast cancer survival data from the SEER program.

The Computerized Adaptable Test Battery (BMT-i) for Rapid Assessment of Children's Academic Skills and Cognitive Functions: A Validation Study.

Background: Learning disabilities in children are a major public health concern worldwide, having a prevalence of 8%. They are associated with lost social, educational, and ultimately, professional opportunities for individuals. These disabilities are also very costly to governments and raise the issue of the appropriate means of screening. Unfortunately, validated tools for preliminary appraisal of learning and cognitive function in struggling children are presently restricted to specific age ranges and cognitive domains. This study sought to validate a first-line battery for assessment of academic skills and cognitive functions. Materials and Methods: The computerized Adaptable Test Battery, or BMT-i, includes a panel of tests for the first-line assessment of children's academic skills and cognitive functions. The tests reflect expected abilities for the age group in question, exploring academic skills (written language and mathematical cognition) and cognitive domains (verbal, non-verbal, and attentional/executive functions). The authors relied on the results of these tests for a sample of 1,074 Francophone children representative of the mainland French school-age population (522 boys and 552 girls, ages 4-13, from 39 classes at 7 public and 5 private schools). Thirteen speech-language pathologists and neuropsychologists individually administered the tests. Results: The psychometric characteristics of the empirical data obtained showed acceptable to good test homogeneity, internal consistency (Cronbach's alpha: > 0.70), test-retest reliability (intraclass correlation coefficients: ~0.80), and consistency with reference test batteries (r: 0.44-0.96). Conclusion: The BMT-i was validated in a large sample of children in mainstream French schools, paving the way for its use in first-line screening of learning disabilities among children with complaints, whether their learning difficulties have been flagged by their parents or by their teachers.

Global blood gene expression profiles following a breast cancer diagnosis-Clinical follow-up in the NOWAC post-genome cohort.

OBJECTIVE: This explorative study aimed to assess if there are any time-dependent blood gene expression changes during the first one to eight years after breast cancer diagnosis, which can be linked to the clinical outcome of the disease. MATERIAL AND METHODS: A random distribution of follow-up time from breast cancer diagnosis till blood sampling was obtained by a nested, matched case-control design in the Norwegian Women and Cancer Post-genome Cohort. From 2002-5, women were invited to donate blood samples, regardless of any cancer diagnosis. At end of the study period in 2015, any cancer diagnoses in the 50 000 participants were obtained via linkage to the Norwegian Cancer Registry. For each breast cancer patient (n = 415), an age- and storage time-matched control was drawn. The design gave a uniform, random length of follow-up time, independent of cancer stage. Differences in blood gene expression between breast cancer cases and controls were identified using the Bioconductor R-package limma, using a moving window in time, to handle the varying time elapsed from diagnosis to blood sample. RESULTS: The number of differentially expressed genes between cases and controls were close to 2,000 in the first year after diagnosis, but fell sharply the second year. During the next years, a transient second increase was observed, but only in women with metastatic disease who later died, both compared to invasive cases that survived (p<0,001) and to metastatic cases that survived (p = 0.024). Among the differentially expressed genes there was an overrepresentation of heme metabolism and T cell-related processes. CONCLUSION: This explorative analysis identified changing trajectories in the years after diagnosis, depending on clinical stage. Hypothetically, this could represent the escape of the metastatic cancer from the immune system.

Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon.

BACKGROUND: The use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT), is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant Plasmodium falciparum. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging. METHODS: Studies were conducted in Cameroonian children with acute uncomplicated P. falciparum malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28) were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta-analysis. FINDINGS: The results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ) is as effective as other drugs (artesunate-sulphadoxine-pyrimethamine [AS-SP], artesunate-chlorproguanil-dapsone [AS-CD], artesunate-mefloquine [AS-MQ], dihydroartemisinin-piperaquine [DH-PP], artemether-lumefantrine [AM-LM], amodiaquine, and amodiaquine-sulphadoxine-pyrimethamine [AQ-SP]). AM-LM appeared to be the most effective with no treatment failure due to recrudescence, closely followed by DH-PP. CONCLUSION: Although AM-LM requires six doses, rather than three doses for other artemisinin-based combinations, it has potential advantages over other forms of ACT. Further studies are needed to evaluate the clinical efficacy and tolerance of these combinations in different epidemiological context.

Analysis of an ordinal outcome in a multicentric randomized controlled trial: application to a 3- arm anti- malarial drug trial in Cameroon.

BACKGROUND: Malaria remains a burden in Sub-Saharan Countries. The strategy proposed by the World Health Organization (WHO) is to systematically compare the therapeutic efficacy of antimalarial drugs using as primary outcome for efficacy, a four-category ordered criterion. The objective of the present work was to analyze the treatment effects on this primary outcome taking into account both a center-effect and individual covariates. A three-arm, three-centre trial of Amodiaquine (AQ), sulfadoxine-pyrimethamine (SP) and their combination (AQ + SP), conducted by OCEAC-IRD in 2003, in 538 children with uncomplicated Plasmodium falciparum malaria, is used as an illustration. METHODS: Analyses were based on ordinal regression methods, assuming an underlying continuous latent variable, using either the proportional odds (PO) or the proportional hazards (PH) models. Different algorithms, corresponding to both frequentist- and bayesian-approaches, were implemented using the freely available softwares R and Winbugs, respectively. The performances of the different methods were evaluated on a simulated data set, and then they were applied on the trial data set. RESULTS: Good coverage probability and type-1 error for the treatment effect were achieved. When the methods were applied on the trial data set, results highlighted a significance decrease of SP efficacy when compared to AQ (PO, odds ratio [OR] 0.14, 95% confidence interval [CI] 0.04-0.57; hazard ratio [HR] 0.605, 95% CI 0.42-0.82), and an equal effectiveness between AQ + SP and AQ (PO, odds ratio [OR] 1.70, 95% confidence interval [CI] 0.25-11.44; hazard ratio [HR] 1.40, 95% CI 0.88-2.18). The body temperature was significantly related to the responses. The patient weights were marginally associated to the clinical response. CONCLUSION: The proposed analyses, based on usual statistical packages, appeared adapted to take into account the full information contained in the four categorical outcome in malaria trials, as defined by WHO, with the possibility of adjusting on individual and global covariates.

Progestogen-only contraceptives and the risk of stroke: a meta-analysis.

BACKGROUND AND PURPOSE: The association between combined oral contraceptives (OC) use and increased risk of stroke has been reported. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular disease remains unclear. METHODS: A meta-analysis based on EMBASE and MEDLINE referenced literature corresponding to OCs marketed since 1960 was carried out. Eligible articles assessing the risk of stroke in relation to OC or POC were reviewed, and relevant studies were extracted. All types of POC and routes of administration were taken into account in the meta-analysis. RESULTS: Six case-control studies were identified. The combined odd ratio (OR) showed no increase in the risk of stroke among POC users (OR=0.96; 95% confidence interval: 0.70 to 1.31). This result was similar according to the route of administration (either implant or injectable or oral POC). CONCLUSIONS: Data from observational studies show that POC use is not associated with an increased risk of stroke. However, these results are based on limited data. Further investigations are needed in women with risk factors of stroke.

Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.

Background: Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated. Methods: To improve access to services, an ambulatory team has been established since 1998, delivering on-site clinical genetics consultations and gradually upgrading services to 502 children and young adults with ASD in their standard environment across 26 day-care hospitals and specialized institutions within the Greater Paris region. The evaluation included a clinical genetics consultation, screening for fragile X syndrome, metabolic workup, chromosomal microarray analysis, and, in a proportion of patients, next-generation sequencing of genes reported in ASD and other neurodevelopmental disorders. Results: Fragile X syndrome and pathogenic copy number variants (CNVs) accounted for the disease in 10% of cases, including 4/312 (1.3%) with fragile X syndrome and 34/388 (8.8%) with pathogenic CNVs (19 de novo and 4 inherited). Importantly, adding high-throughput resequencing of reported intellectual disability/ASD genes to the screening procedure had a major impact on diagnostic yield in the 141 patients examined most recently. Pathogenic or likely pathogenic sequence variants in 27 disease genes were identified in 33/141 patients (23.4%; 23 were de novo and 10 inherited, including five X-linked and five recessive compound heterozygous variants). Diagnosed cases presented atypical and/or syndromic ASD with moderate to severe intellectual disability. The diagnostic yield of fragile X syndrome and array CGH testing combined with next-generation sequencing was significantly higher than fragile X syndrome and array CGH alone (p value 0.009). No inborn errors of metabolism were detected with the metabolic screening. Conclusion: Based on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability.

A big-data approach to producing descriptive anthropometric references: a feasibility and validation study of paediatric growth charts.

BACKGROUND: Both national and WHO growth charts have been found to be poorly calibrated with the physical growth of children in many countries. We aimed to generate new national growth charts for French children in the context of huge datasets of physical growth measurements routinely collected by office-based health practitioners. METHODS: We recruited 32 randomly sampled primary care paediatricians and ten volunteer general practitioners from across the French metropolitan territory who used the same electronic medical records software, from which we extracted all physical growth data for the paediatric patients, with anonymisation. We included measurements from all children born from Jan 1, 1990, and aged 1 month to 18 years by Feb 8, 2018, with birthweight greater than 2500 g, to which an automated process of data cleaning developed to detect and delete measurement or transcription errors was applied. Growth charts for weight and height were derived by using generalised additive models for location, scale, and shape with the Box-Cox power exponential distribution. We compared the new charts to WHO growth charts and existing French national growth charts, and validated our charts using growth data from recent national cross-sectional surveys. FINDINGS: After data cleaning, we included 1 458 468 height and 1 690 340 weight measurements from 238 102 children. When compared with the existing French national and WHO growth charts, all height SD and weight percentile curves for the new growth charts were distinctly above those for the existing French national growth charts, as early as age 1 month, with an average difference of -0·75 SD for height and -0·50 SD for weight for both sexes. Comparison with national cross-sectional surveys showed satisfactory calibration, with generally good fit for children aged 5-6 years and 10-11 years in height and weight and small differences at age 14-15 years. INTERPRETATION: We successfully produced calibrated paediatric growth charts by using a novel big-data approach applied to data routinely collected in clinical practice that could be used in many fields other than anthropometry. FUNDING: The French Ministry of Health; Laboratoires Guigoz-General Pediatrics section of the French Society of Pediatrics-Pediatric Epidemiological Research Group; and the French Association for Ambulatory Pediatrics.

No overdiagnosis in the Norwegian Breast Cancer Screening Program estimated by combining record linkage and questionnaire information in the Norwegian Women and Cancer study.

BACKGROUND: The Norwegian Breast Cancer Screening Program (NBCSP) was implemented across the country in 2005 and has been criticised for potential 'overdiagnosis', i.e. a breast cancer diagnosis that otherwise would not have been detected or treated in a woman's lifetime. We aimed to estimate overdiagnosis in the NBCSP based on the Norwegian Women and Cancer (NOWAC) study using both questionnaire information and record linkage information from NBCSP. METHOD: For 124,978 women aged 49-79 years from the NOWAC study, information on screened women could be cross-validated from the NBCSP database. Based on information from the NOWAC questionnaire, unscreened women were further divided into those who had mammograms taken only outside the NBCSP and those who had never had taken a mammogram. Breast cancers diagnosed in 2005-2013 were identified through linkage to the Cancer Registry of Norway; in situ or DCIS 417; invasive 2845; combined 3262. Cumulative incidence rates (CIRs) for ages 49-79 years of breast cancer were compared using the log-rank test. RESULTS: After exclusion of women with a family history of breast cancer, screened women had a CIR of 9.7% for combined breast cancer, non-significantly lower compared with unscreened women. Screened women had a 1.1% increased CIR or 13.0% increased relative risk of breast cancer diagnosis (significant) compared with women who had never had a mammogram, but for invasive breast cancer alone the difference was reduced to -0.2% (95% CI: -9.1; 8.8). Invasive breast cancers were significantly smaller (<2.5 cm) in screened versus unscreened women. There was a borderline significant decrease in lymph node positive cancer among screened (p = 0.06). CONCLUSION: The findings of no significant overdiagnosis combined with smaller tumours and less lymph node metastases suggest that the prevailing view of overdiagnosis in the NBCSP should be challenged.