queryMed: Semantic Web functions for linking pharmacological and medical knowledge to data.

SUMMARY: In public health research and more precisely in the reuse of electronic health data, selecting patients, identifying specific events and interpreting results typically requires biomedical knowledge. The queryMed R package aims to facilitate the integration of medical and pharmacological knowledge stored in formats compliant with the Linked Data paradigm (e.g. OWL ontologies and RDF datasets) into the R statistical programming environment. We show how it allowed us to identify all the drugs prescribed for critical limb ischemia (CLI) and also to detect one contraindicated prescription for one patient by linking a medical database of 1003 CLI patients to ontologies. AVAILABILITY AND IMPLEMENTATION: queryMed is readily usable for medical data mappings and enrichment. Sources, R vignettes and test data are available on GitHub (https://github.com/yannrivault/queryMed) and are archived on Zenodo (https://doi.org/10.5281/zenodo.1323481).

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

[The use of administrative health databases in infectious disease epidemiology and public health]. / Apport des bases médico-administratives en épidémiologie et santé publique des maladies infectieuses.

BACKGROUND: The public health burden resulting from infectious diseases requires efforts in surveillance and evaluation of health care. The use of administrative health databases (AHD) and in particular the French national health insurance database (SNIIRAM) is an opportunity to improve knowledge in this field. The SNIIRAM data network (REDSIAM) workshop dedicated to infectious diseases conducted a narrative literature review of studies using French AHD. From the results, benefits and limits of these new tools in the field of infectious diseases are presented. METHODS: Publications identified by the members of the workgroup were collected using an analytical framework that documented the pathology of interest, the aim of the study, the goal of the developed algorithm, the kind of data, the study period, and the presence of an evaluation or a discussion of the performance of the performed algorithm. RESULTS: Fifty-five articles were identified. A majority focused on the field of vaccination coverage and joint infections. Excluding vaccine coverage field, the aim of 28 studies was epidemiological surveillance. Twenty-six studies used hospital databases exclusively, 18 used ambulatory databases exclusively and 4 used both. Validation or discussion of the performed algorithm was present in 18 studies. CONCLUSIONS: The literature review confirmed the interest of the French AHD in the infectious diseases field. The AHD are additional tools of the existing surveillance systems and their use will probably be more frequent in the coming years given their advantage and reliability. However, incoming users need to be assisted. Thus, the workgroup will contribute to a reasonable use of AHD and support future developments.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Health insurance database for post-discharge surveillance of surgical site infection following arthroplasty.

BACKGROUND: Surgical site infection surveillance (SSI) is important for the improvement of care and patient safety. Most SSI surveillance systems focus on hospital settings, whereas numerous infectious events occur after discharge. AIM: To evaluate the patient care trajectory after discharge, we linked the hospital discharge database and the National Health Insurance Cross-Schemes Information System (NHI-CIS) to trace hip or knee arthroplasty infection (HKAI). METHODS: A retrospective analysis was performed using the permanent 1/97th sample of the whole NHI-CIS database. A total of 1739 patients underwent hip or knee arthroplasty between January 1st, 2011 and December 31st, 2011. Patients rehospitalized for HKAI were detected using a specific published algorithm. Non-rehospitalized HKAI patients were identified using a novel tracking algorithm based on ambulatory care consumption: nurse intervention, antibiotics and bandage purchase. FINDINGS: Of the 1739 studied patients, 20 patients (1.1%) were rehospitalized for HKAI. Fourteen (70%) of the HKAI events occurred within the first two months after surgery, two occurring during the patients' surgical hospital stay. Using ambulatory care data, 10 additional cases were suspected of developing HKAI in the year following their surgery. HKAI incidence rate was then estimated to be 1.76% (95% confidence interval: 1.14-2.38%). CONCLUSION: Although the study sample was limited, we demonstrated that each HKAI occurring after discharge could not be traced by the in-hospital information system alone. This result emphasizes the need for having a passive routine tool for post-discharge surveillance such as the NHI-CIS database.

Pregnancy outcomes of prenatally diagnosed Turner syndrome: a French multicenter retrospective study including a series of 975 cases.

OBJECTIVES: The objectives of this study were to report pregnancy outcomes after prenatal diagnosis of Turner syndrome (TS) and to compare and assess termination of pregnancy rates during two periods. The intervals selected were before and after 1997 when multidisciplinary centers for prenatal diagnosis (MCPDs) were established in France. METHODS: A database of 975 cases of TS diagnosed between 1980 and 2012 was created from 21 French cytogenetics laboratories. For each case, the karyotype indication, maternal age, year of prenatal testing, sampling procedure, karyotype, associated ultrasound findings, and outcomes were recorded. RESULTS: Karyotypes were mainly performed because of abnormal sonographic findings (84%). Before 1997, there were no changes in the rate of termination (90%) of affected fetuses. After 1997, the rate fell to 80%. This decrease was mainly observed in cases of mosaicism, incidental diagnosis, and in later gestations. US abnormalities were more likely to be associated with a full 45,X karyotype. CONCLUSION: There was an evolution in the way genetic counseling was performed following prenatal diagnosis of Turner syndrome that coincided with the opening of MCPDs in France. This resulted in a decrease in the rate of termination of affected fetuses.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

Pregnancy outcomes in 188 French cases of prenatally diagnosed Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (KS), a common sex chromosome aneuploidy (47,XXY) is diagnosed prenatally with an incidence of 0.15%. The diagnosis is generally incidental, since there are no typical malformations on ultrasound (US). Once detected, genetic counseling is often difficult and the parents' decision to continue or terminate the pregnancy is greatly dependent on the amount and nature of the information provided. We sought to assess the pregnancy outcomes (i.e. continuation versus termination) and the influence of multidisciplinary centers for prenatal diagnosis on parental decisions in cases of KS. METHODS: From 1985 to 2009, 188 prenatal diagnoses of KS were made by 11 participating laboratories in mainland France. In each case, the karyotype indication, parental ages, year of prenatal testing, sampling procedure, karyotype, associated US findings and outcome were recorded. RESULTS AND CONCLUSIONS: The pregnancy termination rate declined markedly over time, from 46.9% before 1997 to 11.6% thereafter, in line with the introduction of new legislation on prenatal diagnosis for medical reasons and, more specifically, the creation of multidisciplinary prenatal diagnosis centers. However, an additional microdeletion in one KS infant who exhibited echogenic bowel on US was unfortunately diagnosed postnatally. This raises the question as to whether array comparative genomic hybridization should be prenatally advised when US abnormalities are detected, in line with advice for fetuses with a normal karyotype.

MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.

BACKGROUND: Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. METHOD: Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. RESULTS: 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. CONCLUSION: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.

Using flowViz to visualize flow cytometry data.

UNLABELLED: Automated analysis of flow cytometry (FCM) data is essential for it to become successful as a high throughput technology. We believe that the principles of Trellis graphics can be adapted to provide useful visualizations that can aid such automation. In this article, we describe the R/Bioconductor package flowViz that implements such visualizations. AVAILABILITY: flowViz is available as an R package from the Bioconductor project: http://bioconductor.org

DNA chip technology in cardiovascular research.

Global and/or dynamic analysis of the cardiac transcriptome may improve our understanding of the adaptation of cardiac tissue or cells to different physiological or pathological conditions. The achievement of sequencing projects on mammalian genomes and the development of DNA chip technology have dramatically extended the scale of gene expression studies from a candidate gene approach to a system approach. In current DNA chip experiments, expression levels of thousands of genes can be determined simultaneously. Obviously, the huge quantities of objects and information generated by these experiments require a computational management of the expression data with adequate mathematical (mostly statistical) algorithms. Here, we will discuss the principle and experimental key points of DNA chips. Four examples will be cited to illustrate applications in the cardiovascular system.

Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis.

The L1CAM gene, which is located in Xq28 and codes for a neuronal cell adhesion molecule, is involved in three distinct conditions: HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, adductus thumbs), and SPG1 (spastic paraplegia). Molecular analysis of the L1CAM gene is labor-intensive because of the size of the coding region, which is fragmented in numerous exons, and because of the great allelic heterogeneity and distribution of the mutations. The FAMA (fluorescent assisted mismatch analysis) method combines the excellent sensitivity of the chemical cleavage method for scanning PCR fragments larger than 1 kb and the power of automated DNA sequencers. In order to optimize this method for L1CAM, we divided the gene into nine genomic fragments, each including three to four exons. These fragments were PCR-amplified using nine sets of primers containing additional rare universal sequences. A second-stage PCR, per formed with the two dye-labeled universal primers, allowed us to generate 1-kb-labeled fragments, which were then submitted to the chemical cleavage analysis. Among 12 French families with HSAS and/or MASA, we identified nine distinct L1CAM mutations, seven of which were novel, and an intronic variation. This study demonstrates that FAMA allows rapid and reliable detection of mutations in the L1CAM gene and thus represents one of the most appropriate methods to provide diagnosis for accurate genetic counseling in families with HSAS, MASA, or SPG1.