Place of concordance-discordance model in evaluating NGS performance.

INTRODUCTION: Ideally, evaluating NGS performance requires a gold standard; in its absence, concordance between replicates is often used as substitute standard. However, the appropriateness of the concordance-discordance criterion has been rarely evaluated. This study analyzes the relationship between the probability of discordance and the probability of error under different conditions. METHODS: This study used a conditional probability approach under conditional dependence then conditional independence between two sequencing results and compares the probabilities of discordance and error in different theoretical conditions of sensitivity, specificity, and correlation between replicates, then on real results of sequencing genome NA12878. The study examines also covariate effects on discordance and error using generalized additive models with smooth functions. RESULTS: With 99% sensitivity and 99.9% specificity under conditional independence, the probability of error for a positive concordant pair of calls is 0.1%. With additional hypotheses of 0.1% prevalence and 0.9 correlation between replicates, the probability of error for a positive concordant pair is 47.4%. With real data, the estimated sensitivity, specificity, and correlation between tests for variants are around 98.98%, 99.996%, and 93%, respectively, and the error rate for positive concordant calls approximates 2.5%. In covariate effect analyses, the effects' functional form are close between discordance and error models, though the parts of deviance explained by the covariates differ between discordance and error models. CONCLUSION: With conditional independence of two sequencing results, the concordance-discordance criterion seems acceptable as substitute standard. However, with high correlation, the criterion becomes questionable because a high percentage of false concordant results appears among concordant results.

Lymph Node Ratio Improves Prediction of Overall Survival in Esophageal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy: A National Cancer Database Analysis.

OBJECTIVE: This study aimed to propose a revised ypN (r-ypN) classification based on lymph node ratio (LNR) and to examine its prognostic value in postneoadjuvant esophageal cancer. BACKGROUND: A new postneoadjuvant pathologic (ypTNM) staging classification has been introduced for esophageal cancer. However, the ypN classification currently defined by the number of positive lymph nodes is influenced by the extent of lymphadenectomy. METHODS: Data on 7195 esophageal cancer patients receiving neoadjuvant chemoradiation were extracted from the National Cancer Database (NCDB). Four r-ypN stages were defined by 3 LNR thresholds (0%, 10%, and 20% using X-tile software). A revised ypTNM (r-ypTNM) classification was developed by solely changing N categories. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. Akaike information criterion (AIC) and Harrell's concordance index ( C -index) were used to compare the predictive performance of the current and the revised classification. External validation was performed using an independent cohort from the NEOCRTEC5010 clinical trial. RESULTS: Both ypN ( P <0.001) and r-ypN ( P <0.001) were independent prognostic factors of overall survival (OS) for esophageal cancer patients. Kaplan-Meier curves demonstrated a better discrimination with r-ypN than ypN categories. Within each ypN category (except ypN3), OS was significantly different comparing r-ypN strata; however, there were no differences between ypN strata within each r-ypN category (except r-ypN3). r-ypN (AIC: 60752 vs 60782; C -index: 0.591 vs 0.587) and r-ypTNM (AIC: 60623 vs 60628; C -index: 0.613 vs 0.610) showed better predictive performance than the current staging system, with a lower AIC (better calibration) and higher C -index (improved discrimination). This advantage was also confirmed by external validation using the NEOCRTEC5010 cohort. CONCLUSIONS: LNR showed better performance than ypN in predicting OS of esophageal cancer patients after neoadjuvant chemoradiation and may be an improvement on the current staging system.

Individualized Net Benefit estimation and meta-analysis using generalized pairwise comparisons in N-of-1 trials.

BACKGROUND: The Net Benefit (Δ) is a measure of the benefit-risk balance in clinical trials, based on generalized pairwise comparisons (GPC) using several prioritized outcomes and thresholds of clinical relevance. We extended Δ to N-of-1 trials, with a focus on patient-level and population-level Δ. METHODS: We developed a Δ estimator at the individual level as an extension of the stratum-specific Δ, and at the population-level as an extension of the stratified Δ. We performed a simulation study mimicking PROFIL, a series of 38 N-of-1 trials testing sildenafil in Raynaud's phenomenon, to assess the power for such an analysis with realistic data. We then reanalyzed PROFIL using GPC. This reanalysis was finally interpreted in the context of the main analysis of PROFIL which used Bayesian individual probabilities of efficacy. RESULTS: Simulations under the null showed good size of the test for both individual and population levels. The test lacked power when being simulated from the true PROFIL data, even when increasing the number of repetitions up to 140 days per patient. PROFIL individual-level estimated Δ were well correlated with the probabilities of efficacy from the Bayesian analysis while showing similarly wide confidence intervals. Population-level estimated Δ was not significantly different from zero, consistently with the previous Bayesian analysis. CONCLUSION: GPC can be used to estimate individual Δ which can then be aggregated in a meta-analytic way in N-of-1 trials. GPC ability to easily incorporate patient preferences allow for more personalized treatment evaluation, while needing much less computing time than Bayesian modeling.

Integrating imaging-based classification and transcriptomics for quality assessment of human oocytes according to their reproductive efficiency.

PURPOSE: Utilising non-invasive imaging parameters to assess human oocyte fertilisation, development and implantation; and their influence on transcriptomic profiles. METHODS: A ranking tool was designed using imaging data from 957 metaphase II stage oocytes retrieved from 102 patients undergoing ART. Hoffman modulation contrast microscopy was conducted with an Olympus IX53 microscope. Images were acquired prior to ICSI and processed using ImageJ for optical density and grey-level co-occurrence matrices texture analysis. Single-cell RNA sequencing of twenty-three mature oocytes classified according to their competence was performed. RESULT(S): Overall fertilisation, blastulation and implantation rates were 73.0%, 62.6% and 50.8%, respectively. Three different algorithms were produced using binary logistic regression methods based on "optimal" quartiles, resulting in an accuracy of prediction of 76.6%, 67% and 80.7% for fertilisation, blastulation and implantation. Optical density, gradient, inverse difference moment (homogeneity) and entropy (structural complexity) were the parameters with highest predictive properties. The ranking tool showed high sensitivity (68.9-90.8%) but with limited specificity (26.5-62.5%) for outcome prediction. Furthermore, five differentially expressed genes were identified when comparing "good" versus "poor" competent oocytes. CONCLUSION(S): Imaging properties can be used as a tool to assess differences in the ooplasm and predict laboratory and clinical outcomes. Transcriptomic analysis suggested that oocytes with lower competence may have compromised cell cycle either by non-reparable DNA damage or insufficient ooplasmic maturation. Further development of algorithms based on image parameters is encouraged, with an increased balanced cohort and validated prospectively in multicentric studies.

The impact of left truncation of exposure in environmental case-control studies: evidence from breast cancer risk associated with airborne dioxin.

In epidemiology, left-truncated data may bias exposure effect estimates. We analyzed the bias induced by left truncation in estimating breast cancer risk associated with exposure to airborne dioxins. Simulations were run with exposure estimates from a Geographic Information System (GIS)-based metric and considered two hypotheses for historical exposure, three scenarios for intra-individual correlation of annual exposures, and three exposure-effect models. For each correlation/model combination, 500 nested matched case-control studies were simulated and data fitted using a conditional logistic regression model. Bias magnitude was assessed by estimated odds-ratios (ORs) versus theoretical relative risks (TRRs) comparisons. With strong intra-individual correlation and continuous exposure, left truncation overestimated the Beta parameter associated with cumulative dioxin exposure. Versus a theoretical Beta of 4.17, the estimated mean Beta (5%; 95%) was 73.2 (67.7; 78.8) with left-truncated exposure and 4.37 (4.05; 4.66) with lifetime exposure. With exposure categorized in quintiles, the TRR was 2.0, the estimated ORQ5 vs. Q1 2.19 (2.04; 2.33) with truncated exposure versus 2.17 (2.02; 2.32) with lifetime exposure. However, the difference in exposure between Q5 and Q1 was 18× smaller with truncated data, indicating an important overestimation of the dose effect. No intra-individual correlation resulted in effect dilution and statistical power loss. Left truncation induced substantial bias in estimating breast cancer risk associated with exposure with continuous and categorical models. With strong intra-individual exposure correlation, both models detected associations, but categorical models provided better estimates of effect trends. This calls for careful consideration of left truncation-induced bias in interpreting environmental epidemiological data.

Coffee consumption and seizure frequency in patients with drug-resistant focal epilepsy.

OBJECTIVE: To assess the relation between coffee consumption and seizure frequency in patients with drug-resistant focal epilepsy. METHODS: Cross-sectional analysis of data collected in the SAVE study, which included patients with drug-resistant focal epilepsy during long-term EEG monitoring. Patients in whom both coffee consumption and data about seizure frequency, including focal to bilateral tonic-clonic seizures (FBTCS), were available were selected. Coffee consumption was collected using a standardized self-report questionnaire and classified into four groups: none, rare (from less than 1 cup/week to up 3 cups/week), moderate (from 4 cups/week to 3 cups/day), and high (more than 4 cups/day). RESULTS: Six hundred and nineteen patients were included. There was no relation between coffee consumption and total seizure frequency (p = 0.902). In contrast, the number of FBTCS reported over the past year was significantly associated with usual coffee consumption (p = 0.029). Specifically, number of FBCTS in patients who reported moderate coffee consumption was lower than in others. In comparison with patients with moderate coffee consumption, the odds ratio (95%CI) for reporting at least 1 FBTCS per year was 1.6 (1.03-2.49) in patients who never take coffee, 1.62 (1.02-2.57) in those with rare consumption and 2.05 (1.24-3.4) in those with high consumption. Multiple ordinal logistic regression showed a trend toward an association between coffee consumption and number of FBTCS (p = 0.08). CONCLUSIONS AND RELEVANCE: Our data suggest that effect of coffee consumption on seizures might depend on dose with potential benefits on FBTCS frequency at moderate doses. These results will have to be confirmed by prospective studies.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

Correcting the bias of the net benefit estimator due to right-censored observations.

Generalized pairwise comparisons (GPCs) are a statistical method used in randomized clinical trials to simultaneously analyze several prioritized outcomes. This procedure estimates the net benefit (Δ). Δ may be interpreted as the probability for a random patient in the treatment group to have a better overall outcome than a random patient in the control group, minus the probability of the opposite situation. However, the presence of right censoring introduces uninformative pairs that will typically bias the estimate of Δ toward 0. We propose a correction to GPCs that estimates the contribution of each uninformative pair based on the average contribution of the informative pairs. The correction can be applied to the analysis of several prioritized outcomes. We perform a simulation study to evaluate the bias associated with this correction. When only one time-to-event outcome was generated, the corrected estimates were unbiased except in the presence of very heavy censoring. The correction had no effect on the power or type-1 error of the tests based on the Δ. Finally, we illustrate the impact of the correction using data from two randomized trials. The illustrative datasets showed that the correction had limited impact when the proportion of censored observations was around 20% and was most useful when this proportion was close to 70%. Overall, we propose an estimator for the net benefit that is minimally affected by censoring under the assumption that uninformative pairs are exchangeable with informative pairs.

Individualized quantification of the benefit from reperfusion therapy using stroke predictive models.

PURPOSE: Recent imaging developments have shown the potential of voxel-based models in assessing infarct growth after stroke. Many models have been proposed but their relevance in predicting the benefit of a reperfusion therapy remains unclear. We searched for a predictive model whose volumetric predictions would identify stroke patients who are to benefit from tissue plasminogen activator (t-PA)-induced reperfusion. MATERIAL AND METHODS: Forty-five cases were used to study retrospectively stroke progression from admission to end of follow-up. Predictive approaches based on various statistical models, predictive variables and spatial filtering methods were compared. The optimal approach was chosen according to the area under the precision-recall curve (AUPRC). The final lesion volume was then predicted assuming that the patient would or would not reperfuse. Patients, with an acute lesion of ≤50 ml and a predicted reduction in the presence of reperfusion >6 ml and >25% of the acute lesion, were classified as responders. RESULTS: The optimal model was a logistic regression using the voxel distance to the acute lesion, the volume of the acute lesion and Gaussian-filtered MRI contrast parameters as predictive variables. The predictions gave a median AUPRC of 0.655, a median AUC of 0.976 and a median volumetric error of 8.29 ml. Nineteen patients matched the responder profile. A non-significant trend of improved reduction in NIHSS score (-42.8%, p = .09) and in lesion volume (-78.1%, p = 0.21) following reperfusion was observed for responder patients. CONCLUSION: Despite limited volumetric accuracy, predictive stroke models can be used to quantify the benefit of reperfusion therapies.

Centralization errors in comparative genomic hybridization array analysis of pituitary tumor samples.

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization-normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty-six pituitary tumors were analyzed (Agilent aCGH + SNP 4 × 180K microarray). For each tumor, the FISH-based log2 (ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log2 (ratios). With our new normalization-centralization process, this difference was added to all log2 (ratios), before performing loess regression on non-altered probes only. Finally, the mean log2 (ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH-based method. For 11 tumors, FISH results and raw CGH log2 (ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new-method. Such discrepancies seemed to occur with tumours with many abnormalities (0%-40% normal probes), rather than in those tumours with fewer abnormalities (31%-100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data.

Variance component analysis to assess protein quantification in biomarker validation: application to selected reaction monitoring-mass spectrometry.

BACKGROUND: In the field of biomarker validation with mass spectrometry, controlling the technical variability is a critical issue. In selected reaction monitoring (SRM) measurements, this issue provides the opportunity of using variance component analysis to distinguish various sources of variability. However, in case of unbalanced data (unequal number of observations in all factor combinations), the classical methods cannot correctly estimate the various sources of variability, particularly in presence of interaction. The present paper proposes an extension of the variance component analysis to estimate the various components of the variance, including an interaction component in case of unbalanced data. RESULTS: We applied an experimental design that uses a serial dilution to generate known relative protein concentrations and estimated these concentrations by two processing algorithms, a classical and a more recent one. The extended method allowed estimating the variances explained by the dilution and the technical process by each algorithm in an experiment with 9 proteins: L-FABP, 14.3.3 sigma, Calgi, Def.A6, Villin, Calmo, I-FABP, Peroxi-5, and S100A14. Whereas, the recent algorithm gave a higher dilution variance and a lower technical variance than the classical one in two proteins with three peptides (L-FABP and Villin), there were no significant difference between the two algorithms on all proteins. CONCLUSIONS: The extension of the variance component analysis was able to estimate correctly the variance components of protein concentration measurement in case of unbalanced design.

Renal transplantation in children under 3 years of age: Experience from a single-center study.

RTx remains challenging in children under 3 years of age. This single-center study reviewed the medical records of children <3 years transplanted since 1987 (N = 32, Group 1). They were matched for donor type and RTx period with children aged 3-13 years (N = 32, Group 2) and 13-18 years (N = 32, Group 3). There were no between-group significant differences regarding distributions of gender, primary renal disease, proportion of dialysis before RTx, and growth (SDS). Compared to Groups 2 and 3, Group 1 had more peritoneal dialyses (P < .001), more EBV mismatches (P = .04), and longer warm ischemia times (P < .001). The risk of graft loss was not significantly different among age groups (hazard ratio, 2.4 in Group 2 and 2.0 in Group 3 vs Group 1; P = .2). Death occurred in four patients (3 in Group 1 and 1 in Group 2) and graft loss occurred in 28 patients, mainly due to chronic allograft nephropathy. In recipients <3 years of age, the outcomes of RTx are close to those obtained in older pediatric age groups. Thus, young patients may be transplanted in experienced multidisciplinary teams without additional risks provided that particular attention is paid to donor selection and prevention/early diagnosis of comorbidities and complications.

Adding sufentanil to ropivacaine in continuous thoracic paravertebral block fails to improve analgesia after video-assisted thoracic surgery: A randomised controlled trial.

BACKGROUND: The benefit of adding opioid to a local anaesthetic for continuous thoracic paravertebral analgesia after video-assisted thoracic surgery (VATS) is unclear. OBJECTIVES: To analyse the analgesic efficacy of ropivacaine and sufentanil in combination compared with ropivacaine alone after VATS. DESIGN: A randomised, double-blinded, single-centre clinical trial. SETTING: A tertiary university hospital between March 2010 and April 2014. PATIENTS: Ninety patients were recruited, two were not included leaving 88 randomised into two groups. Eighteen patients were excluded from analysis and 70 completed the study. INTERVENTION: To receive thoracic paravertebral analgesia with either 2 mg ml ropivacaine and 0.25 µg ml sufentanil (ropivacaine + sufentanil group) or 2 mg ml ropivacaine alone (ropivacaine group) for 48 h postoperatively. Infusion rate was set at 0.15 ml kg h in both groups. MAIN OUTCOME MEASURES: The primary endpoint was the mean total amount of self-administered morphine by the patients in each group at 48 h postoperatively. RESULTS: The mean ± SD total amount of self-administered morphine was not significantly different between groups (53.1 ±â€Š27.2 mg in the ropivacaine + sufentanil group vs. 58.8 ±â€Š34.3 mg in the ropivacaine group; P = 0.72). No significant differences were found between the two groups in either pain scores at rest or during movement, in opioid-related adverse reactions, in patient satisfaction or length of hospital stay. CONCLUSION: Adding 0.25 µg ml sufentanil to 2 mg ml ropivacaine in continuous thoracic paravertebral analgesia for VATS did not reduce morphine consumption or pain scores when compared with ropivacaine alone. We cannot recommend its use for routine clinical practice. Further studies analysing different concentrations and infusion rates of sufentanil are needed before a lack of efficacy can be confirmed. TRIAL REGISTRATION: Clinical trial registrations: EudraCT: 2009-014832-38. ClinicalTrials.gov: NCT 01082744.

Variance component analysis to assess protein quantification in biomarker discovery. Application to MALDI-TOF mass spectrometry.

Controlling the technological variability on an analytical chain is critical for biomarker discovery. The sources of technological variability should be modeled, which calls for specific experimental design, signal processing, and statistical analysis. Furthermore, with unbalanced data, the various components of variability cannot be estimated with the sequential or adjusted sums of squares of usual software programs. We propose a novel approach to variance component analysis with application to the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) technology and use this approach for protein quantification by a classical signal processing algorithm and two more recent ones (BHI-PRO 1 and 2). Given the high technological variability, the quantification failed to restitute the known quantities of five out of nine proteins present in a controlled solution. There was a linear relationship between protein quantities and peak intensities for four out of nine peaks with all algorithms. The biological component of the variance was higher with BHI-PRO than with the classical algorithm (80-95% with BHI-PRO 1, 79-95% with BHI-PRO 2 vs. 56-90%); thus, BHI-PRO were more efficient in protein quantification. The technological component of the variance was higher with the classical algorithm than with BHI-PRO (6-25% vs. 2.5-9.6% with BHI-PRO 1 and 3.5-11.9% with BHI-PRO 2). The chemical component was also higher with the classical algorithm (3.6-18.7% vs. < 3.5%). Thus, BHI-PRO were better in removing noise from signal when the expected peaks are detected. Overall, either BHI-PRO algorithm may reduce the technological variance from 25 to 10% and thus improve protein quantification and biomarker validation.

Stroke With Unknown Time of Symptom Onset: Baseline Clinical and Magnetic Resonance Imaging Data of the First Thousand Patients in WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial).

BACKGROUND AND PURPOSE: We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort. METHODS: We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery. RESULTS: Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P<0.001), and more often aphasia (72.5% versus 34.0%; P<0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30). CONCLUSIONS: Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32.

Partial validation of a French version of the ADHD-rating scale IV on a French population of children with ADHD and epilepsy. Factorial structure, reliability, and responsiveness.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a well-known comorbidity in children with epilepsy. In English-speaking countries, the scores of the original ADHD-rating scale IV are currently used as main outcomes in various clinical trials in children with epilepsy. In French-speaking countries, several French versions are in use though none has been fully validated yet. We sought here for a partial validation of a French version of the ADHD-RS IV regarding construct validity, internal consistency (i.e., scale reliability), item reliability, and responsiveness in a group of French children with ADHD and epilepsy. METHOD: The study involved 167 children aged 6-15years in 10 French neuropediatric units. The factorial structure and item reliability were assessed with a confirmatory factorial analysis for ordered categorical variables. The dimensions' internal consistency was assessed with Guttman's lambda 6 coefficient. The responsiveness was assessed by the change in score under methylphenidate and in comparison with a control group. RESULTS: The results confirmed the original two-dimensional factorial structure (inattention, hyperactivity/impulsivity) and showed a satisfactory reliability of most items, a good dimension internal consistency, and a good responsiveness of the total score and the two subscores. CONCLUSION: The studied French version of the ADHD-RS IV is thus validated regarding construct validity, reliability, and responsiveness. It can now be used in French-speaking countries in clinical trials of treatments involving children with ADHD and epilepsy. The full validation requires further investigations.

The impact of mosaicism in preimplantation genetic diagnosis (PGD): approaches to PGD for dominant disorders in couples without family history.

OBJECTIVES: Mosaicism in certain dominant disorders may result in a 'non-Mendelian' transmission for the causative mutation. Preimplantation genetic diagnosis (PGD) is available for patients with inherited disorders to achieve an unaffected pregnancy. We present our experience for two female patients with different dominantly inherited autosomal disorders; neurofibromatosis type 1 (NF1) and tuberous sclerosis complex type 2 (TSC2). METHODS: PGD protocol development was carried out using single cells from the patients. PGD was carried out on polar bodies and different embryonic cells. RESULTS: Protocol development for NF1 using lymphocytes from the patient suggested mosaicism for the mutation. This was supported further by quantitative fluorescent-PCR performed on genomic DNA. During PGD, polar bodies and blastomeres lacked the mutation that probably was absent or present at very low levels in the patient's germline. Single lymphocyte analysis during protocol development for TSC2 did not indicate mosaicism; however, analysis of single buccal cells and multiple embryo biopsies across two consecutive IVF/PGD cycles confirmed gonosomal mosaicism. CONCLUSIONS: The trend in PGD is for blastocyst biopsy followed by whole genome amplification, eliminating single cell analysis. In the case of certain dominantly inherited disorders, pre-PGD single cell analysis is beneficial to identify potential mosaicism that ensures robust protocols. © 2016 John Wiley & Sons, Ltd.

Severity of post-partum hemorrhage after vaginal delivery is not predictable from clinical variables available at the time post-partum hemorrhage is diagnosed.

AIM: Identify women at risk of severe post-partum hemorrhage (PPH) by building a prediction model based on clinical variables available at PPH diagnosis. METHODS: We analyzed data on a cohort of 7236 women with PPH after vaginal delivery from 106 maternity units. Severe PPH was defined as the loss of more than 2000 mL of blood, peripartum drop in hemoglobin of 4 g/dL or more, transfusion of at least four packed red blood cells, embolization, hemostasis surgery, transfer to an intensive care unit or death. The Akaike criterion helped selecting the covariates of a multivariate logistic regression model. The performance of the model was studied through building a receiver-operator curve (ROC). The relative utility of the final model was used to determine the importance of the model in decision-making. RESULTS: Among all PPH, the prevalence of severe cases was 18.5%. Several clinical variables were significantly associated with severe PPH (e.g. parity, multiple pregnancy, labor induction, instrumental delivery). The multivariate prediction model was built. The area under the ROC for prediction of severe cases was 0.63 (95% confidence interval, 0.62-0.65). Nevertheless, the sensitivity and specificity of the prediction model were 0.49 and 0.70, respectively, for a threshold at 0.20 (near prevalence). The relative utility was 0.19 for a threshold near prevalence (20%). CONCLUSION: Because of important misclassifications, even the best model we could build with the available clinical data cannot be reasonably recommended for routine use. Every patient with PPH should receive most optimal management. Other types of information, possibly laboratory data, are probably needed.

Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities. METHODS: We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands. RESULTS: ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations. CONCLUSIONS: Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.