Extreme Gradient Boosting Tuned with Metaheuristic Algorithms for Predicting Myeloid NGS Onco-Somatic Variant Pathogenicity.

The advent of next-generation sequencing (NGS) technologies has revolutionized the field of bioinformatics and genomics, particularly in the area of onco-somatic genetics. NGS has provided a wealth of information about the genetic changes that underlie cancer and has considerably improved our ability to diagnose and treat cancer. However, the large amount of data generated by NGS makes it difficult to interpret the variants. To address this, machine learning algorithms such as Extreme Gradient Boosting (XGBoost) have become increasingly important tools in the analysis of NGS data. In this paper, we present a machine learning tool that uses XGBoost to predict the pathogenicity of a mutation in the myeloid panel. We optimized the performance of XGBoost using metaheuristic algorithms and compared our predictions with the decisions of biologists and other prediction tools. The myeloid panel is a critical component in the diagnosis and treatment of myeloid neoplasms, and the sequencing of this panel allows for the identification of specific genetic mutations, enabling more accurate diagnoses and tailored treatment plans. We used datasets collected from our myeloid panel NGS analysis to train the XGBoost algorithm. It represents a data collection of 15,977 mutations variants composed of a collection of 13,221 Single Nucleotide Variants (SNVs), 73 Multiple Nucleoid Variants (MNVs), and 2683 insertion deletions (INDELs). The optimal XGBoost hyperparameters were found with Differential Evolution (DE), with an accuracy of 99.35%, precision of 98.70%, specificity of 98.71%, and sensitivity of 1.

Assessment of a Screening Questionnaire to Identify Exposure to Lead in Pregnant Women.

Lead readily crosses the placenta and displays adverse effects on birth outcomes and neurodevelopment. Systematic identification of the risk of exposure during pregnancy is essential but rarely performed, probably due to hospital staff's workload and their lack of awareness. We aimed to evaluate the relevance of a questionnaire to screen pregnant women for lead exposure. A cross-sectional, multicentre study was carried out on a population of 792 pregnant women from February 2018 to May 2020. A total of 596 women had a blood lead test: 68.5% had blood lead levels below 10 µg/L. The estimated prevalence above 25 µg/L was 4% (95% confidence interval (CI) [2.6-5.9]) and 1.3% had levels above 50 µg/L (95% CI [0.6-2.6]). Multivariate analysis showed that three risk factors significantly increased the probability of blood lead levels above 25 µg/L: the use of traditional cosmetics (adjusted odds ratio [aOR]: 3.90; 95% CI [1.65-9.21]; p = 0.002), degraded old housing (aOR: 2.67; 95% CI [1.19-6.038]; p = 0.018), and (marginally) eating bread more than twice a day (aOR: 2.40; 95% CI [0.96-6.11]; p = 0.060). Our study reveals that a three-question tool can be used to quickly screen for the risk of lead exposure in our population and to trigger lead blood tests and special vigilance during pregnancy follow-up.

Plasma 7-Hydroxymethotrexate Levels Versus Methotrexate to Predict Delayed Elimination in Children Receiving High-Dose Methotrexate.

BACKGROUND: The aim of this study was to investigate the correlation between 7-hydroxymethotrexate (7-OHMTX) and creatinine and to evaluate the predictive value of 7-OHMTX levels on delayed elimination at 24 and 48 hours. In addition, differences in methotrexate (MTX), 7-OHMTX levels, and MTX metabolism using the ratio MTX/7-OHMTX were determined according to age. METHODS: The authors included a total of 106 cycles, corresponding to 33 patients (mean age: 9.8 years, range: 2-18 years) suffering from acute lymphoblastic leukemia, non-Hodgkin lymphoma and osteosarcoma and receiving high-dose MTX (HD-MTX). Plasma MTX, 7-OHMTX, and creatinine at T24 and T48 hours were measured. RESULTS: Children older than 14 years had significantly higher MTX levels at T48 hours (1.25 versus 0.5 µmol/L, P < 0.05) and a higher MTX/7-OHMTX ratio (0.63 versus 0.20, P < 0.05) than children younger than 6 years. Plasma 7-OHMTX at T24 and T48 hours was positively correlated with serum creatinine and creatinine ratio at T24 and T48 hours. MTX levels provided a better specificity and sensitivity at both 24 and 48 hours than 7-OHMTX to predict delayed MTX elimination. A MTX threshold close to 0.83 µmol/L at T48 hours improved specificity from 58% to 82% and keeps sensitivity at 100%. The authors identified a cut-off at 65 µmol/L for MTX at T24 hours with a good sensitivity (75%) and specificity above 50%. CONCLUSIONS: These results confirm the concentration-dependent nephrotoxicity of 7-OHMTX. Children older than 14 years old had a higher MTX levels at 48 hours and a higher MTX/7-OHMTX ratio, suggesting a faster metabolism in younger children. This study identified a higher and more specific MTX threshold at T48 hours compared to those currently used, and a new threshold at T24 hours.

HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 "Aging" study.

BACKGROUND: The ANRS EP45 "Aging" study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence. METHODS: 49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm(3). ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting. RESULTS: Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria. CONCLUSIONS: In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging.