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In-depth multiomic phenotyping provides molecular insights into complex physiological processes and their pathologies. Here, we report on integrating 18 diverse deep molecular phenotyping (omics-) technologies applied to urine, blood, and saliva samples from 391 participants of the multiethnic diabetes Qatar Metabolomics Study of Diabetes (QMDiab). Using 6,304 quantitative molecular traits with 1,221,345 genetic variants, methylation at 470,837 DNA CpG sites, and gene expression of 57,000 transcripts, we determine (1) within-platform partial correlations, (2) between-platform mutual best correlations, and (3) genome-, epigenome-, transcriptome-, and phenome-wide associations. Combined into a molecular network of > 34,000 statistically significant trait-trait links in biofluids, our study portrays "The Molecular Human". We describe the variances explained by each omics in the phenotypes (age, sex, BMI, and diabetes state), platform complementarity, and the inherent correlation structures of multiomics data. Further, we construct multi-molecular network of diabetes subtypes. Finally, we generated an open-access web interface to "The Molecular Human" ( http://comics.metabolomix.com ), providing interactive data exploration and hypotheses generation possibilities., (© 2024. The Author(s).)

Background: Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic disorder caused by variants in genes involved in the function of the primary cilium. We have harnessed genomics to identify BBS and ophthalmic technologies to describe novel features of BBS., Case Presentation: A patient with an unclear diagnosis of syndromic type 2 diabetes mellitus, another affected sibling and unaffected siblings and parents were sequenced using DNA extracted from saliva samples. Corneal confocal microscopy (CCM) and retinal spectral domain optical coherence tomography (SD-OCT) were used to identify novel ophthalmic features in these patients. The two affected individuals had a homozygous variant in C8orf37 (p.Trp185*). SD-OCT and CCM demonstrated a marked and patchy reduction in the retinal nerve fiber layer thickness and loss of corneal nerve fibers, respectively., Conclusion: This report highlights the use of ophthalmic imaging to identify novel retinal and corneal abnormalities that extend the phenotype of BBS in a patient with syndromic type 2 diabetes., (© 2023. The Author(s).)

Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power and higher uncertainty in their quantification. Here we propose ratios between related drug metabolites as GWAS phenotypes that can drastically increase power to detect genetic associations between pairs of biochemically related molecules. As a proof-of-concept we conducted a GWAS with 520 individuals from the Qatar Biobank for who at least five of the nine available acetaminophen metabolites have been detected. We identified compelling evidence for genetic variance in acetaminophen glucuronidation and methylation by UGT2A15 and COMT, respectively. Based on the metabolite ratio association profiles of these two loci we hypothesized the chemical structure of one of their products or substrates as being 3-methoxyacetaminophen, which we then confirmed experimentally. Taken together, our study suggests a novel approach to analyze metabolites with a high degree of missingness in a GWAS setting with ratios, and it also demonstrates how pharmacological pathways can be mapped out using non-targeted metabolomics measurements in large population-based studies.

Modern metabolomics platforms are able to identify many drug-related metabolites in blood samples. Applied to population-based biobank studies, the detection of drug metabolites can then be used as a proxy for medication use or serve as a validation tool for questionnaire-based health assessments. However, it is not clear how well detection of drug metabolites in blood samples matches information on self-reported medication provided by study participants. Here, we curate free-text responses to a drug-usage questionnaire from 6000 participants of the Qatar Biobank (QBB) using standardized WHO Anatomical Therapeutic Chemical (ATC) Classification System codes and compare the occurrence of these ATC terms to the detection of drug-related metabolites in matching blood plasma samples from 2807 QBB participants for which we collected non-targeted metabolomics data. We found that the detection of 22 drug-related metabolites significantly associated with the self-reported use of the corresponding medication. Good agreement of self-reported medication with non-targeted metabolomics was observed, with self-reported drugs and their metabolites being detected in a same blood sample in 79.4% of the cases. On the other hand, only 29.5% of detected drug metabolites matched to self-reported medication. Possible explanations for differences include under-reporting of over-the-counter medications from the study participants, such as paracetamol, misannotation of low abundance metabolites, such as metformin, and inability of the current methods to detect them. Taken together, our study provides a broad real-world view of what to expect from large non-targeted metabolomics measurements in population-based biobank studies and indicates areas where further improvements can be made.

Pediatric medulloblastomas (MBs) are the most common type of malignant brain tumors in children. They are among the most aggressive types of tumors due to their potential for metastasis. Although this disease was initially considered a single disease, pediatric MBs can be considerably heterogeneous. Current MB classification schemes are heavily reliant on histopathology. However, the classification of MB from histopathological images is a manual process that is expensive, time-consuming, and prone to error. Previous studies have classified MB subtypes using a single feature extraction method that was based on either deep learning or textural analysis. Here, we combine textural analysis with deep learning techniques to improve subtype identification using histopathological images from two medical centers. Three state-of-the-art deep learning models were trained with textural images created from two texture analysis methods in addition to the original histopathological images, enabling the proposed pipeline to benefit from both the spatial and textural information of the images. Using a relatively small number of features, we show that our automated pipeline can yield an increase in the accuracy of classification of pediatric MB compared with previously reported methods. A refined classification of pediatric MB subgroups may provide a powerful tool for individualized therapies and identification of children with increased risk of complications.

Background: Limited reports are available on the role of 4% citrate as a locking solution for temporary dialysis catheters. Hence, the aim of this study is to investigate the role of 4% citrate vs. heparin 5,000 µ/mL as a catheter-locking solution in a randomized controlled trial., Materials and Methods: The trial was conducted in Egypt where the use of non-tunneled temporary catheters is prevalent compared to tunneled long-term catheters. The efficacy of catheter-locking solutions was compared regarding observation of rate of catheter dysfunction, low-flow pump, fever as a sign of central-line blood-stream infection (CLBSI), catheter-site infection, thrombosis, local bleeding, and systemic bleeding in each group of the study., Results: Each group consisted of 105 patients. The number of patients who developed CLBSI in the citrate group was 11 (10.5%) compared to 23 (21.9%) in the heparin group (p < 0.025). The number of patients who developed catheter dysfunction in the citrate group was similar to those in the heparin group. The incidence of catheter-site infection, thrombosis, and local bleeding in the citrate group was similar to that in the heparin group., Conclusion: Citrate 4% lock solution is equally effective as heparin in maintaining catheter patency in dialysis patients. It may have a favorable effect on prevention of catheter-related infection due to its additional antiseptic properties as compared to heparin. Citrate-based locking solutions are a promising alternative to unfractionated heparin as a locking solution for dialysis catheters.
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Background and Aim: Rheumatic mitral regurgitation is rather common in developing countries. It usually progresses insidiously, because the heart compensates for increasing regurgitant volume by left-atrial enlargement, causes left-ventricular overload and dysfunction, and yields poor outcome when it becomes severe. Doppler-echocardiographic methods can be used to quantify the severity of mitral regurgitation. It is known that ejection fraction underestimates the presence of left ventricular dysfunction in these patients. This study aimed to study global cardiac function of these patients by using LV Tei index., Methods: One hundred patients with rheumatic mitral regurge predominantly were included (40 males and 60 females; aged 10-24 years, median 20.6 years). All participants were subjected to full echocardiographic study including total isovolumic index (Tei index = isovolumic relaxation time IRT + isovolumic contraction time ICT/ejection time ET) for the left ventricle. Special attention was paid to grading of severity of the mitral regurgitation., Results: LV ejection fraction was preserved in all cases but, however, the total left isovolumic index was prolonged 0.56 ± 3 in 64 of them (34 females and 30 males) denoting masked LV dysfunction P < .00001. There was a correlation of increasing severity of dysfunction with the degree of mitral regurgitation., Conclusion: Ejection fraction underestimates the presence of left ventricular dysfunction in these patients. However, this was unmasked by the Tei index which could be an additive data for detecting early left ventricular dysfunction.