Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood.

To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.

Swim drink study: a randomised controlled trial of during-exercise rehydration and swimming performance.

OBJECTIVE: To determine whether during-exercise rehydration improves swimming performance and whether sports drink or water have differential effects on performance. DESIGN: Randomised controlled multiple crossover trial. SETTING: A UK competitive swimming club. SUBJECTS: 19 club-level competitive swimmers, median age (range) 13 (11-17) years. INTERVENTIONS: Subjects were scheduled to drink ad libitum commercial isotonic sports drink (3.9 g sugars and 0.13 g salt per 100 mL) or water (three sessions each) or no drink (six sessions) in the course of twelve 75 min training sessions, each of which was followed by a 30 min test set of ten 100 m maximum-effort freestyle sprints each starting at 3 min intervals. MAIN OUTCOME MEASURE: Times for the middle 50 m of each sprint measured using electronic timing equipment in a Federation Internationale de Natation (FINA)-compliant six-lane 25 m competition swimming pool. RANDOMISATION: Software-generated individual random session order in sealed envelopes. Analysis subset of eight sessions randomly selected by software after data collection completed. MASKING: Participants blind to drink allocation until session start. RESULTS: In the analysis data set of 1118 swims, there was no significant difference between swim times for drinking and not drinking nor between drinking water or a sports drink. Mean (SEM) 50 m time for no-drink swims was 38.077 (0.128) s and 38.105 (0.131) s for drink swims, p=0.701. Mean 50 m times were 38.031 (0.184) s for drinking sports drink and 38.182 (0.186) s for drinking water, p=0.073. Times after not drinking were 0.027 s faster than after drinking (95% CI 0.186 s faster to 0.113 s slower). Times after drinking sports drink were 0.151 s faster than after water (95% CI 0.309 s faster to 0.002 s slower). Mean (SEM) dehydration from exercise was 0.42 (0.11)%. CONCLUSIONS: Drinking water or sports drink over 105 min of sustained effort swimming training does not improve swimming performance. TRIAL REGISTRATION: ISRCTN: 49860006.