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This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

PURPOSETo provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids (GA4K) program.METHODSExtensive analyses of 960 families with suspected genetic disorders including short-read exome (ES) and genome sequencing (srGS); PacBio HiFi long-read GS (HiFi-GS); variant calling for small-nucleotide (SNV), structural (SV) and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants and pedigrees are stored in PhenoTips database, with data sharing through controlled access (dbGAP).RESULTSDiagnostic rates ranged from 11% for cases with prior negative genetic tests to 34.5% in naïve patients. Incorporating SVs from GS added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs than srGS. Variants and genes of unknown significance (VUS/GUS) remain the most common finding (58% of non-diagnostic cases).CONCLUSIONComputational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated by HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation, and by providing HiFi variant (SNV/SV) resources from >1,000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

After elective outpatient upper extremity surgery, patients' need for opioid analgesic medication may be considerably less than typically dispensed. Our goal for this study was to evaluate pain control and quantify the amount of leftover pain medication.We recruited patients scheduled for elective outpatient upper extremity surgery, who met the inclusion criteria, to participate in a phone interview 7 to 14 days after surgery. Information collected included age, gender, procedure performed, analgesic medication and regimen prescribed, satisfaction with pain control, number of tablets remaining, reasons for not taking medication, other analgesic medications used, payer classification, and any adverse drug reactions.A total of 287 eligible subjects consented to participate. Of these, 36 patients failed phone contact and 1 patient canceled surgery, which left 250 patients who completed the study. Oxycodone, hydrocodone, and propoxyphene accounted for over 95% of the prescription medications, with adequate pain control reported by 230 (92%) patients. Patients most frequently received 30 pills. Patients undergoing bone procedures reported the highest medication use (14 pills), whereas patients undergoing soft tissue procedures reported the lowest use (9 pills). Over half of the subjects reported taking the opioid medication for 2 days or less. Medicare patients consumed significantly less medication (7 pills, P.05) than patients covered by all other types of insurance. Overall, patients consumed a mean of 10 opioid pills, whereas 19 pills per subject were reported unused, which resulted in 4,639 leftover tablets for the entire cohort.Our data show that excess opioid analgesics are made available after elective upper extremity surgery and could potentially become a source for diversion. A prescription of 30 opioid pills for outpatient surgery appears excessive and unnecessary, especially for soft tissue procedures of the hand and wrist.Prognostic I.