ABSTRACT
Death in the fetal, perinatal, and early infant age-group has a multitude of causes, a proportion of which is presumed to be genetic. Defining a specific genetic aberration leading to the death is problematic at this young age, due to limited phenotype-genotype correlation inherent in the underdeveloped phenotype, the inability to assess certain phenotypic traits after death, and the problems of dealing with rare disorders. In this study, our aim was to increase the yield of identification of a defined genetic cause of an early death. Therefore, we employed whole genome sequencing and bioinformatic filtering techniques as a comprehensive, unbiased genetic investigation into 16 fetal, perinatal, and early infant deaths, which had undergone a full autopsy. A likely genetic cause was identified in two cases (in genes; COL2A1 and RYR1) and a speculative genetic cause in a further six cases (in genes: ARHGAP35, BBS7, CASZ1, CRIM1, DHCR7, HADHB, HAPLN3, HSPG2, MYO18B, and SRGAP2). This investigation indicates that whole genome sequencing is a significantly enabling technology when determining genetic causes of early death.
Subject(s)
Fetal Death/etiology , Genetic Diseases, Inborn/diagnosis , Infant Death/etiology , Perinatal Death/etiology , Whole Genome Sequencing , Female , Genetic Diseases, Inborn/genetics , Genetic Markers , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Risk FactorsABSTRACT
PURPOSE: To compare the efficacy of whole genome sequencing (WGS) with targeted next-generation sequencing (NGS) in the diagnosis of inherited retinal disease (IRD). DESIGN: Case series. PARTICIPANTS: A total of 562 patients diagnosed with IRD. METHODS: We performed a direct comparative analysis of current molecular diagnostics with WGS. We retrospectively reviewed the findings from a diagnostic NGS DNA test for 562 patients with IRD. A subset of 46 of 562 patients (encompassing potential clinical outcomes of diagnostic analysis) also underwent WGS, and we compared mutation detection rates and molecular diagnostic yields. In addition, we compared the sensitivity and specificity of the 2 techniques to identify known single nucleotide variants (SNVs) using 6 control samples with publically available genotype data. MAIN OUTCOME MEASURES: Diagnostic yield of genomic testing. RESULTS: Across known disease-causing genes, targeted NGS and WGS achieved similar levels of sensitivity and specificity for SNV detection. However, WGS also identified 14 clinically relevant genetic variants through WGS that had not been identified by NGS diagnostic testing for the 46 individuals with IRD. These variants included large deletions and variants in noncoding regions of the genome. Identification of these variants confirmed a molecular diagnosis of IRD for 11 of the 33 individuals referred for WGS who had not obtained a molecular diagnosis through targeted NGS testing. Weighted estimates, accounting for population structure, suggest that WGS methods could result in an overall 29% (95% confidence interval, 15-45) uplift in diagnostic yield. CONCLUSIONS: We show that WGS methods can detect disease-causing genetic variants missed by current NGS diagnostic methodologies for IRD and thereby demonstrate the clinical utility and additional value of WGS.
Subject(s)
Eye Diseases, Hereditary/genetics , Genome , Molecular Diagnostic Techniques , Retinal Diseases/genetics , Sequence Analysis, DNA , Female , Genotype , High-Throughput Nucleotide Sequencing , Humans , Male , Polymorphism, Single Nucleotide , Retrospective Studies , Sensitivity and SpecificityABSTRACT
Children's National Medical Center's approach to preventing denials and managing response to audits includes the following: Mapping out problem areas in the claims submission process and developing solutions with the help of a multidisciplinary team. Using case managers to help prevent denials and assist in the appeal of rejected claims. Requesting oral reconsideration of pended claims and supporting attending physicians in orally responding to the payer's medical team regarding the case.
Subject(s)
Economics, Hospital/organization & administration , Insurance, Health, Reimbursement , Interdisciplinary Communication , Case Management , District of Columbia , Efficiency, Organizational , Hospitals, Pediatric , Humans , Organizational Case StudiesABSTRACT
A patient recruiting process was developed for a youth weight-management program in a metropolitan area, and the clinical effects of the program on overweight and obese children aged 7 to 17 years old were assessed. During the 12-month effort, 68 overweight children were enrolled. The program included exercise, nutrition coaching, and behavior change counseling. Clinical outcomes were measured. Patient recruiting methods were monitored and included working with physicians and schools and marketing to consumers. Program adherence was 71% attendance, 5% noncompliance, and 5% drop out rates. Clinical outcomes were excellent: 68% of participants lowered their body mass index by an average of 2.5% (mean, 24 weeks). The program was clinically successful, but patient recruitment initiatives were unsuccessful and the program was discontinued. Parents were the largest obstacle to patient recruiting efforts. For children's weight-management programs to be commercially viable, new models of patient recruiting and promotion of parental acceptance are needed.
