Clinical Impact and Cost-Effectiveness of Whole Exome Sequencing as a Diagnostic Tool: A Pediatric Center's Experience.

BACKGROUND: There are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. Moreover, there are no reports addressing the cost burden associated with genetic tests performed prior to WES. OBJECTIVE: We demonstrate the performance characteristics of WES in a pediatric setting by describing our patient cohort, calculating the diagnostic yield, and detailing the patients for whom clinical management was altered. Moreover, we examined the potential cost-effectiveness of WES by examining the cost burden of diagnostic workups. METHODS: To determine the clinical utility of our hospital's clinical WES, we performed a retrospective review of the first 40 cases. We utilized dual bioinformatics analyses pipelines based on commercially available software and in-house tools. RESULTS: Of the first 40 clinical cases, we identified genetic defects in 12 (30%) patients, of which 47% of the mutations were previously unreported in the literature. Among the 12 patients with positive findings, seven have autosomal dominant disease and five have autosomal recessive disease. Ninety percent of the cohort opted to receive secondary findings and of those, secondary medical actionable results were returned in three cases. Among these positive cases, there are a number of novel mutations that are being reported here. The diagnostic workup included a significant number of genetic tests with microarray and single-gene sequencing being the most popular tests. Significantly, genetic diagnosis from WES led to altered patient medical management in positive cases. CONCLUSION: We demonstrate the clinical utility of WES by establishing the clinical diagnostic rate and its impact on medical management in a large pediatric center. The cost-effectiveness of WES was demonstrated by ending the diagnostic odyssey in positive cases. Also, in some cases it may be most cost-effective to directly perform WES. WES provides a unique glimpse into the complexity of genetic disorders.

Feasibility of the hydrogen sulfide test for the assessment of drinking water quality in post-earthquake Haiti.

In 2010, a magnitude 7.0 earthquake struck Haiti, severely damaging the drinking and wastewater infrastructure and leaving millions homeless. Compounding this problem, the introduction of Vibrio cholerae resulted in a massive cholera outbreak that infected over 700,000 people and threatened the safety of Haiti's drinking water. To mitigate this public health crisis, non-government organizations installed thousands of wells to provide communities with safe drinking water. However, despite increased access, Haiti currently lacks the monitoring capacity to assure the microbial safety of any of its water resources. For these reasons, this study was designed to assess the feasibility of using a simple, low-cost method to detect indicators of fecal contamination of drinking water that could be implemented at the community level. Water samples from 358 sources of drinking water in the Léogâne flood basin were screened with a commercially available hydrogen sulfide test and a standard membrane method for the enumeration of thermotolerant coliforms. When compared with the gold standard method, the hydrogen sulfide test had a sensitivity of 65 % and a specificity of 93 %. While the sensitivity of the assay increased at higher fecal coliform concentrations, it never exceeded 88 %, even with fecal coliform concentrations greater than 100 colony-forming units per 100 ml. While its simplicity makes the hydrogen sulfide test attractive for assessing water quality in low-resource settings, the low sensitivity raises concerns about its use as the sole indicator of the presence or absence of fecal coliforms in individual or community water sources.

Testing spatiotemporal hypothesis of bacterial evolution using methicillin-resistant Staphylococcus aureus ST239 genome-wide data within a bayesian framework.

Staphylococcus aureus is a common cause of infections that has undergone rapid global spread over recent decades. Formal phylogeographic methods have not yet been applied to the molecular epidemiology of bacterial pathogens because the limited genetic diversity of data sets based on individual genes usually results in poor phylogenetic resolution. Here, we investigated a whole-genome single nucleotide polymorphism (SNP) data set of health care-associated Methicillin-resistant S. aureus sequence type 239 (HA-MRSA ST239) strains, which we analyzed using Markov spatial models that incorporate geographical sampling distributions. The reconstructed timescale indicated a temporal origin of this strain shortly after the introduction of Methicillin, followed by global pandemic spread. The estimate of the temporal origin was robust to the molecular clock, coalescent prior, full/intergenic/synonymous SNP inclusion, and correction for excluded invariant site patterns. Finally, phylogeographic analyses statistically supported the role of human movement in the global dissemination of HA-MRSA ST239, although it was unable to conclusively resolve the location of the root. This study demonstrates that bacterial genomes can indeed contain sufficient evolutionary information to elucidate the temporal and spatial dynamics of transmission. Future applications of this approach to other bacterial strains may provide valuable epidemiological insights that may justify the cost of genome-wide typing.

Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen.

BACKGROUND: The treatment of patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin sodium therapy is a common clinical problem. We investigated the efficacy and safety of a standardized periprocedural anticoagulation regimen with low-molecular-weight heparin. METHODS: We studied 650 consecutive patients with a mechanical heart valve, chronic atrial fibrillation, or embolic stroke who required interruption of warfarin therapy because of an invasive procedure. Warfarin was stopped 5 or 6 days before the procedure, and patients received subcutaneous dalteparin sodium, 100 IU/kg twice daily, starting 3 days before the procedure. The risk of postprocedural bleeding determined postprocedural anticoagulant management. In patients undergoing a non-high-bleeding-risk procedure who had adequate postprocedural hemostasis, warfarin was resumed on the evening of the procedure, and dalteparin sodium, 100 IU/kg twice daily, was resumed on the next day and continued until the international normalized ratio was 2.0 or more. If postprocedural hemostasis was not secured, the resumption of dalteparin was delayed. In patients undergoing a high-bleeding-risk procedure, warfarin was resumed on the evening of the procedure, but dalteparin was not given after the procedure. RESULTS: Patients were followed up during the preprocedural and postprocedural period for a mean of 13.8 days (range, 10-18 days). In 542 patients who underwent a non-high-bleeding-risk procedure, there were 2 thromboembolic events (0.4%), 4 major bleeding episodes (0.7%), and 32 episodes of increased wound-related blood loss that precluded postprocedural dalteparin administration (5.9%). In 108 patients who underwent a high-bleeding-risk procedure, there were 2 deaths (1.8%) possibly due to thromboembolism and 2 major bleeding episodes (1.8%). CONCLUSIONS: In patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin therapy, a standardized periprocedural anticoagulant regimen with low-molecular-weight heparin is associated with a low risk of thromboembolic and major bleeding complications.