Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis.

Whole genome sequencing (WGS) improves Mendelian disorder diagnosis over whole exome sequencing (WES); however, additional diagnostic yields and costs remain undefined. We investigated differences between diagnostic and cost outcomes of WGS and WES in a cohort with suspected Mendelian disorders. WGS was performed in 38 WES-negative families derived from a 64 family Mendelian cohort that previously underwent WES. For new WGS diagnoses, contemporary WES reanalysis determined whether variants were diagnosable by original WES or unique to WGS. Diagnostic rates were estimated for WES and WGS to simulate outcomes if both had been applied to the 64 families. Diagnostic costs were calculated for various genomic testing scenarios. WGS diagnosed 34% (13/38) of WES-negative families. However, contemporary WES reanalysis on average 2 years later would have diagnosed 18% (7/38 families) resulting in a WGS-specific diagnostic yield of 19% (6/31 remaining families). In WES-negative families, the incremental cost per additional diagnosis using WGS following WES reanalysis was AU$36,710 (£19,407;US$23,727) and WGS alone was AU$41,916 (£22,159;US$27,093) compared to WES-reanalysis. When we simulated the use of WGS alone as an initial genomic test, the incremental cost for each additional diagnosis was AU$29,708 (£15,705;US$19,201) whereas contemporary WES followed by WGS was AU$36,710 (£19,407;US$23,727) compared to contemporary WES. Our findings confirm that WGS is the optimal genomic test choice for maximal diagnosis in Mendelian disorders. However, accepting a small reduction in diagnostic yield, WES with subsequent reanalysis confers the lowest costs. Whether WES or WGS is utilised will depend on clinical scenario and local resourcing and availability.

The effect of metoprolol and aspirin on cardiovascular risk in bereavement: A randomized controlled trial.

BACKGROUND: Bereavement is associated with an increased risk of cardiovascular disease; however, no reports exist of interventions to reduce risk. In a randomized, double-blind, placebo-controlled trial of 85 recently bereaved participants, we determined whether ß-blocker (metoprolol 25 mg) and aspirin (100 mg) reduce cardiovascular risk markers and anxiety, without adversely affecting bereavement intensity. METHODS: Participants were spouses (n = 73) or parents (n = 12) of deceased from 5 hospitals in Sydney, Australia, 55 females, 30 males, aged 66.1 ±â€¯9.4 years. After assessment within 2 weeks of bereavement, subjects were randomized to 6 weeks of daily treatment or placebo, and the effect evaluated using ANCOVA, adjusted for baseline values (primary analysis). RESULTS: Participants on metoprolol and aspirin had lower levels of home systolic pressure (P = .03), 24-hour average heart rate (P < .001) and anxiety (P = .01) platelet response to arachidonic acid (P < .001) and depression symptoms (P = .046) than placebo with no difference in standard deviation of NN intervals index (SDNNi), von Willebrand Factor antigen, platelet-granulocyte aggregates or bereavement intensity. No significant adverse safety impact was observed. CONCLUSIONS: In early bereavement, low dose metoprolol and aspirin for 6 weeks reduces physiological and psychological surrogate measures of cardiovascular risk. Although further research is needed, results suggest a potential preventive benefit of this approach during heightened cardiovascular risk associated with early bereavement.