Cost-benefit analysis of introducing next-generation sequencing (metagenomic) pathogen testing in the setting of pyrexia of unknown origin.

Pyrexia of unknown origin (PUO) is defined as a temperature of >38.3°C that lasts for >3 weeks, where no cause can be found despite appropriate investigation. Existing protocols for the work-up of PUO can be extensive and costly, motivating the application of recent advances in molecular diagnostics to pathogen testing. There have been many reports describing various analytical methods and performance of metagenomic pathogen testing in clinical samples but the economics of it has been less well studied. This study pragmatically evaluates the feasibility of introducing metagenomic testing in this setting by assessing the relative cost of clinically-relevant strategies employing this investigative tool under various cost and performance scenarios using Singapore as a demonstration case, and assessing the price and performance benchmarks, which would need to be achieved for metagenomic testing to be potentially considered financially viable relative to the current diagnostic standard. This study has some important limitations: we examined only impact of introducing the metagenomic test to the overall diagnostic cost and excluded costs associated with hospitalization and makes assumptions about the performance of the routine diagnostic tests, limiting the cost of metagenomic test, and the lack of further work-up after positive pathogen detection by the metagenomic test. However, these assumptions were necessary to keep the model within reasonable limits. In spite of these, the simplified presentation lends itself to the illustration of the key insights of our paper. In general, we find the use of metagenomic testing as second-line investigation is effectively dominated, and that use of metagenomic testing at first-line would typically require higher rates of detection or lower cost than currently available in order to be justifiable purely as a cost-saving measure. We conclude that current conditions do not warrant a widespread rush to deploy metagenomic testing to resolve any and all uncertainty, but rather as a front-line technology that should be used in specific contexts, as a supplement to rather than a replacement for careful clinical judgement.

Ministry of Health Clinical Practice Guidelines: Hypertension.

The Ministry of Health (MOH) has updated the clinical practice guidelines on hypertension to provide doctors and patients in Singapore with evidence-based treatment for hypertension. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on hypertension, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Variant screening of the serum amyloid A1 gene and functional study of the p.Gly90Asp variant for its role in atherosclerosis.

OBJECTIVES: Serum amyloid A1 (SAA1) is a major acute-phase protein that is increasingly used as a reliable predictor of coronary artery disease (CAD). In this study we aim to screen the SAAI promoter and exons for genetic variants and to determine their association with CAD. In addition, we also carried out functional study on a variant of p.Gly90Asp encoded by the SAA1 gene. METHODS: Variant screening of SAA1 was performed using high resolution melting (HRM) analysis. Genetic association of p.Gly90Asp with CAD was determined in 800 CAD patients and 773 Chinese control subjects. Functional study of p.Gly90Asp was carried out using THP-1-derived macrophages and HL-60 promyelocytic leukemia cells. RESULTS: A total of 6 SNPs were identified, of which 2 were found to be novel (c.-913G > A and c.92-5T > G). The rare allele of p.Gly90Asp has a lower frequency of 0.013 in the CAD patients although this is not statistically significant. Functional studies of p.Gly90Asp revealed that the variant has decreased upregulation of key cytokines such as IL-8, MCP-1 and TNF-α as well as SERPINB2. CONCLUSIONS: We found the variant p.Gly90Asp SAA1 protein eliciting significantly reduced inflammatory responses in macrophages through a reduction in the secretion of inflammatory cytokines. Despite strong functional effects, the minor allele frequency is too low in the population to attain statistical significance difference between cases and controls.