Genomics and AI in Personalized Medicine

The use of liquid chromatography/tandem mass spectrometry has been a key development in expanded newborn screening, as it enables the simultaneous determination of many metabolites from a single dried blood spot collected shortly after birth, and enables both first tier and confirmatory testing. The method is highly analytical specific, but there are still issues to be resolved regarding the harmonization of results, thresholds and methods between laboratories. The aim of this systematic review was to find out the analytical problems, to assess the standardization processes and to sum up the future directions mentioned in the primary literature. Twenty-four studies were identified and included in the systematic search of four electronic databases, mostly from single centers in high-income countries, and appraised. Three interrelated areas of analytical challenge were identified: preanalytical effects of the dried blood specimen such as effect of the hematocrit, biological and exogenous contamination, and preparation of the quality control materials; analytical interferences, primarily isobaric and isomeric species that must be chromatographically separated, and matrix effects and the compromises between derivatized and underivatized methods; and quantitative difficulties associated with population-dependent thresholds and the lack of commutable reference materials. There were four levels of standardization: external quality assessment and proficiency testing, consensus guidelines and accreditation, post-analytical harmonization of covariate-adjusted interpretation of results and analyte-ratio algorithms, and metrological traceability, with the latter two being the most immediate sources of the reductions in false-positive results. The future directions that were reported were focused on high resolution and untargeted profiling, proteomic multiplexing, integration with genomic sequencing, and machine learning. The platform analytics was therefore determined to be well-developed, while harmonisation between laboratories remained the main constraint and the development of commutable reference materials and the addition of underrepresented populations were determined to be priorities for future research.