Genotype first: Clinical genomics research through a reverse phenotyping approach.

Although genomic research has predominantly relied on phenotypic ascertainment of individuals affected with heritable disease, the falling costs of sequencing allow consideration of genomic ascertainment and reverse phenotyping (the ascertainment of individuals with specific genomic variants and subsequent evaluation of physical characteristics). In this research modality, the scientific question is inverted: investigators gather individuals with a genomic variant and test the hypothesis that there is an associated phenotype via targeted phenotypic evaluations. Genomic ascertainment research is thus a model of predictive genomic medicine and genomic screening. Here, we provide our experience implementing this research method. We describe the infrastructure we developed to perform reverse phenotyping studies, including aggregating a super-cohort of sequenced individuals who consented to recontact for genomic ascertainment research. We assessed 13 studies completed at the National Institutes of Health (NIH) that piloted our reverse phenotyping approach. The studies can be broadly categorized as (1) facilitating novel genotype-disease associations, (2) expanding the phenotypic spectra, or (3) demonstrating ex vivo functional mechanisms of disease. We highlight three examples of reverse phenotyping studies in detail and describe how using a targeted reverse phenotyping approach (as opposed to phenotypic ascertainment or clinical informatics approaches) was crucial to the conclusions reached. Finally, we propose a framework and address challenges to building collaborative genomic ascertainment research programs at other institutions. Our goal is for more researchers to take advantage of this approach, which will expand our understanding of the predictive capability of genomic medicine and increase the opportunity to mitigate genomic disease.

Pressure-Mediated Reflection Spectroscopy Criterion Validity as a Biomarker of Fruit and Vegetable Intake: A 2-Site Cross-Sectional Study of 4 Racial or Ethnic Groups.

BACKGROUND: Valid biomarkers of fruit and vegetable (FV) intake are needed for field-based nutrition research. OBJECTIVES: To examine criterion-related validity of pressure-mediated reflection spectroscopy as a proxy measure of FV intake, using plasma carotenoids and self-reported FV and carotenoid intake as primary and secondary criterion measures, respectively. METHODS: Healthy adults 18-65 y of age, self-identifying as African American/black (n = 61), Asian (n = 53), white (n = 70), or Hispanic (n = 29), in North Carolina and Minnesota were recruited. Skin carotenoids were assessed via pressure-mediated reflection spectroscopy (Veggie Meter), skin melanin via spectrophotometer, and total plasma carotenoid concentration by HPLC-photodiode array detection. Self-reported carotenoid and FV intake was assessed using a semiquantitative FFQ. Relations between skin carotenoids, plasma carotenoids, FV, and carotenoid intake, with differences by race or ethnicity, age, sex, weight status, cholesterol, and melanin index, were examined by bivariate correlations and adjusted multivariate linear regressions. RESULTS: The overall unadjusted correlation between skin and total plasma carotenoids was r = 0.71 and ranged from 0.64 (non-Hispanic black) to 0.80 (Hispanic). Correlations between skin carotenoids and self-reported FV intake ranged from 0.24 (non-Hispanic black) to 0.53 (non-Hispanic white), with an overall correlation of r = 0.35. In models adjusted for age, sex, racial or ethnic group, and BMI, skin carotenoids were associated with plasma carotenoids (R2 = 0.55), FV (R2 = 0.17), and carotenoid intake (R2 = 0.20). For both plasma carotenoid and FV measures, associations with skin carotenoids did not vary by race, but these relations did differ by skin melanin-those with lower melanin had a lower correlation between skin and plasma carotenoids. CONCLUSIONS: Reflection spectroscopy-assessed skin carotenoids may be a reasonable alternative to measurement of plasma carotenoids, a biomarker used to approximate FV intake.

A meta-analysis of studies examining associations between resonance Raman spectroscopy-assessed skin carotenoids and plasma carotenoids among adults and children.

CONTEXT: No meta-analyses appeared to have been conducted to examine overall correlations between resonance Raman spectroscopy (RRS)-assessed skin carotenoids and plasma/serum carotenoids. OBJECTIVE: To review the available literature and quantify the association between RRS-assessed skin carotenoids and plasma/serum carotenoids via a meta-analysis of observational studies. DATA SOURCES: To identify relevant publications, we searched the PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ProQuest, and Scopus databases in April 2020 for items combining 3 concepts: Raman spectroscopy, skin, and plasma or serum. DATA EXTRACTION: Criteria for inclusion were publication in a peer-reviewed journal between 1990 and 2020, available in English language, and results reported as a baseline Pearson correlation coefficient. In teams of 2, the researchers independently reviewed titles and abstracts of 2212 nonduplicate papers with initial screening yielding 62 papers for full-text review, of which 15 were deemed eligible for inclusion. DATA ANALYSIS: A random-effects model in R (version 4.0.0) "meta" package was used to analyze the correlation between RRS-assessed skin and plasma/serum carotenoids. A subgroup analysis was conducted for studies involving adults and children, respectively. CONCLUSIONS: The 15 studies included 1155 individuals: 963 adults and 192 children. One study included children and adults. The random-effects model yielded an overall correlation of 0.68 (95%CI, 0.61-0.74; I2 = 74%; P < 0.01). The results were similar when grouped by adults and children. Among 963 adults, the correlation in the random-effects model was 0.69 (95%CI, 0.61-0.75; I2 = 78%; P < 0.01). Among 192 children, the correlation in the random-effects model was 0.66 (95%CI, 0.52- 0.77; I2 = 55%; P = 0.06). Overall, there was a positive, statistically significant correlation between RRS-assessed skin carotenoids and plasma/serum carotenoids in a pooled meta-analysis of 15 studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (record number 178835).