Ethnic variability in newborn metabolic screening markers associated with false-positive outcomes

J Inherit Metab Dis. 2020 Sep;43(5):934-943. doi: 10.1002/jimd.12236. Epub 2020 Apr 17.


Newborn screening (NBS) programmes utilise information on a variety of clinical variables such as gestational age, sex, and birth weight to reduce false-positive screens for inborn metabolic disorders. Here we study the influence of ethnicity on metabolic marker levels in a diverse newborn population. NBS data from screen-negative singleton babies (n = 100 000) were analysed, which included blood metabolic markers measured by tandem mass spectrometry and ethnicity status reported by the parents. Metabolic marker levels were compared between major ethnic groups (Asian, Black, Hispanic, White) using effect size analysis, which controlled for group size differences and influence from clinical variables. Marker level differences found between ethnic groups were correlated to NBS data from 2532 false-positive cases for four metabolic diseases: glutaric acidemia type 1 (GA-1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). In the result, 79% of the metabolic markers (34 of 43) had ethnicity-related differences. Compared to the other groups, Black infants had elevated GA-1 markers (C5DC, Cohen's d = .37, P < .001), Hispanics had elevated MMA markers (C3, Cohen's d = .13, P < .001, and C3/C2, Cohen's d = .27, P < .001); and Whites had elevated VLCADD markers (C14, Cohen's d = .28, P < .001, and C14:1, Cohen's d = .22, P < .001) and decreased OTCD markers (citrulline, Cohen's d = -.26, P < .001). These findings correlated with the higher false-positive rates in Black infants for GA-1, in Hispanics for MMA, and in Whites for OTCD and for VLCADD. Web-based tools are available to analyse ethnicity-related changes in newborn metabolism and to support developing methods to identify false-positives in metabolic screening.

Keywords: inborn metabolic disorders; informatics and statistics; newborn screening; paediatric clinical chemistry; racial/ethnic-disparities.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acyl-CoA Dehydrogenase, Long-Chain / blood
  • Amino Acid Metabolism, Inborn Errors / blood
  • Amino Acid Metabolism, Inborn Errors / diagnosis*
  • Biomarkers / blood
  • Brain Diseases, Metabolic / blood
  • California
  • Congenital Bone Marrow Failure Syndromes / blood
  • Congenital Bone Marrow Failure Syndromes / diagnosis*
  • Ethnicity / statistics & numerical data*
  • False Positive Reactions
  • Female
  • Gestational Age
  • Glutaryl-CoA Dehydrogenase / blood
  • Glutaryl-CoA Dehydrogenase / deficiency
  • Humans
  • Infant, Newborn
  • Lipid Metabolism, Inborn Errors / blood
  • Lipid Metabolism, Inborn Errors / diagnosis*
  • Male
  • Mitochondrial Diseases / blood
  • Mitochondrial Diseases / diagnosis*
  • Muscular Diseases / blood
  • Muscular Diseases / diagnosis*
  • Neonatal Screening / methods*
  • Ornithine Carbamoyltransferase Deficiency Disease / blood
  • Ornithine Carbamoyltransferase Deficiency Disease / diagnosis*
  • Tandem Mass Spectrometry


  • Biomarkers
  • Glutaryl-CoA Dehydrogenase
  • Acyl-CoA Dehydrogenase, Long-Chain

Supplementary concepts

  • Glutaric Acidemia I
  • Methylmalonic acidemia
  • VLCAD deficiency