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

Peng, Gang; Tang, Yishuo; Gandotra, Neeru; Enns, Gregory M.; Cowan, Tina M.; Zhao, Hongyu; Scharfe, Curt

doi:10.1002/jimd.12236

Cited by 28 publications

(35 citation statements)

References 42 publications

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“…At AaBC under 72 h, the four selected metabolites displayed similar patterns in relation to differences in GA, sex and ethnicity, while patterns changed at AaBC after 96 h. A potential cause for these changes could be limitations in sample size, which decreased with increasing AaBC (97–120 h: n = 1657; 121–144 h: n = 627; 145–168 h: n = 326) leading to increased variance of the estimated mean. Other reasons for the metabolic pattern changes related to later AaBC may be the postnatal advance and increasing environmental changes, or differences related to race/ethnicity status ( 17 , 25 ). We found that White infants had a tendency for later blood collection (26.0% between 24–48 h, 32.6% between 49–168 h, P < 0.001), which could lead to differences in metabolic patterns in later AaBC groups.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies examining the association between AaBC and MS/MS-based screening have focused on a single or a few metabolic analytes or groups of metabolic disorders ( 4 – 9 ). In addition to AaBC, metabolic changes have also been associated with other confounding clinical variables such as gestational age (GA), birth weight (BW), sex, season of birth and race/ethnicity status reported by the parents ( 10 – 17 ).…”

Section: Introductionmentioning

confidence: 99%

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Timing of Newborn Blood Collection Alters Metabolic Disease Screening Performance

et al. 2021

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Blood collection for newborn genetic disease screening is preferably performed within 24–48 h after birth. We used population-level newborn screening (NBS) data to study early postnatal metabolic changes and whether timing of blood collection could impact screening performance. Newborns were grouped based on their reported age at blood collection (AaBC) into early (12–23 h), standard (24–48 h), and late (49–168 h) collection groups. Metabolic marker levels were compared between the groups using effect size analysis, which controlled for group size differences and influence from the clinical variables of birth weight and gestational age. Metabolite level differences identified between groups were correlated to NBS data from false-positive cases for inborn metabolic disorders including carnitine transport defect (CTD), isovaleric acidemia (IVA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Our results showed that 56% of the metabolites had AaBC-related differences, which included metabolites with either decreasing or increasing levels after birth. Compared to the standard group, the early-collection group had elevated marker levels for PKU (phenylalanine, Cohen's d = 0.55), IVA (C5, Cohen's d = 0.24), MMA (C3, Cohen's d = 0.23), and CTD (C0, Cohen's d = 0.23). These findings correlated with higher false-positive rates for PKU (P < 0.05), IVA (P < 0.05), and MMA (P < 0.001), and lower false-positive rate for CTD (P < 0.001) in the early-collection group. Blood collection before 24 h could affect screening performance for some metabolic disorders. We have developed web-based tools integrating AaBC and other variables for interpretive analysis of screening data.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Timing of Newborn Blood Collection Alters Metabolic Disease Screening Performance

et al. 2021

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“…and/or C3/C2 ratio; Peng et al, 2019) and increased levels of C3 levels in Hispanic newborns generally (Peng, Tang, Gandotra, et al, 2020). More studies are required to confirm this overrepresentation Hispanic newborns with elevated C3.…”

Section: Discussionmentioning

confidence: 96%

Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene

Pangilinan

Watkins

Bernard

et al. 2022

American J of Med Genetics Pt A

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The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies.Fibroblasts from 16 CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p < 6 Â 10 À5 ). Using population data, we estimate that $85% of the p.E88del homozygotes born in the same period did not have elevated C3, suggesting that cobalamin metabolism in the majority of these infants with this genotype is unaffected. Clinical follow-up of 4/9 homozygous individuals uncovered neuropsychological findings, mostly in speech and language development. None of these nine individuals exhibited perturbation of cobalamin metabolism beyond the newborn stage even during periods of acute illness.

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“…In our study all of pseu- (Ross, 2008), the importance of screens including secondary mechanisms to reduce false positive rates is essential to build trust. Furthermore, the field is accumulating evidence of many types of markers and the ethnic risk for false positive rates (described and reviewed in Peng et al, 2020). Thus, this work is another piece of the complex puzzle to create a newborn screen that ensures the highest sensitivity and specificity possible for each newborn.…”

Section: Pseudodeficiency Allelesmentioning

confidence: 99%

“…Identifying true positives in a population can be challenging due to a broad range of biochemical cut-offs, barriers to follow-up testing, limited access to genetic sequencing, and lack of available genetic providers with knowledge on interpretation of results. Differences in metabolic screening markers may vary based on the infants' ethnic background resulting in false-positive reporting (Peng et al, 2020;Wasserstein et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Mucopolysaccharidosis type I newborn screening: Importance of second tier testing for ethnically diverse populations

Bosfield

Regier

Viall

et al. 2020

American J of Med Genetics Pt A

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Mucopolysaccharidosis type I (MPS I)/Hurler syndrome newborn screening was added to the recommended uniform screening panel (RUSP) in 2016. As states have added screening for MPS I, programs have reported increased rates of false positives. Reasons for false positive screens include carrier status, true false positive, late‐onset/attenuated forms, and in about half of cases, pseudodeficiency alleles. These alleles have DNA variants that can cause falsely decreased enzyme activity on biochemical enzyme studies and have increased frequency in individuals of African American and African descent. We describe the District of Columbia (DC) experience with MPS I screening from December 2017 to February 2019. In the context of a review of the literature on newborn screening and family experiences and this DC‐based experience, we offer potential solutions to address preliminary concerns regarding this screening. The impact of overrepresentation of screen positives in a minority group and unintentional creation of health disparities and community wariness regarding medical genetics evaluations must be considered to improve the newborn screen programs nationally and internationally.

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

Cited by 28 publications

References 42 publications

Timing of Newborn Blood Collection Alters Metabolic Disease Screening Performance

Timing of Newborn Blood Collection Alters Metabolic Disease Screening Performance

Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene

Mucopolysaccharidosis type I newborn screening: Importance of second tier testing for ethnically diverse populations

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