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The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.Genet Med 19 1, 121-126.

Long-term follow-up of newborn screening for conditions such as sickle cell disease can be conducted using linkages to population-based data. We sought to estimate childhood sickle cell disease mortality and risk factors among a statewide birth cohort with sickle cell disease identified through newborn screening.Children with sickle cell disease identified by newborn screening and born to New York residents in 2000-2008 were matched to birth and death certificates. Mortality rates were calculated (using numbers of deaths and observed person-years at risk) and compared with mortality rates for all New York children by maternal race/ethnicity. Stratified analyses were conducted to examine associations between selected factors and mortality.Among 1,911 infants with sickle cell disease matched to birth certificates, 21 deaths were identified. All-cause mortality following diagnosis was 3.8 per 1,000 person-years in the first 2 years of life and 1.0 per 1,000 person-years at ages 2-9 years. The mortality rate was significantly lower among children of foreign-born mothers and was significantly higher among preterm infants with low birth weight. The mortality rates were not significantly higher for infants after 28 days with sickle cell disease than for all New York births, but they were 2.7-8.4 times higher for children 1 through 9 years old with homozygous sickle cell disease than for those of all non-Hispanic black or Hispanic children born to New York residents.Estimated mortality risk in children with homozygous sickle cell disease remains elevated even after adjustment for maternal race/ethnicity. These results provide evidence regarding the current burden of child mortality among children with sickle cell disease despite newborn screening.Genet Med 17 6, 452-459.

The US Secretary of Health and Human Services provides guidance to state newborn screening programs about which conditions should be included in screening (i.e., the “Recommended Uniform Screening Panel”). This guidance is informed by evidence-based recommendations from the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children. This report describes the Advisory Committee’s revised decision-making process for considering conditions nominated to the panel. An expert panel meeting was held in April 2012 to revise the decision matrix, which helps to guide the recommendation process. In January 2013, the Advisory Committee voted to adopt the revised decision matrix. The revised decision matrix clarifies the approach to rating magnitude and certainty of the net benefit of screening to the population of screened newborns for nominated conditions, and now includes the consideration of the capability of state newborn screening programs for population-wide implementation by evaluating the feasibility and readiness of states to adopt screening for nominated conditions. The revised decision matrix will bring increased quality, transparency, and consistency to the process of modifying the recommended uniform screening panel and will now allow formal evaluation of the challenges that state newborn screening programs face in adopting screening for new conditions. Genet Med 16 2, 183–187.

Sickle cell disease is estimated to occur in 1:300–400 African-American births, with higher rates among immigrants from Africa and the Caribbean, and is less common among Hispanic births. This study determined sickle cell disease incidence among New York State newborns stratified by maternal race/ethnicity and nativity. Newborns with confirmed sickle cell disease born to New York State residents were identified by the New York State newborn screening program for the years 2000–2008 and matched to birth records to obtain birth and maternal information. Annual incidence rates were computed and bivariate analyses were conducted to examine associations with maternal race/ethnicity and nativity. From 2000 to 2008, 1,911 New York State newborns were diagnosed with sickle cell disease and matched to the birth certificate files. One in every 1,146 live births was diagnosed with sickle cell disease. Newborns of non-Hispanic black mothers accounted for 86% of sickle cell disease cases whereas newborns of Hispanic mothers accounted for 12% of cases. The estimated incidence was 1:230 live births for non-Hispanic black mothers, 1:2,320 births for Hispanic mothers, and 1:41,647 births for non-Hispanic white mothers. Newborns of foreign-born non-Hispanic black mothers had a twofold higher incidence of sickle cell disease than those born to US-born non-Hispanic black mothers (P < 0.001). This study provides the first US estimates of sickle cell disease incidence by maternal nativity. Women born outside the United States account for the majority of children with sickle cell disease born in New York State. Such findings identify at-risk populations and inform outreach activities that promote ongoing, high-quality medical management to affected children. Genet Med 2013:15(3):222–228

Purpose: To summarize the evidence regarding screening, diagnosis, and treatment of early-infantile Krabbe disease in consideration of its addition to the core panel for newborn screening as has been done in New York state. Methods: Systematic review of articles indexed in MEDLINE and Embase published between January 1988 and July 2009. Thirteen articles describing studies related to screening, diagnosis, or treatment were included in this review. Results: Case series studies suggest that allogeneic hematopoietic stem-cell transplantation soon after the development of signs or symptoms of early-infantile Krabbe disease decreases early-childhood mortality and may improve neurodevelopment. However, limited data suggest there may be loss of motor function among some children who undergo transplantation. No long-term follow-up data are available from these case series. Of the ∼550,000 newborns reported to have been screened in New York, 25 tested positive. None of these were clinically recognized to have Krabbe disease prior these results. Four were considered to be high risk for early-onset Krabbe disease. Two were subsequently diagnosed and underwent stem-cell transplantation, of whom one died from complications. No data are available regarding the impact on families of a positive newborn screen. Conclusions: Although early treatment with hematopoietic stem-cell transplant seems to alter early-childhood mortality and some of the morbidity associated with early-infantile Krabbe disease, significant gaps in knowledge exist regarding the accuracy of screening, the strategy for establishing diagnosis, the affect of a positive screen on families, the benefits and harms of treatment, and long-term prognosis.

SUMMARY This article describes the background, development, and ini-tial implementation of new procedures for the systematic reviewof key issues in newborn screening. Building on the work ofother systematic review efforts, the ERG described here hasaimed to develop consistent and transparent strategies for evi-dence review. This process has helped to strengthen a complexanalysis and decision system by providing balanced evi-dence, taking into account available high-quality data, expertopinion, and other levels of evidence, in a transparent man-ner. The methods developed and the identification of areas ofmissing data may also help investigators begin to standardizethe clinical and laboratory data they collect pertaining to thenewborn screening and diagnosis of rare disorders and theiroutcomes and focus future research efforts in the mostneeded areas.ACKNOWLEDGEMENTSThis review was made possible by subcontract number SC-07-028 to Massachusetts General Hospital, Center for Child andAdolescent Health Policy under prime contract numberHHSP23320045014XI to Altarum Institute, from the Maternaland Child Health Bureau (MCHB) (Title V, Social SecurityAct), Health Resources and Services Administration (HRSA),U.S. Department of Health and Human Services (DHHS).REFERENCES

The Secretary's Advisory Committee on Heritable Disorders in Newborns and Children is charged with evaluating conditions nominated for addition to the uniform screening panel and consequently making recommendations to the secretary of the US Department of Health and Human Services. This report describes the framework by which the committee approaches its task. Key decision nodes include initial review of every nomination to determine whether conditions are amenable for systematic evidence review, review of systematic evidence reviews conducted by the committee's external review group, and deliberation and formal recommendation for addition or exclusion to the uniform panel. Data analyzed include the accuracy and specificity of screening and diagnostic tests for nominated disorders, the extent of predicted health benefits, harms impact on disease course, and cost from early diagnosis and treatment. The committee process is guided by approaches used by similar entities, but more flexible criteria are sometimes needed to accommodate data limitations stemming from the rarity of many of these conditions. Possible outcomes of committee review range from recommendation to add a nominated condition to the uniform panel; provide feedback on specific gaps in evidence that must be addressed before making a decision; or rejection of a nomination (e.g., because of identified harms). The committee's structured evidence-based assessment of nominated conditions supports a consistently rigorous, iterative and transparent approach to its making recommendations regarding broad population-based screening programs for rare conditions in infants and children.