Enhanced interpretation of newborn screening results without analyte cutoff values.

PURPOSE: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. METHODS: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. RESULTS: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. CONCLUSION: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.

Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: prevalence, predictive value and test validity based on 1.5 million screened babies.

BACKGROUND: Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain. OBJECTIVE: To estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance. SETTING: All births in areas of high ethnic minority prevalence in England. METHODS: Prospective multicentre pilot screening service; testing at age five to eight days; standardized screening, diagnostic and management protocols; independent expert review of screen-positive cases to assign MCADD diagnosis and predicted clinical importance (definite or uncertain). RESULTS: Approximately 1.5 million babies (79% white; 10% Asian) were screened. MCADD was confirmed in 147 of 190 babies with a positive screening result (screen-positive prevalence: 1.20 per 10,000; MCADD prevalence: 0.94 per 10,000; PPV 77% [95% CI 71-83]), comprising 103 (70%) with MCADD variants of definite clinical importance (95 white [95%]; 2 Asian [2%]) and 44 (30%) with variants of uncertain clinical importance (29 white [67%]; 12 Asian [28%]). CONCLUSION: One baby in every 10,000 born in England is diagnosed with MCADD by newborn screening; around 60 babies each year. While the majority of MCADD variants detected are predicted to be of definite clinical importance, this varies according to ethnic group, with variants of uncertain importance most commonly found in Asian babies. These findings provide support for MCADD screening but highlight the need to take account of the ethnic diversity of the population tested at implementation.

Elevated phenylalanine on newborn screening: follow-up testing may reveal undiagnosed galactosaemia.

UNLABELLED: Introduction Newborn screening for phenylketonuria (PKU) can reveal other conditions which lead to an increased blood spot phenylalanine (Phe) concentration. We have investigated the proportion of blood spot samples that gave a positive screen due to clinically significant conditions other than PKU, compared the positive predictive value (PPV) of our referral Phe cut-off with that recommended by the UK Newborn Screening Programme Centre (UKNSPC) (>210 and >240 µmol/L, respectively) and evaluated the effectiveness of reflex testing for galactosaemia using a lower blood spot Phe cut-off concentration of 130 µmol/L. METHODS: All blood spot samples that screened positive, for an increased Phe concentration, between April 2001 and March 2008, were identified from the records of the Sheffield Newborn Screening Laboratory and the diagnoses noted. In addition, all cases of galactosaemia detected in or notified to our screening laboratory within this time were also examined and the screened Phe concentrations compared. RESULTS: Out of 438,674 babies who were screened, 67 had Phe concentration >210 µmol/L (15 per 100,000). Of these, 40 had PKU or persistent hyperphenylalaninaemia with a Phe concentration identified by screening between 270 and 2350 µmol/L. A further 11 were diagnosed with another clinically significant disorder: galactosaemia (n = 8), biopterin defects (n = 2), tyrosinaemia Type 1 (n = 1). In addition, 16 had transient elevations in Phe. In total, nine cases of galactosaemia were identified, of whom, three had Phe concentrations <240 µmol/L with one asymptomatic individual having a concentration <210 µmol/L. CONCLUSIONS: Adoption of the UKNSPC recommended cut-off (>240 µmol/L) will not affect the detection rate of classical PKU, but will improve the PPV from 76% to 80%. The use of a lower cut-off (130 µmol/L) for reflex galactosaemia testing enables the timely identification of asymptomatic cases that benefit particularly from early treatment, without prompting any unnecessary clinical referrals or delaying any referrals. This intervention may reduce mortality in this vulnerable group.

Relationship of octanoylcarnitine concentrations to age at sampling in unaffected newborns screened for medium-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Although octanoylcarnitine (C8) concentrations measured from newborn screening dried blood spots are used to identify those at high risk of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), age-related reference values are currently not available for unaffected newborn populations. Because age at sampling may vary within and between screening programs, variations in C8 concentrations by age may affect screening program performance. We determined whether C8 concentrations vary by age at sampling, sex, birth weight, or gestational age in unaffected newborns. METHODS: We analyzed C8 concentrations from 227,098 unaffected newborns, including 179,729 from 6 English laboratories participating in a multicenter study and 47,369 from the single laboratory serving the New South Wales (NSW) Newborn Screening Program in Australia. In England, the majority of samples were collected at age 5-8 days and analyzed underivatized by use of tandem mass spectrometry (MS/MS); in NSW, samples were obtained at a median age of 3 days and analyzed derivatized by MS/MS. Information on infants' sex, birth weight, gestation, hospitalization, and transfusion status was recorded at time of sampling. RESULTS: C8 concentrations did not vary significantly by age at sampling, sex, birth weight, or gestational age and remained relatively constant during the first 2 weeks of life in unaffected babies being screened for MCADD. CONCLUSIONS: Newborn MCADD screening programs using this biomarker for screening samples collected after the first day and during the first 14 days of life do not need to adjust cutoff values to account for postnatal age, prematurity, or size at birth.

Implementation of the newborn screening programme for sickle cell disease in England: results for 2003-2005.

OBJECTIVES: This paper reports early screening results from the newborn sickle cell disease screening programme recently implemented in England. SETTING: England. Screening is offered at 5-8 days of age as part of the existing bloodspot test and offered to all babies irrespective of ethnicity. METHODS: The laboratory methods recommended are high performance liquid chromatography (HPLC) and iso-electric focusing (IEF). Two methods of analysis must be applied to all screen positive results. The conditions screened for are:- Sickle cell anaemia (Hb SS), Hb SC disease, Hb S/beta-thalassaemia, Hb S/D(Punjab), Hb S/O(Arab), Hb S/HPFH. Carriers identified for the common haemoglobin variants are reported to parents and follow-up counselling is offered. A bespoke laboratory quality assurance programme has been established which has defined standards of satisfactory performance. RESULTS: Provisional figures from the first seven months of screening (up to March 2004) 108,255 infants were screened gave a screen positive rate of 1:900 for these high prevalence areas and a carrier rate of 2.7%. Figures for 2004-2005 show about 250 significant screen positive results for sickle cell disorders and about 6,500 carriers were identified. The birth prevalence for screen positive results from 2004-05 is 1:1500. We estimate that when there is countrywide data, the national birth prevalence will be about 1:2000-1:2,500. CONCLUSION: The results from the national newborn sickle cell screening programme in England-show that the sickle cell disorders are as common as cystic fibrosis (CF) in England, although the distribution of cases is concentrated in London and other urban areas. The findings and approach to implementation adopted in England may be of interest to other Western European countries with increasing rates of sickle cell disease who are considering such programmes and also to other developed countries.

Newborn bloodspot screening in the UK--past, present and future.

Screening newborn babies for inherited metabolic disease began in the UK in the late 1950s with the 'nappy test' for phenylketonuria. In 1969 the Department of Health recommended changing to bloodspot screening using the techniques developed in the USA by Robert Guthrie and his associates. Bloodspot screening for various other disorders (galactosaemia, maple syrup urine disease, homocystinuria, cystic fibrosis and others) was introduced on a patchy local basis but, until 2000, the only additional disorder officially recommended was congenital hypothyroidism. Screening for haemoglobinopathies received official support in 2000 and for cystic fibrosis in 2001 though implementation was slow, particularly for the latter. Both these screens have raised difficult issues relating to genetic privacy and the detection of carrier status in children. During the last decade screening has become increasingly subject to central control. Though a more consistent and systematic approach was clearly needed, this has undoubtedly slowed the rate of innovation. In particular the UK has lagged behind many other European countries in the application of tandem mass spectrometry (MS-MS) though, following a major pilot study, screening for medium-chain acyl-CoA dehydrogenase deficiency is now in the process of introduction. Attempts to codify clinical and laboratory procedures have also proved controversial, highlighting marked differences in practice in various parts of the country and the difficulty of rationalizing these within a practicable and scientifically justified framework. Notwithstanding this, there are many positive developments and newborn screening remains a stimulating and rewarding field in which to work.

Screening for cystic fibrosis: the practice and the debate.

UNLABELLED: Cystic fibrosis is a serious disorder that has been defined on the basis of clinical description, physiological abnormality and more recently by DNA based testing. Newborn screening based upon measurement of immunoreactive trypsin with follow up by DNA testing is capable of detecting cases very often without the need of a sweat test and with the requirement for a second sample reduced to only 1 in 4,200 of those tested. While this efficient system avoids substantial parental anxiety, it does reveal a significant number of heterozygous parents who will require genetic counselling. There is some preliminary evidence for improved growth in the screened population; however, the main benefits of screening result from the improved efficiency of the healthcare system and reduction in the length of time required to make a diagnosis. The arguments relating to screening for cystic fibrosis are more finely balanced than those of previous programmes such as phenylketonuria screening and the benefits of early intervention are less obvious. In addition, the potential harmful effects of unwanted genetic information are more apparent. CONCLUSION: On this basis while the case for screening appears justified the need to ensure properly informed consent appears even more pressing.