Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases.

Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases.

A genetic study of Wilson's disease in the United Kingdom.

Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.

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%.

Putting a value on the avoidance of false positive results when screening for inherited metabolic disease in the newborn.

Despite the increase in the number of inherited metabolic diseases that can be detected at birth using a single dried blood spot sample, the impact of false positive results on parents remains a concern. We used an economic approach - the contingent valuation method - which asks parents to give their maximum willingness to pay for an extension in a screening programme and the degree to which the potential for false positive results diminishes their valuations. 160 parents of a child or children under the age of 16 years were surveyed and given descriptions of the current screening programme in the UK, an extended programme and an extended programme with no false positives. 148 (92.5%) respondents said they would accept the screen for the five extra conditions in an expanded screening programme whilst 10 (6.3%) said they would not and two were unsure. When asked to indicate if they would choose to be screened under an expanded screening programme with no false positive results, 152 (95%) said they would, five (3.1%) said they would not, two were unsure, and there was one non-response. 151 (94.4%) said they preferred the hypothetical test with no false-positives. The mean willingness to pay for the expanded programme was £178 compared to £219 for the hypothetical expanded programme without false positives (p > 0.05). The results suggest that there is widespread parental support for extended screening in the UK and that the number of false-positives is a relatively small issue.

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.

PURPOSE: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25­30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders.

Qualitative exploration of health professionals' experiences of communicating positive newborn bloodspot screening results for nine conditions in England.

OBJECTIVE: To explore health professionals' experiences of communicating positive newborn bloodspot screening (NBS) results, highlight differences, share good practice and make recommendations for future research. DESIGN: Qualitative exploratory design was employed using semi-structured interviews SETTING: Three National Health Service provider organisations in England PARTICIPANTS: Seventeen health professionals involved in communicating positive newborn bloodspot screening results to parents for all nine conditions currently included in the newborn bloodspot screening programme in England. RESULTS: Findings indicated variation in approaches to communicating positive newborn bloodspot screening results to parents, largely influenced by resources available and the lack of clear guidance. Health professionals emphasised the importance of communicating results to families in a way that is sensitive to their needs. However, many challenges hindered communication including logistical considerations; difficulty contacting the family and other health professionals; language barriers; parental reactions; resource considerations; lack of training; and insufficient time. CONCLUSION: Health professionals invest a lot of time and energy trying to ensure communication of positive newborn bloodspot screening results to families is done well. However, there continues to be great variation in the way these results are communicated to parents and this is largely influenced by resources available but also the lack of concrete guidance. How best to support health professionals undertaking this challenging and emotive task requires further exploration. We recommend evaluation of a more cohesive approach that meets the needs of parents and staff while being sensitive to the subtleties of each condition. TRIAL REGISTRATION NUMBER: ISRCTN15330120.

Rethinking Strategies for Positive Newborn Screening Result (NBS+) Delivery (ReSPoND): a process evaluation of co-designing interventions to minimise impact on parental emotional well-being and stress.

BACKGROUND: Newborn blood spot (NBS) screening seeks to prevent ill health, disability and death through early diagnosis and effective intervention. Each year, around 10,000 parents of babies born in England are given a positive NBS result indicating their child may be affected or carriers of one of the nine conditions currently screened for. Despite guidance, these results are inconsistently delivered to parents across geographical regions. There is evidence that many parents are dissatisfied with how NBS results are communicated to them and that poor communication practices can lead to various negative sequelae. The purpose of this study is to co-design, implement and undertake a process evaluation of new, co-designed interventions to improve delivery of initial positive NBS results to parents. METHODS: This mixed-methods study will use four phases with defined outputs. Family Systems Theory will form the theoretical basis for the study. The principles and methods of experience-based co-design will underpin intervention development. Normalisation Process Theory will underpin the process evaluation of the interventions co-designed to improve the delivery of positive NBS results to parents. An economic analysis will determine resource use and costs of current practice and of implementing the new co-designed interventions. The nominal group technique will be used to inform the selection of suitable outcome measures for a future evaluation study. DISCUSSION: The main output of the proposed study will be co-designed interventions for initial communication of positive NBS results to parents ready to be evaluated in a definitive evaluation study.The interventions, co-designed with parents, will help to minimise potential negative sequelae associated with poor communication practices by considering parental and staff experiences as well as healthcare challenges such as finite resources. In addition, information about indicative costs associated with different communication strategies will be determined.It is anticipated it may also be possible to extrapolate principles of good communication practices from the present study for the delivery of bad news to parents for children newly diagnosed with other conditions including cancer and other chronic conditions such as diabetes or epilepsy. TRIAL REGISTRATION: ISRCTN 15330120 date of registration 17/01/2018.

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.

A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease.

OBJECTIVES: (1) to assess the effect of 1 mg folic acid supplementation of cholinesterase inhibitors (ChI) in a 6 month double-blind placebo-controlled study of patients with Alzheimer's Disease (AD) and (2) to assess whether outcome measures were affected by changes in homocysteine levels. METHOD: Fifty-seven consecutive outpatients with probable AD were treated concurrently with a ChI and either folic acid or placebo. None had conditions or medication known to interfere with folate metabolism. Fasting folate and homocysteine levels were measured prior to commencing ChI and 6 months later. Response was categorised using criteria of the National Institute of Clinical Excellence (NICE). RESULTS: Twelve males and 29 females completed treatment (mean age 76.27 SD 6.23 years, Mini-Mental State Examination (MMSE) 23.49 SD 3.53, baseline homocysteine 18.39 SD 4.62 micromoles per litre). 23 received folic acid and 18 placebo. There were no significant baseline differences or use of individual ChI between the two arms. After 6 months a significant difference was seen in the change from baseline in combined Instrumental Activities of Daily Living and Social Behaviour scores between arms (folate+1.50 (SD 5.32) vs placebo -2.29 (SD 6.16) (p=0.03) but not change in MMSE scores. Sixteen of 23 subjects receiving folic acid and 7/18 placebo subjects were classified as NICE responders (p=0.05). CONCLUSION: This pilot double blind study suggests that response to ChI in patients with AD may be improved by the use of folic acid. The relationship between any change in homocysteine levels and response to treatment is discussed.