What do we mean by critical and ethical global engagement? Questions from a research partnership between universities in Canada and Rwanda.

Language - the words we use - can play a key role in enabling or limiting transformation of inequalities in the field of global health. At the same time, given the interdisciplinary, intersectoral, and international nature of much global health work, intended meanings, commitments, and underlying values for words used cannot be taken for granted. This commentary sets out to clarify, and in this manner render available for further discussion and debate, the phrase 'critical and ethical global engagement' (CEGE). It derives from discussions between scholars and partners in research, education, and healthcare practice based at one Canadian and two Rwanda institutions. Initially, our aim was to conceptualise the term 'critical and ethical global engagement' in order to guide our own practices. As the complexity of the values, commitments, and considerations underlying our use of this phrase emerged, however, we realised these discussions merited being captured and shared, to facilitate further exploration and exchange on this phrase.

Informing 'good' global health research partnerships: A scoping review of guiding principles.

Background: Several sets of principles have been proposed to guide global health research partnerships and mitigate inequities inadvertently caused by them. The existence of multiple sets of principles poses a challenge for those seeking to critically engage with and develop their practice. Which of these is best to use, and why? To what extent, if any, is there agreement across proposed principles?Objective: The objectives of this review were to: (1) identify and consolidate existing documents and principles to guide global health research partnerships; (2) identify areas of overlapping consensus, if any, regarding which principles are fundamental in these partnerships; (3) identify any lack of consensus in the literature on core principles to support these partnerships.Methods: A scoping review was conducted to gather documents outlining 'principles' of good global health research partnerships. A broad search of academic databases to gather peerreviewed literature was conducted, complemented by a hand-search of key global health funding institutions for grey literature guidelines.Results: Our search yielded nine sets of principles designed to guide and support global health research partnerships. No single principle recurred across all documents reviewed. Most frequently cited were concerns with mutual benefits between partners (n = 6) and equity (n = 4). Despite a lack of consistency in the inclusion and definition of principles, all sources highlighted principles that identified attention to fairness, equity, or justice as an integral part of good global health research partnerships.Conclusions: Lack of consensus regarding how principles are defined suggests a need for further discussion on what global health researchers mean by 'core' principles. Research partnerships should seek to interpret the practical meanings and requirements of these principles through international consultation. Finally, a need exists for tools to assist with implementation of these principles to ensure their application in research practice.

Postanalytical tools improve performance of newborn screening by tandem mass spectrometry.

PURPOSE: The purpose of this study was to compare performance metrics of postanalytical interpretive tools of the Region 4 Stork collaborative project to the actual outcome based on cutoff values for amino acids and acylcarnitines selected by the California newborn screening program. METHODS: This study was a retrospective review of the outcome of 176,186 subjects born in California between 1 January and 30 June 2012. Raw data were uploaded to the Region 4 Stork Web portal as .csv files to calculate tool scores for 48 conditions simultaneously using a previously unpublished functionality, the tool runner. Scores for individual target conditions were deemed informative when equal or greater to the value representing the first percentile rank of known true-positive cases (17,099 cases in total). RESULTS: In the study period, the actual false-positive rate and positive predictive value were 0.26 and 10%, respectively. Utilization of the Region 4 Stork tools, simple interpretation rules, and second-tier tests could have achieved a false-positive rate as low as 0.02% and a positive predictive value >50% by replacing the cutoff system with Region 4 Stork tools as the primary method for postanalytical interpretation. CONCLUSION: Region 4 Stork interpretive tools, second-tier tests, and other evidence-based interpretation rules could have reduced false-positive cases by up to 90% in California.

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%.

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.

Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.

Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.