8 research outputs found
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.
Pulmonary Arterial Elastance and INTERMACS-Defined Right Heart Failure Following Left Ventricular Assist Device
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%. © 2012 American College of Medical Genetics and Genomics
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%. © 2012 American College of Medical Genetics and Genomics
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
215 spectrometry through a worldwide collaboration. Methods: Cumulative percentiles of amino
216 acids and acylcarnitines in dried blood spots of approximately 30 million normal newborns and
217 10,615 true positive cases are compared to assign clinical significance, which is achieved when
218 the median of a disease range is either >99%ile or <1%ile of the normal population. The cutoff
219 target ranges of analytes and ratios are then defined as the interval between the limits of the two
220 populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity
221 taking in consideration all available factors. Results: As of December 1, 2010, 129 sites in 45
222 countries have uploaded to the project website a total of 23,970 percentile data points, 558,168
223 analyte results of 10,615 true positive cases with 64 conditions, and 5,088 cutoff values. The
224 average rate of submission of true positive cases between December 1, 2008 and December 1,
225 2010 was 4.7 cases per day (3,418 cases). This cumulative evidence generated 91 and 23 high
226 and low target cutoff ranges, respectively. The overall proportion of cutoff values within the
227 respective target range was 43% (2,176/5,088). Conclusions: An unprecedented level of
228 cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114
229 markers applied to newborn screening of rare metabolic disorders. This set of data could be used
230 as baseline for monitoring of future performance
Enhanced interpretation of newborn screening results without analyte cutoff values
A collaboration among 157 newborn screening programs in 47 countries has lead to the
creation of a database of 705,333 discrete analyte concentrations from 11,462 cases affected with
57 metabolic disorders, and from 631 heterozygotes for 12 conditions. This evidence was first
applied to establish disease ranges for amino acids and acylcarnitines, and clinically validate 114
cutoff target ranges.
Objective: To improve quality and performance with an evidence-based approach, multivariate
pattern recognition software has been developed to aid in the interpretation of complex analyte
profiles. The software generates tools that convert multiple clinically significant results into a
single numerical score based on overlap between normal and disease ranges, penetration within
the disease range, differences between specific conditions, and weighted correction factors.
Design: Eighty-five on-line tools target either a single condition or the differential diagnosis
between two or more conditions. Scores are expressed as a numerical value and as the percentile
rank among all cases with the condition chosen as primary target, and are compared to
interpretation guidelines. Tools are updated automatically after any new data submission (2009-
2011: 5.2 new cases added per day on average).
Main outcome measures: Retrospective evaluation of past cases suggest that these tools could
have avoided at least half of 277 false positive outcomes caused by carrier status for fatty acid
oxidation disorders, and could have prevented 88% of false negative events caused by cutoff
7
values set inappropriately. In Minnesota, their prospective application has been a major
contributing factor to the sustained achievement of a false positive rate below 0.1% and a
positive predictive value above 60%.
Conclusions: Application of this computational approach to raw data could make cutoff values
for single analytes effectively obsolete. This paradigm is not limited to newborn screening and is
applicable to the interpretation of diverse multi-analyte profiles utilized in laboratory medicine.
Abstract wor
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 25-30 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. © 2011 Lippincott Williams & Wilkins