Introduction Methylmalonic acidemia(MMA)is a disorder of autosomal recessive inheritance,with an estimated prevalence of 1:50,000.First-tier clinical diagnostic tests often return many false positives[fve false positi...Introduction Methylmalonic acidemia(MMA)is a disorder of autosomal recessive inheritance,with an estimated prevalence of 1:50,000.First-tier clinical diagnostic tests often return many false positives[fve false positive(FP):one true positive(TP)].In this work,our goal was to refne a classifcation model that can minimize the number of false positives,currently an unmet need in the upstream diagnostics of MMA.Methods We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction.We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients,followed by additional ratio feature construction.Feature selection strategies(selection by flter,recursive feature elimination,and learned vector quantization)were used to determine the input set for evaluating the performance of 14 classifcation models to identify a candidate model set for an ensemble model development.Results Our work identifed computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity.The best results[area under the receiver operating characteristic curve(AUROC)of 97%,sensitivity of 92%,and specifcity of 95%]were obtained utilizing an ensemble of the algorithms random forest,C5.0,sparse linear discriminant analysis,and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor.The model achieved a good performance trade-of for a screening application with 6%false-positive rate(FPR)at 95%sensitivity,35%FPR at 99%sensitivity,and 39%FPR at 100%sensitivity.Conclusions The classifcation results and approach of this research can be utilized by clinicians globally,to improve the overall discovery of MMA in pediatric patients.The improved method,when adjusted to 100%precision,can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families展开更多
Background Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. Methods Since August 2016, a prospective study evaluati...Background Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. Methods Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidel-berg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated. Results Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4%of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 13-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample. Conclusions Within 13 months, the study 'Newborn Screening 2020' identified additional 12 children with treatable con-ditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries.展开更多
Background:Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-β-synthase deficiency).Newborn screening for classica...Background:Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-β-synthase deficiency).Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar.Methods:A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine,methionine-phenylalanine-ratio and propionylcarnitine as second-tiers.Proposed cnt-offs were also retrospectively evaluated in newborn screening samples of 12 patients with remethylation disorders and vitamin B12 deficiency from Qatar and Germany.Results:Over a 12 months period,the proposed strategy led to a decrease in the recall rate in homocysteine screening for Qatar from 1.09% to 0.68%,while allowing for additional systematic inclusion of remethylation disorders and vitamin B12 deficiency into the screening panel for Qatar.In the evaluated period the applied strategy would have detected all patients with classical homocystinuria identified by the previous strategy and in addition 5 children with maternal nutritional vitamin B12 deficiency and one patient with an isolated remethylation disorder.Additional retrospective evaluation of newborn screening samples of 12 patients from Germany and Qatar with remethlyation disorders or vitamin B12 deficiency showed that all of these patients would have been detected by the cutoffs used in the proposed new strategy.In addition,an adapted strategy for Germany using methionine,methionine-phenylalanine-ratio and propionylcarnitine as first-tier,and homocysteine as a second-tier test was also positively evaluated retrospectively.Conclusions:The proposed strategy for samples from Qatar allows inclusion of remethylation disorders and vitamin B12 deficiency in the screening panel,while lowering the reca展开更多
The second-tier extended metropolises in the Changjiang (Yangtze) River Delta, including Suzhou, Wuxi and Changzhou near Shanghai, are becoming the most active and new innovative industrial agglomerating areas. Manufa...The second-tier extended metropolises in the Changjiang (Yangtze) River Delta, including Suzhou, Wuxi and Changzhou near Shanghai, are becoming the most active and new innovative industrial agglomerating areas. Manufacturing industries in these second-tier cities have been in rapid growth due to increasing foreign investment. Nevertheless, the economic prospect of these cities is still constrained by a lack of local R&D capacity and production services, which are mainly dependent upon Shanghai. This paper analyses the impact of globalization on the new economic sectors in these cities, the change of industrial structure, the limitation of urban development and the problem of sustainability. Then, the paper analyses the conditions for the high-tech industry and production services in these areas. Also, it applies the industrial organization theory to these cities and examines how these cities can cooperate with each other in terms of horizontal linkages. Finally, the paper gives the future growth prospects in high-tech industry and production services.展开更多
基金supported by the National Key R&D Program of China grand No.2022YFC2703103the Clinical Research Plan of SHDC(SHDC2020CR6028,SHDC2020CR1047B)+1 种基金the Science and Technology Commission of Shanghai Municipality grant 22Y11906900the Second Century Fund(C2F),Chulalongkorn University,Bangkok,Thailand.
文摘Introduction Methylmalonic acidemia(MMA)is a disorder of autosomal recessive inheritance,with an estimated prevalence of 1:50,000.First-tier clinical diagnostic tests often return many false positives[fve false positive(FP):one true positive(TP)].In this work,our goal was to refne a classifcation model that can minimize the number of false positives,currently an unmet need in the upstream diagnostics of MMA.Methods We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction.We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients,followed by additional ratio feature construction.Feature selection strategies(selection by flter,recursive feature elimination,and learned vector quantization)were used to determine the input set for evaluating the performance of 14 classifcation models to identify a candidate model set for an ensemble model development.Results Our work identifed computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity.The best results[area under the receiver operating characteristic curve(AUROC)of 97%,sensitivity of 92%,and specifcity of 95%]were obtained utilizing an ensemble of the algorithms random forest,C5.0,sparse linear discriminant analysis,and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor.The model achieved a good performance trade-of for a screening application with 6%false-positive rate(FPR)at 95%sensitivity,35%FPR at 99%sensitivity,and 39%FPR at 100%sensitivity.Conclusions The classifcation results and approach of this research can be utilized by clinicians globally,to improve the overall discovery of MMA in pediatric patients.The improved method,when adjusted to 100%precision,can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families
文摘Background Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. Methods Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidel-berg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated. Results Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4%of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 13-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample. Conclusions Within 13 months, the study 'Newborn Screening 2020' identified additional 12 children with treatable con-ditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries.
文摘Background:Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-β-synthase deficiency).Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar.Methods:A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine,methionine-phenylalanine-ratio and propionylcarnitine as second-tiers.Proposed cnt-offs were also retrospectively evaluated in newborn screening samples of 12 patients with remethylation disorders and vitamin B12 deficiency from Qatar and Germany.Results:Over a 12 months period,the proposed strategy led to a decrease in the recall rate in homocysteine screening for Qatar from 1.09% to 0.68%,while allowing for additional systematic inclusion of remethylation disorders and vitamin B12 deficiency into the screening panel for Qatar.In the evaluated period the applied strategy would have detected all patients with classical homocystinuria identified by the previous strategy and in addition 5 children with maternal nutritional vitamin B12 deficiency and one patient with an isolated remethylation disorder.Additional retrospective evaluation of newborn screening samples of 12 patients from Germany and Qatar with remethlyation disorders or vitamin B12 deficiency showed that all of these patients would have been detected by the cutoffs used in the proposed new strategy.In addition,an adapted strategy for Germany using methionine,methionine-phenylalanine-ratio and propionylcarnitine as first-tier,and homocysteine as a second-tier test was also positively evaluated retrospectively.Conclusions:The proposed strategy for samples from Qatar allows inclusion of remethylation disorders and vitamin B12 deficiency in the screening panel,while lowering the reca
文摘The second-tier extended metropolises in the Changjiang (Yangtze) River Delta, including Suzhou, Wuxi and Changzhou near Shanghai, are becoming the most active and new innovative industrial agglomerating areas. Manufacturing industries in these second-tier cities have been in rapid growth due to increasing foreign investment. Nevertheless, the economic prospect of these cities is still constrained by a lack of local R&D capacity and production services, which are mainly dependent upon Shanghai. This paper analyses the impact of globalization on the new economic sectors in these cities, the change of industrial structure, the limitation of urban development and the problem of sustainability. Then, the paper analyses the conditions for the high-tech industry and production services in these areas. Also, it applies the industrial organization theory to these cities and examines how these cities can cooperate with each other in terms of horizontal linkages. Finally, the paper gives the future growth prospects in high-tech industry and production services.
