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Improving the second-tier classification of methylmalonic acidemia patients using a machine learning ensemble method

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World Journal of Pediatrics 2024年第10期20卷 1090-1101页

作者： Zhi-Xing Zhu Georgi ZGenchev Yan-Min Wang Wei Ji Yong-Yong Ren Guo-Li Tian Sira Sriswasdi Hui Lu Shanghai Engineering Research Center for Big Datain Pediatric Precision Medicine Center for BiomedicalInformaticsShanghai Children’s HospitalSchoolof MedicineShanghai Jiao Tong UniversityShanghaiChina Center of Excellence in Computational Molecular Biology Faculty of MedicineChulalongkorn UniversityBangkokThailand Newborn Screening Center Shanghai Children’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina SJTU-Yale Joint Center for Biostatistics and Data Science National Center for Translational MedicineShanghai JiaoTong UniversityShanghaiChina Center for Artifcial Intelligence in Medicine ResearchAfairsFaculty of MedicineChulalongkorn UniversityBangkokThailand State Key Laboratory of Microbial Metabolism JointInternational Research Laboratory of Metabolic&Developmental SciencesDepartment of Bioinformaticsand BiostatisticsSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina

Introduction methylmalonic acidemia(MMA)is a disorder of autosomal recessive inheritance,with an estimated prevalence of 1:50,***-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 *** We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives *** 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 *** 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 *** Our work identifed computational models that explore metabolic analytes to reduce the number of false positives without compromising *** 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 *** 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%*** The classifcation results and approach of this research can be utilized by clinicians globally,to improve the overall discovery of MMA in pediatric *** improved method,when adjusted to 100%precision,can be used to further inform the diagnostic process journey of MMA and help r

关键词： Machine learning methylmalonic acidemia Second-tier test Stacking

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Clinical features and MUT gene mutation spectrum in Chinese patients with isolated methylmalonic acidemia:identification of ten novel allelic variants

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World Journal of Pediatrics 2015年第4期11卷 358-365页

作者： Lian-Shu Han Zhuo Huang Feng Han Jun Ye Wen-Juan Qiu Hui-Wen Zhang Yu Wang Zhu-Wen Gong Xue-Fan Gu Department of Pediatric Endocrinology and Genetic Metabolism Xinhua HospitalShanghai Institute for Pediatric ResearchShanghai Jiaotong University School of MedicineShanghaiChina

Background: This study aims to study MUT gene mutation spectrum in Chinese patients with isolated methylmalonic academia (MMA) and their clinical features for the potential genotype-phenotype correlation. Methods: Forty-three patients were diagnosed with isolated MMA by elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and urine methylmalonate without hyperhomocysteinemia. The MUT gene was amplifi ed by polymerase chain reaction and directly sequenced. Those patients with at least one variant allele were included. The novel missense mutations were assessed by bioinformatic analysis and screened against alleles sequenced from 50 control participants. Results: Among the 43 patients, 38 had typical clinical presentations, and the majority (30/38) experienced early-onset MMA. Eight patients died and seven were lost to follow-up. Twenty patients had poor outcomes and eight showed normal development. The 43 identified MUT gene mutations had at least one variant allele, whereas 35 had two mutant alleles. Of the 33 mutations reported before, eight recurrent mutations were identified in 32 patients, and c.729_730insTT (p.D244Lfs*39) was the most common (12/78) in the mutant alleles. Of the 10 novel mutations, six were missense mutations and four were premature termination codon mutations. The six novel missense mutations seemed to be pathogenic. Conclusions: A total of 10 novelMUT mutations were detected in the Chinese population. c.729_730insTT (p.D244Lfs*39) was the most frequent mutation. A genotype-phenotype correlation could not be found, but the genotypic characterization indicated the need of genetic counseling for MMA patients and early prenatal diagnoses for high-risk families.

关键词： methylmalonic acidemia missense mutation MUT gene

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methylmalonic acidemia: An Unusual Cause of Chronic Renal Disease in Adults

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Open Journal of Nephrology 2024年第3期14卷 334-339页

作者： Kamel El Reshaid Abdulrahman Al Kanderi Department of Medicine Faculty of Medicine Kuwait University Kuwait City Kuwait Department of Nephrology Al-Jahra Hospital Ministry of Health Kuwait City Kuwait

Background: methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typically present at the age of 1 month to 1 year with dehydration, renal impairment as well as neurologic manifestations viz. seizure, encephalopathy, strokes and disease in the globus pallidi. The case: a 26-year-old man presented with severe acute on top of chronic renal disease with serum creatinine at 590 umol/L and bilateral 8 cm kidneys with thin and echogenic cortex. He had: (a) hypernatremic dehydration, metabolic acidosis and high ammonia level with (b) a history of multiple similar attacks since the age of 8 months. Diagnosis of MMA was confirmed by high serum and urine enzymatic levels as well as genetic testing. His initial management included support with replacements of fluids, electrolytes, and bicarbonates as well as intravenous dextrose, vitamin B12 and broad-spectrum antibiotic (Meropenem) for his chest infection. Subsequently, he received 1) CARBAGLU (carglumic acid) for 7 days to lower his ammonia level to Conclusion: Untreated homozygous MMA variants, can achieve adulthood with significant renal disease yet their morbidity and mortality can be ameliorated with diet and specific therapy.

关键词： methylmalonic acidemia Kidney Failure Metabolic Acidosis Autosomal Recessive Amino Acid Disorder Kreps Cycle Hyperammonia Vitamin 12 Carnitine

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Fractional anisotropy for assessment of white matter tracts injury in methylmalonic acidemia

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Chinese Medical Journal 2009年第8期122卷 945-949页

作者： GAO Yu GUAN Wen-ye WANG Jiang ZHANG Yu-zhen LI Yu-hua HAN Lian-shu Department of Radiology Xinhua Hospital Medical School of Shanghai Jiao Tong University Shanghai 200092 China Neuroscience Research Group School of Electrical and Automation Engineering Tianjin University Tianjin 300072 China Department of Pediatric Internal Medicine Xinhua Hospital Medical School of Shanghai Jiao Tong University Shanghai 200092 China

Background methylmalonic acidemia （MMA） is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to white matter injury, diffusion tensor imaging （DTI） is an excellent tool for assessment of white matter injury and possibly for diagnosing this disorder. Methods We retrospectively analyzed DTI images of 12 patients with MMA （7 males, 5 females, age range： 7-12 months, mean age： 9.25±1.70 months） with negative MRI findings. And another 12 age-matched and gender-matched infants were enrolled as control subjects. Fractional anisotropy （FA） of different white matter tracts of the brain was measured in both groups. Results For patients with negative MRI findings, compared with healthy infants, a statistically significant reduction in DTI FA value of the frontal white matter, temporal white matter, and occipital white matter was observed （P〈0.01）. Conclusions In addition to conventional TlW and T2W MR Image, Brain DTI presents a useful, sensitive and complementary tool for the assessment of brain damage in patients with MMA.

关键词： diffusion tensor imaging magnetic resonance imaging fractional anisotropy methylmalonic acidemia children

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甲基丙二酸血症16例并文献复习

甲基丙二酸血症16例并文献复习

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作者：殷星郑州大学

学位级别：硕士

甲基丙二酸血症是一种常染色体隐性遗传的有机酸血症,在先天性有机酸代谢异常中最为常见。其发病率据报道美国为1/48000,意大利为1/115000,德国为1/169000,日本为1/50000。目前我国对于本症的认识、生化检查技术与上述发达国家有很大差... 详细信息

甲基丙二酸血症是一种常染色体隐性遗传的有机酸血症,在先天性有机酸代谢异常中最为常见。其发病率据报道美国为1/48000,意大利为1/115000,德国为1/169000,日本为1/50000。目前我国对于本症的认识、生化检查技术与上述发达国家有很大差距,诊断、治疗方面存在许多困难。而本病预后较差,存活者多遗留有神经系统后遗症。为提高本病认识,本文就甲基丙二酸血症临床表现、实验室检查、治疗及预后进行总结。目的甲基丙二酸血症临床表现复杂多样,多存有不同程度神经系统损害,给家庭和社会带来沉重的负担。目前确诊甲基丙二酸血症有效方法是气相色谱／质谱法（gas chromatography/mass spectrometry, GC/MS）尿有机酸分析。早期诊断、早期治疗是改善预后的重要条件。但由于目前实验条件所限,该疾病在我国尚未列入新生儿筛查项目,所以熟悉甲基丙二酸血症的临床和实验室特征,尽早行GC/MS尿有机酸分析是早期诊断及合理治疗的前提及关键,从而为降甲基丙二酸血症的病死率,改善预后奠定基础。方法对本院通过气相色谱-质谱法尿有机酸分析确诊16例甲基丙二酸血症患儿进行分析,复习有明确年龄及临床特征的71例患儿临床文献,共87例资料,根据发病年龄将其分为出生至1个月组、1个月至1岁组、大于1岁组,分别对其临床特征分析。结果 1.本组患儿发病年龄出生后5天-2岁,其主要表现为喂养困难（37.5%）、发育落后（37.5%）、嗜睡和反应差（31.3%）、惊厥发作（6.3%）、呼吸急促（6.3%）、肌张力异常（25.0%）、肝脏增大（18.8%）、皮肤苍白（18.3%）、水肿/高血压（12.5%）、小头畸形（6.3%）,并有可疑家族史（37.5%）、代谢性酸中毒（50.0%）、贫血（12.5%）、尿红细胞增多（18.8%）、尿蛋白阳性（12.5%）、尿白细胞增多（6.3%）。 2.本组患儿的治疗及预后：2例确诊前死亡,6例确诊后放弃治疗,7例长期接受维生素B12、左旋肉碱治疗,对于接受治疗者进行随访,随访时间2个月-2年（平均11个月）,均存在发育落后,较治疗前有明显进步,1例失访。 3.文献复习：不同年龄组患儿临床表现不同。出生至28天主要表现为喂养困难（83.7%）、呼吸急促（25.6%）、嗜睡（23.3%）、惊厥（14.0%）,29天至1岁者多表现为发育落后（57.9%）、嗜睡（42.1%）、喂养困难（31.6%）、惊厥（21.1%）,大于1岁者表现为发育落后/倒退（72.0%）、痫性发作（44.0%）、呕吐（24.0%）、嗜睡（16.0%）、精神行为异常（8.0%）。查体可见肌张力异常、肝脏增大、小头畸形,实验室检查可见代谢性酸中毒、高氨血症、头颅MRI出现基底核对称异常信号影。结论甲基丙二酸血症中不同年龄组临床表现不同,早发型起病急骤,晚发型症状隐匿。查体可见肌张力异常、发育落后或倒退、肝大、小头畸形。实验室检查可见代谢性酸中毒、高氨血症、头颅MRI出现基底核对称异常信号是甲基丙二酸血症的主要临床特征。本病病死率较高,预后欠佳。属性不符

关键词：甲基丙二酸血症维生素B12 气相色谱/质谱法临床症状治疗 methylmalonic acidemia vitamin B12 gas chromatography-mass spectrometry clinical manifestation treatment

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