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2.
Sci Data ; 6(1): 24, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975992

RESUMO

Studies have established the importance of physical activity and fitness for long-term cardiovascular health, yet limited data exist on the association between objective, real-world large-scale physical activity patterns, fitness, sleep, and cardiovascular health primarily due to difficulties in collecting such datasets. We present data from the MyHeart Counts Cardiovascular Health Study, wherein participants contributed data via an iPhone application built using Apple's ResearchKit framework and consented to make this data available freely for further research applications. In this smartphone-based study of cardiovascular health, participants recorded daily physical activity, completed health questionnaires, and performed a 6-minute walk fitness test. Data from English-speaking participants aged 18 years or older with a US-registered iPhone who agreed to share their data broadly and who enrolled between the study's launch and the time of the data freeze for this data release (March 10 2015-October 28 2015) are now available for further research. It is anticipated that releasing this large-scale collection of real-world physical activity, fitness, sleep, and cardiovascular health data will enable the research community to work collaboratively towards improving our understanding of the relationship between cardiovascular indicators, lifestyle, and overall health, as well as inform mobile health research best practices.


Assuntos
Sistema Cardiovascular , Exercício , Sono , Adulto , Glicemia/análise , Pressão Sanguínea , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Humanos , Smartphone , Inquéritos e Questionários , Telemedicina
3.
Nat Biotechnol ; 35(4): 354-362, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28288104

RESUMO

The feasibility of using mobile health applications to conduct observational clinical studies requires rigorous validation. Here, we report initial findings from the Asthma Mobile Health Study, a research study, including recruitment, consent, and enrollment, conducted entirely remotely by smartphone. We achieved secure bidirectional data flow between investigators and 7,593 participants from across the United States, including many with severe asthma. Our platform enabled prospective collection of longitudinal, multidimensional data (e.g., surveys, devices, geolocation, and air quality) in a subset of users over the 6-month study period. Consistent trending and correlation of interrelated variables support the quality of data obtained via this method. We detected increased reporting of asthma symptoms in regions affected by heat, pollen, and wildfires. Potential challenges with this technology include selection bias, low retention rates, reporting bias, and data security. These issues require attention to realize the full potential of mobile platforms in research and patient care.


Assuntos
Asma/epidemiologia , Pesquisa sobre Serviços de Saúde/organização & administração , Inquéritos Epidemiológicos/estatística & dados numéricos , Vigilância da População/métodos , Projetos de Pesquisa , Telemedicina/estatística & dados numéricos , Adolescente , Adulto , Idoso , Asma/diagnóstico , Feminino , Inquéritos Epidemiológicos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Estudos Observacionais como Assunto/métodos , Seleção de Pacientes , Prevalência , Fatores de Risco , Adulto Jovem
4.
Pac Symp Biocomput ; 22: 300-311, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27896984

RESUMO

In our recent Asthma Mobile Health Study (AMHS), thousands of asthma patients across the country contributed medical data through the iPhone Asthma Health App on a daily basis for an extended period of time. The collected data included daily self-reported asthma symptoms, symptom triggers, and real time geographic location information. The AMHS is just one of many studies occurring in the context of now many thousands of mobile health apps aimed at improving wellness and better managing chronic disease conditions, leveraging the passive and active collection of data from mobile, handheld smart devices. The ability to identify patient groups or patterns of symptoms that might predict adverse outcomes such as asthma exacerbations or hospitalizations from these types of large, prospectively collected data sets, would be of significant general interest. However, conventional clustering methods cannot be applied to these types of longitudinally collected data, especially survey data actively collected from app users, given heterogeneous patterns of missing values due to: 1) varying survey response rates among different users, 2) varying survey response rates over time of each user, and 3) non-overlapping periods of enrollment among different users. To handle such complicated missing data structure, we proposed a probability imputation model to infer missing data. We also employed a consensus clustering strategy in tandem with the multiple imputation procedure. Through simulation studies under a range of scenarios reflecting real data conditions, we identified favorable performance of the proposed method over other strategies that impute the missing value through low-rank matrix completion. When applying the proposed new method to study asthma triggers and symptoms collected as part of the AMHS, we identified several patient groups with distinct phenotype patterns. Further validation of the methods described in this paper might be used to identify clinically important patterns in large data sets with complicated missing data structure, improving the ability to use such data sets to identify at-risk populations for potential intervention.


Assuntos
Aplicativos Móveis , Telemedicina , Asma/classificação , Asma/diagnóstico , Asma/terapia , Telefone Celular , Análise por Conglomerados , Biologia Computacional/métodos , Simulação por Computador , Coleta de Dados , Humanos , Inquéritos e Questionários , Fatores de Tempo
5.
BMC Med Genet ; 15: 30, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24602372

RESUMO

BACKGROUND: D-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia. CASE PRESENTATION: An adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10-13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic:phytanic acid and arachidonic:docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation. CONCLUSION: Our case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome.


Assuntos
Anormalidades Múltiplas/diagnóstico , Ataxia/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Doenças Mitocondriais/diagnóstico , Proteína Multifuncional do Peroxissomo-2/deficiência , Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/genética , Adulto , Ataxia/enzimologia , Ataxia/genética , Azoospermia/diagnóstico , Azoospermia/enzimologia , Azoospermia/genética , Sequência de Bases , Variações do Número de Cópias de DNA , Dosagem de Genes , Perda Auditiva Neurossensorial/enzimologia , Perda Auditiva Neurossensorial/genética , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Técnicas de Diagnóstico Molecular , Dados de Sequência Molecular , Proteína Multifuncional do Peroxissomo-2/genética , Fenótipo , Análise de Sequência de DNA , Deleção de Sequência
6.
Neurology ; 80(19): 1762-70, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23596069

RESUMO

OBJECTIVE: To evaluate the utility of targeted exome sequencing for the molecular diagnosis of mitochondrial disorders, which exhibit marked phenotypic and genetic heterogeneity. METHODS: We considered a diverse set of 102 patients with suspected mitochondrial disorders based on clinical, biochemical, and/or molecular findings, and whose disease ranged from mild to severe, with varying age at onset. We sequenced the mitochondrial genome (mtDNA) and the exons of 1,598 nuclear-encoded genes implicated in mitochondrial biology, mitochondrial disease, or monogenic disorders with phenotypic overlap. We prioritized variants likely to underlie disease and established molecular diagnoses in accordance with current clinical genetic guidelines. RESULTS: Targeted exome sequencing yielded molecular diagnoses in established disease loci in 22% of cases, including 17 of 18 (94%) with prior molecular diagnoses and 5 of 84 (6%) without. The 5 new diagnoses implicated 2 genes associated with canonical mitochondrial disorders (NDUFV1, POLG2), and 3 genes known to underlie other neurologic disorders (DPYD, KARS, WFS1), underscoring the phenotypic and biochemical overlap with other inborn errors. We prioritized variants in an additional 26 patients, including recessive, X-linked, and mtDNA variants that were enriched 2-fold over background and await further support of pathogenicity. In one case, we modeled patient mutations in yeast to provide evidence that recessive mutations in ATP5A1 can underlie combined respiratory chain deficiency. CONCLUSION: The results demonstrate that targeted exome sequencing is an effective alternative to the sequential testing of mtDNA and individual nuclear genes as part of the investigation of mitochondrial disease. Our study underscores the ongoing challenge of variant interpretation in the clinical setting.


Assuntos
DNA Mitocondrial/genética , Exoma/genética , Marcação de Genes/métodos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Adulto Jovem
7.
Sci Transl Med ; 4(118): 118ra10, 2012 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-22277967

RESUMO

Advances in next-generation sequencing (NGS) promise to facilitate diagnosis of inherited disorders. Although in research settings NGS has pinpointed causal alleles using segregation in large families, the key challenge for clinical diagnosis is application to single individuals. To explore its diagnostic use, we performed targeted NGS in 42 unrelated infants with clinical and biochemical evidence of mitochondrial oxidative phosphorylation disease. These devastating mitochondrial disorders are characterized by phenotypic and genetic heterogeneity, with more than 100 causal genes identified to date. We performed "MitoExome" sequencing of the mitochondrial DNA (mtDNA) and exons of ~1000 nuclear genes encoding mitochondrial proteins and prioritized rare mutations predicted to disrupt function. Because patients and healthy control individuals harbored a comparable number of such heterozygous alleles, we could not prioritize dominant-acting genes. However, patients showed a fivefold enrichment of genes with two such mutations that could underlie recessive disease. In total, 23 of 42 (55%) patients harbored such recessive genes or pathogenic mtDNA variants. Firm diagnoses were enabled in 10 patients (24%) who had mutations in genes previously linked to disease. Thirteen patients (31%) had mutations in nuclear genes not previously linked to disease. The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings.


Assuntos
Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Análise de Sequência de DNA/métodos , Sequência de Aminoácidos , Sequência de Bases , Estudos de Casos e Controles , Núcleo Celular/genética , Criança , Pré-Escolar , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/genética , Exoma/genética , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Genes Mitocondriais/genética , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/enzimologia , Miopatias Mitocondriais/genética , Dados de Sequência Molecular , Mutação/genética , Fosforilação Oxidativa , Fosfotransferases (Aceptor do Grupo Álcool)/química , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Reprodutibilidade dos Testes
8.
Cell Metab ; 14(3): 428-34, 2011 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-21907147

RESUMO

The metazoan mitochondrial translation machinery is unusual in having a single tRNA(Met) that fulfills the dual role of the initiator and elongator tRNA(Met). A portion of the Met-tRNA(Met) pool is formylated by mitochondrial methionyl-tRNA formyltransferase (MTFMT) to generate N-formylmethionine-tRNA(Met) (fMet-tRNA(met)), which is used for translation initiation; however, the requirement of formylation for initiation in human mitochondria is still under debate. Using targeted sequencing of the mtDNA and nuclear exons encoding the mitochondrial proteome (MitoExome), we identified compound heterozygous mutations in MTFMT in two unrelated children presenting with Leigh syndrome and combined OXPHOS deficiency. Patient fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of MTFMT. Furthermore, patient fibroblasts have dramatically reduced fMet-tRNA(Met) levels and an abnormal formylation profile of mitochondrially translated COX1. Our findings demonstrate that MTFMT is critical for efficient human mitochondrial translation and reveal a human disorder of Met-tRNA(Met) formylation.


Assuntos
Ciclo-Oxigenase 1/metabolismo , DNA Mitocondrial/química , Fibroblastos/metabolismo , Doença de Leigh/genética , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Biossíntese de Proteínas , RNA de Transferência de Metionina/metabolismo , Células Cultivadas , Criança , Ciclo-Oxigenase 1/genética , DNA Mitocondrial/genética , Fibroblastos/patologia , Heterozigoto , Humanos , Hidroximetil e Formil Transferases , Immunoblotting , Doença de Leigh/metabolismo , Doença de Leigh/patologia , Lentivirus , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mutação , Biossíntese de Proteínas/genética , Análise de Sequência de DNA , Transdução Genética , Vírion
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