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1.
J Med Internet Res ; 26: e57827, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39226552

RESUMO

BACKGROUND: Wearable digital health technologies and mobile apps (personal digital health technologies [DHTs]) hold great promise for transforming health research and care. However, engagement in personal DHT research is poor. OBJECTIVE: The objective of this paper is to describe how participant engagement techniques and different study designs affect participant adherence, retention, and overall engagement in research involving personal DHTs. METHODS: Quantitative and qualitative analysis of engagement factors are reported across 6 unique personal DHT research studies that adopted aspects of a participant-centric design. Study populations included (1) frontline health care workers; (2) a conception, pregnant, and postpartum population; (3) individuals with Crohn disease; (4) individuals with pancreatic cancer; (5) individuals with central nervous system tumors; and (6) families with a Li-Fraumeni syndrome affected member. All included studies involved the use of a study smartphone app that collected both daily and intermittent passive and active tasks, as well as using multiple wearable devices including smartwatches, smart rings, and smart scales. All studies included a variety of participant-centric engagement strategies centered on working with participants as co-designers and regular check-in phone calls to provide support over study participation. Overall retention, probability of staying in the study, and median adherence to study activities are reported. RESULTS: The median proportion of participants retained in the study across the 6 studies was 77.2% (IQR 72.6%-88%). The probability of staying in the study stayed above 80% for all studies during the first month of study participation and stayed above 50% for the entire active study period across all studies. Median adherence to study activities varied by study population. Severely ill cancer populations and postpartum mothers showed the lowest adherence to personal DHT research tasks, largely the result of physical, mental, and situational barriers. Except for the cancer and postpartum populations, median adherences for the Oura smart ring, Garmin, and Apple smartwatches were over 80% and 90%, respectively. Median adherence to the scheduled check-in calls was high across all but one cohort (50%, IQR 20%-75%: low-engagement cohort). Median adherence to study-related activities in this low-engagement cohort was lower than in all other included studies. CONCLUSIONS: Participant-centric engagement strategies aid in participant retention and maintain good adherence in some populations. Primary barriers to engagement were participant burden (task fatigue and inconvenience), physical, mental, and situational barriers (unable to complete tasks), and low perceived benefit (lack of understanding of the value of personal DHTs). More population-specific tailoring of personal DHT designs is needed so that these new tools can be perceived as personally valuable to the end user.


Assuntos
Aplicativos Móveis , Humanos , Estudos de Coortes , Feminino , Tecnologia Digital , Participação do Paciente/métodos , Dispositivos Eletrônicos Vestíveis , Tecnologia Biomédica/métodos , Masculino , Adulto , Gravidez , Saúde Digital
2.
Nucleic Acids Res ; 52(17): 10068-10084, 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39149897

RESUMO

AIMers are short, chemically modified oligonucleotides that induce A-to-I RNA editing through interaction with endogenous adenosine deaminases acting on RNA (ADAR) enzymes. Here, we describe the development of new AIMer designs with base, sugar and backbone modifications that improve RNA editing efficiency over our previous design. AIMers incorporating a novel pattern of backbone and 2' sugar modifications support enhanced editing efficiency across multiple sequences. Further efficiency gains were achieved through incorporation of an N-3-uridine (N3U), in place of cytidine (C), in the 'orphan base' position opposite the edit site. Molecular modeling suggests that N3U might enhance ADAR catalytic activity by stabilizing the AIMer-ADAR interaction and potentially reducing the energy required to flip the target base into the active site. Supporting this hypothesis, AIMers containing N3U consistently enhanced RNA editing over those containing C across multiple target sequences and multiple nearest neighbor sequence combinations. AIMers combining N3U and the novel pattern of 2' sugar chemistry and backbone modifications improved RNA editing both in vitro and in vivo. We provide detailed N3U synthesis methods and, for the first time, explore the impact of N3U and its analogs on ADAR-mediated RNA editing efficiency and targetable sequence space.


Assuntos
Adenosina Desaminase , Edição de RNA , Proteínas de Ligação a RNA , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/química , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Humanos , Uridina/metabolismo , Uridina/química , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , RNA/química , RNA/metabolismo , Citidina/química , Citidina/metabolismo , Modelos Moleculares , Células HEK293
3.
Eur J Gastroenterol Hepatol ; 33(12): 1511-1516, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33512845

RESUMO

OBJECTIVES: A link between stress and Crohn's disease activity suggests an association, but results have been conflicting. The purpose of this study was to assess whether the stress related to the coronavirus disease 2019 (COVID-19) pandemic affected disease activity in patients with Crohn's disease. BASIC METHODS: An anonymous survey was distributed to patients through gastroenterology clinics and networks. Patients were asked to report their Crohn's disease symptoms in the months prior to the COVID-19 pandemic and again during the early stages of the COVID-19 pandemic using the Manitoba inflammatory bowel disease index in addition to questions about stress, perception of reasons for symptom change and personal impact. MAIN RESULTS: Out of 243 individuals with a confirmed diagnosis of Crohn's disease, there was a 24% relative increase in active symptoms between the pre-COVID-19 period to the during-COVID-19 period (P < 0.0001) reflecting an absolute change from 45 to 56%, respectively. The most frequent reported reason for a change in symptoms was 'Increased stress/and or feeling overwhelmed' (118/236), and personal impact of the pandemic was, 'I'm worrying a lot about the future' (113/236), both reported by approximately half of respondents. PRINCIPAL CONCLUSIONS: This study serves as a 'proof of concept' demonstrating the impact of a significant and uniquely uniform stressor as a natural experiment on Crohn's disease activity. The severity of symptoms of Crohn's disease increased during the COVID-19 pandemic. The primary reported reason for symptom change was an increase in stress, not a change in diet, exercise or other lifestyle behaviours, corroborating the hypothesis that stress affects Crohn's disease activity.


Assuntos
COVID-19 , Doença de Crohn , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Humanos , Pandemias , SARS-CoV-2 , Inquéritos e Questionários
4.
JAMA Netw Open ; 3(3): e200265, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32119094

RESUMO

Importance: Mammography screening currently relies on subjective human interpretation. Artificial intelligence (AI) advances could be used to increase mammography screening accuracy by reducing missed cancers and false positives. Objective: To evaluate whether AI can overcome human mammography interpretation limitations with a rigorous, unbiased evaluation of machine learning algorithms. Design, Setting, and Participants: In this diagnostic accuracy study conducted between September 2016 and November 2017, an international, crowdsourced challenge was hosted to foster AI algorithm development focused on interpreting screening mammography. More than 1100 participants comprising 126 teams from 44 countries participated. Analysis began November 18, 2016. Main Outcomes and Measurements: Algorithms used images alone (challenge 1) or combined images, previous examinations (if available), and clinical and demographic risk factor data (challenge 2) and output a score that translated to cancer yes/no within 12 months. Algorithm accuracy for breast cancer detection was evaluated using area under the curve and algorithm specificity compared with radiologists' specificity with radiologists' sensitivity set at 85.9% (United States) and 83.9% (Sweden). An ensemble method aggregating top-performing AI algorithms and radiologists' recall assessment was developed and evaluated. Results: Overall, 144 231 screening mammograms from 85 580 US women (952 cancer positive ≤12 months from screening) were used for algorithm training and validation. A second independent validation cohort included 166 578 examinations from 68 008 Swedish women (780 cancer positive). The top-performing algorithm achieved an area under the curve of 0.858 (United States) and 0.903 (Sweden) and 66.2% (United States) and 81.2% (Sweden) specificity at the radiologists' sensitivity, lower than community-practice radiologists' specificity of 90.5% (United States) and 98.5% (Sweden). Combining top-performing algorithms and US radiologist assessments resulted in a higher area under the curve of 0.942 and achieved a significantly improved specificity (92.0%) at the same sensitivity. Conclusions and Relevance: While no single AI algorithm outperformed radiologists, an ensemble of AI algorithms combined with radiologist assessment in a single-reader screening environment improved overall accuracy. This study underscores the potential of using machine learning methods for enhancing mammography screening interpretation.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Aprendizado Profundo , Interpretação de Imagem Assistida por Computador/métodos , Mamografia/métodos , Radiologistas , Adulto , Idoso , Algoritmos , Inteligência Artificial , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Radiologia , Sensibilidade e Especificidade , Suécia , Estados Unidos
5.
Genome Biol ; 19(1): 188, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400818

RESUMO

BACKGROUND: The phenotypes of cancer cells are driven in part by somatic structural variants. Structural variants can initiate tumors, enhance their aggressiveness, and provide unique therapeutic opportunities. Whole-genome sequencing of tumors can allow exhaustive identification of the specific structural variants present in an individual cancer, facilitating both clinical diagnostics and the discovery of novel mutagenic mechanisms. A plethora of somatic structural variant detection algorithms have been created to enable these discoveries; however, there are no systematic benchmarks of them. Rigorous performance evaluation of somatic structural variant detection methods has been challenged by the lack of gold standards, extensive resource requirements, and difficulties arising from the need to share personal genomic information. RESULTS: To facilitate structural variant detection algorithm evaluations, we create a robust simulation framework for somatic structural variants by extending the BAMSurgeon algorithm. We then organize and enable a crowdsourced benchmarking within the ICGC-TCGA DREAM Somatic Mutation Calling Challenge (SMC-DNA). We report here the results of structural variant benchmarking on three different tumors, comprising 204 submissions from 15 teams. In addition to ranking methods, we identify characteristic error profiles of individual algorithms and general trends across them. Surprisingly, we find that ensembles of analysis pipelines do not always outperform the best individual method, indicating a need for new ways to aggregate somatic structural variant detection approaches. CONCLUSIONS: The synthetic tumors and somatic structural variant detection leaderboards remain available as a community benchmarking resource, and BAMSurgeon is available at https://github.com/adamewing/bamsurgeon .


Assuntos
Benchmarking , Simulação por Computador , Crowdsourcing , Variação Genética , Genoma Humano , Genômica/métodos , Neoplasias/genética , Algoritmos , Bases de Dados Genéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Software
6.
Acad Med ; 92(2): 157-160, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27119325

RESUMO

Because of their growing popularity and functionality, smartphones are increasingly valuable potential tools for health and medical research. Using ResearchKit, Apple's open-source platform to build applications ("apps") for smartphone research, collaborators have developed apps for researching asthma, breast cancer, cardiovascular disease, type 2 diabetes, and Parkinson disease. These research apps enhance widespread participation by removing geographical barriers to participation, provide novel ways to motivate healthy behaviors, facilitate high-frequency assessments, and enable more objective data collection. Although the studies have great potential, they also have notable limitations. These include selection bias, identity uncertainty, design limitations, retention, and privacy. As smartphone technology becomes increasingly available, researchers must recognize these factors to ensure that medical research is conducted appropriately. Despite these limitations, the future of smartphones in health research is bright. Their convenience grants unprecedented geographic freedom to researchers and participants alike and transforms the way clinical research can be conducted.


Assuntos
Pesquisa Biomédica/métodos , Técnicas e Procedimentos Diagnósticos , Doença/classificação , Aplicativos Móveis/estatística & dados numéricos , Smartphone/estatística & dados numéricos , Humanos
7.
Lancet Oncol ; 18(1): 132-142, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27864015

RESUMO

BACKGROUND: Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. METHODS: Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. FINDINGS: 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·39-4·62, p<0·0001; reference model: 2·56, 1·85-3·53, p<0·0001). The new model was validated further on the ENTHUSE M1 cohort with similarly high performance (iAUC 0·768). Meta-analysis across all methods confirmed previously identified predictive clinical variables and revealed aspartate aminotransferase as an important, albeit previously under-reported, prognostic biomarker. INTERPRETATION: Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer. FUNDING: Sanofi US Services, Project Data Sphere.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Modelos Estatísticos , Nomogramas , Neoplasias de Próstata Resistentes à Castração/mortalidade , Adolescente , Adulto , Idoso , Teorema de Bayes , Crowdsourcing , Docetaxel , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/secundário , Taxa de Sobrevida , Taxoides/administração & dosagem , Adulto Jovem
8.
Nat Commun ; 7: 12096, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27417679

RESUMO

Massively parallel sequencing has permitted an unprecedented examination of the cancer exome, leading to predictions that all genes important to cancer will soon be identified by genetic analysis of tumours. To examine this potential, here we evaluate the ability of state-of-the-art sequence analysis methods to specifically recover known cancer genes. While some cancer genes are identified by analysis of recurrence, spatial clustering or predicted impact of somatic mutations, many remain undetected due to lack of power to discriminate driver mutations from the background mutational load (13-60% recall of cancer genes impacted by somatic single-nucleotide variants, depending on the method). Cancer genes not detected by mutation recurrence also tend to be missed by all types of exome analysis. Nonetheless, these genes are implicated by other experiments such as functional genetic screens and expression profiling. These challenges are only partially addressed by increasing sample size and will likely hold even as greater numbers of tumours are analysed.


Assuntos
Exoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Bases de Dados Genéticas , Humanos , Mutação , Taxa de Mutação
9.
PLoS Comput Biol ; 12(6): e1004890, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27351836

RESUMO

Acute Myeloid Leukemia (AML) is a fatal hematological cancer. The genetic abnormalities underlying AML are extremely heterogeneous among patients, making prognosis and treatment selection very difficult. While clinical proteomics data has the potential to improve prognosis accuracy, thus far, the quantitative means to do so have yet to be developed. Here we report the results and insights gained from the DREAM 9 Acute Myeloid Prediction Outcome Prediction Challenge (AML-OPC), a crowdsourcing effort designed to promote the development of quantitative methods for AML prognosis prediction. We identify the most accurate and robust models in predicting patient response to therapy, remission duration, and overall survival. We further investigate patient response to therapy, a clinically actionable prediction, and find that patients that are classified as resistant to therapy are harder to predict than responsive patients across the 31 models submitted to the challenge. The top two performing models, which held a high sensitivity to these patients, substantially utilized the proteomics data to make predictions. Using these models, we also identify which signaling proteins were useful in predicting patient therapeutic response.


Assuntos
Algoritmos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/terapia , Crowdsourcing/métodos , Avaliação de Processos e Resultados em Cuidados de Saúde/métodos , Proteoma/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Biomarcadores/metabolismo , Humanos , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade , Resultado do Tratamento
12.
Nat Methods ; 13(4): 310-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26901648

RESUMO

It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense.


Assuntos
Causalidade , Redes Reguladoras de Genes , Neoplasias/genética , Mapeamento de Interação de Proteínas/métodos , Software , Biologia de Sistemas , Algoritmos , Biologia Computacional , Simulação por Computador , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Transdução de Sinais , Células Tumorais Cultivadas
13.
Nat Med ; 21(11): 1350-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26457759

RESUMO

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-ß activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.


Assuntos
Carcinoma/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/genética , Fator de Crescimento Transformador beta/genética , Carcinoma/classificação , Carcinoma/patologia , Neoplasias Colorretais/classificação , Neoplasias Colorretais/patologia , Consenso , Ilhas de CpG , Variações do Número de Cópias de DNA/genética , Metilação de DNA , Perfilação da Expressão Gênica , Genes myc/genética , Humanos , Disseminação de Informação , Instabilidade de Microssatélites , Mutação/genética , Neovascularização Patológica/patologia , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Via de Sinalização Wnt/genética , Proteínas ras/genética
14.
Nat Methods ; 12(7): 623-30, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25984700

RESUMO

The detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/.


Assuntos
Benchmarking , Crowdsourcing , Genoma , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Algoritmos , Humanos
16.
Cancer Discov ; 5(2): 118-23, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25656898

RESUMO

SUMMARY: Comprehensive genomic profiling is expected to revolutionize cancer therapy. In this Prospective, we present the prevalence of mutations and copy-number alterations with predictive associations across solid tumors at different levels of stringency for gene-drug targetability. More than 90% of The Cancer Genome Atlas samples have potentially targetable alterations, the majority with multiple events, illustrating the challenges for treatment prioritization given the complexity of the genomic landscape. Nearly 80% of the variants in rarely mutated oncogenes are of uncertain functional significance, reflecting the gap in our understanding of the relevance of many alterations potentially linked to therapeutic actions. Access to targeted agents in early clinical trials could affect treatment decision in 75% of patients with cancer. Prospective implementation of large-scale molecular profiling and standardized reports of predictive biomarkers are fundamental steps for making precision cancer medicine a reality.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Genômica/métodos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Humanos , Terapia de Alvo Molecular
17.
Cancer Discov ; 4(11): 1265-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25367949

RESUMO

SUMMARY: Data-driven analyses of scientific abstracts with web apps such as "abstract interactomes" provide a new visualization tool for the biomedical research community to interactively navigate a rich assembly of investigators and identify common research topics. Alternative conference formats such as "social interactomes," with structured, albeit informal, discussions among attendees, are able to engage fellows and top investigators, facilitate the exchange of ideas, and encourage data sharing and future collaborations.


Assuntos
Pesquisa Biomédica , Congressos como Assunto , Comportamento Cooperativo , Relações Interpessoais , Genes ras , Humanos , Disseminação de Informação , Pesquisadores
19.
Pac Symp Biocomput ; : 27-38, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24297531

RESUMO

Computational efficiency is important for learning algorithms operating in the "large p, small n" setting. In computational biology, the analysis of data sets containing tens of thousands of features ("large p"), but only a few hundred samples ("small n"), is nowadays routine, and regularized regression approaches such as ridge-regression, lasso, and elastic-net are popular choices. In this paper we propose a novel and highly efficient Bayesian inference method for fitting ridge-regression. Our method is fully analytical, and bypasses the need for expensive tuning parameter optimization, via cross-validation, by employing Bayesian model averaging over the grid of tuning parameters. Additional computational efficiency is achieved by adopting the singular value decomposition reparametrization of the ridge-regression model, replacing computationally expensive inversions of large p × p matrices by efficient inversions of small and diagonal n × n matrices. We show in simulation studies and in the analysis of two large cancer cell line data panels that our algorithm achieves slightly better predictive performance than cross-validated ridge-regression while requiring only a fraction of the computation time. Furthermore, in comparisons based on the cell line data sets, our algorithm systematically out-performs the lasso in both predictive performance and computation time, and shows equivalent predictive performance, but considerably smaller computation time, than the elastic-net.


Assuntos
Algoritmos , Farmacogenética/estatística & dados numéricos , Antineoplásicos/farmacologia , Inteligência Artificial , Teorema de Bayes , Linhagem Celular Tumoral , Biologia Computacional , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Análise de Regressão
20.
Pac Symp Biocomput ; : 63-74, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24297534

RESUMO

Large-scale pharmacogenomic screens of cancer cell lines have emerged as an attractive pre-clinical system for identifying tumor genetic subtypes with selective sensitivity to targeted therapeutic strategies. Application of modern machine learning approaches to pharmacogenomic datasets have demonstrated the ability to infer genomic predictors of compound sensitivity. Such modeling approaches entail many analytical design choices; however, a systematic study evaluating the relative performance attributable to each design choice is not yet available. In this work, we evaluated over 110,000 different models, based on a multifactorial experimental design testing systematic combinations of modeling factors within several categories of modeling choices, including: type of algorithm, type of molecular feature data, compound being predicted, method of summarizing compound sensitivity values, and whether predictions are based on discretized or continuous response values. Our results suggest that model input data (type of molecular features and choice of compound) are the primary factors explaining model performance, followed by choice of algorithm. Our results also provide a statistically principled set of recommended modeling guidelines, including: using elastic net or ridge regression with input features from all genomic profiling platforms, most importantly, gene expression features, to predict continuous-valued sensitivity scores summarized using the area under the dose response curve, with pathway targeted compounds most likely to yield the most accurate predictors. In addition, our study provides a publicly available resource of all modeling results, an open source code base, and experimental design for researchers throughout the community to build on our results and assess novel methodologies or applications in related predictive modeling problems.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/genética , Farmacogenética/estatística & dados numéricos , Algoritmos , Inteligência Artificial , Linhagem Celular Tumoral , Biologia Computacional , Bases de Dados Genéticas/estatística & dados numéricos , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Modelos Genéticos , Análise de Regressão
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