Faculty Bibliography
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137
Crowdsourced estimation of cognitive decline and resilience in Alzheimer's disease
Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance.
PMCID:5474755
PMID: 27079753
ISSN: 1552-5279
CID: 2143082
A Crowdsourcing Approach to Developing and Assessing Prediction Algorithms for AML Prognosis
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.
PMCID:4924788
PMID: 27351836
ISSN: 1553-7358
CID: 5822492
A computational method for designing diverse linear epitopes including citrullinated peptides with desired binding affinities to intravenous immunoglobulin
BACKGROUND:Understanding the interactions between antibodies and the linear epitopes that they recognize is an important task in the study of immunological diseases. We present a novel computational method for the design of linear epitopes of specified binding affinity to Intravenous Immunoglobulin (IVIg). RESULTS:We show that the method, called Pythia-design can accurately design peptides with both high-binding affinity and low binding affinity to IVIg. To show this, we experimentally constructed and tested the computationally constructed designs. We further show experimentally that these designed peptides are more accurate that those produced by a recent method for the same task. Pythia-design is based on combining random walks with an ensemble of probabilistic support vector machines (SVM) classifiers, and we show that it produces a diverse set of designed peptides, an important property to develop robust sets of candidates for construction. We show that by combining Pythia-design and the method of (PloS ONE 6(8):23616, 2011), we are able to produce an even more accurate collection of designed peptides. Analysis of the experimental validation of Pythia-design peptides indicates that binding of IVIg is favored by epitopes that contain trypthophan and cysteine. CONCLUSIONS:Our method, Pythia-design, is able to generate a diverse set of binding and non-binding peptides, and its designs have been experimentally shown to be accurate.
PMCID:4826543
PMID: 27059896
ISSN: 1471-2105
CID: 5822472
Inferring causal molecular networks: empirical assessment through a community-based effort
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.
PMCID:4854847
PMID: 26901648
ISSN: 1548-7105
CID: 5822462
Voices of biotech
PMID: 26963549
ISSN: 1546-1696
CID: 5824942
Erratum: Prediction of human population responses to toxic compounds by a collaborative competition
PMID: 26448092
ISSN: 1546-1696
CID: 5822452
Prediction of human population responses to toxic compounds by a collaborative competition
The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson's r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.
PMID: 26258538
ISSN: 1546-1696
CID: 5822442
Combining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection
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/.
PMCID:4856034
PMID: 25984700
ISSN: 1548-7105
CID: 5822412
Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models
Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model's structure and in silico "experimental" data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation.
PMCID:4447414
PMID: 26020786
ISSN: 1553-7358
CID: 5822422
The Prostate Cancer DREAM Challenge: A Community-Wide Effort to Use Open Clinical Trial Data for the Quantitative Prediction of Outcomes in Metastatic Prostate Cancer [Editorial]
Project Data Share and Sage Bionetworks/DREAM are launching the Prostate Cancer DREAM Challenge to improve a predictive model of disease progression and treatment toxicity in prostate cancer using historical trial data. Predictions identified through this challenge have the potential to translate into reduced trial redundancy, better clinical decision tools, and improved patient outcomes. The challenge launches on March 16, 2015.
PMCID:4425397
PMID: 25777346
ISSN: 1549-490x
CID: 5822382
