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.

[1]  Vanessa E. Gray,et al.  Evolutionary diagnosis method for variants in personal exomes , 2012, Nature Methods.

[2]  Pedro M. Valero-Mora,et al.  ggplot2: Elegant Graphics for Data Analysis , 2010 .

[3]  Nci Dream Community A community effort to assess and improve drug sensitivity prediction algorithms , 2014 .

[4]  Julio Saez-Rodriguez,et al.  Network topology and parameter estimation: from experimental design methods to gene regulatory network kinetics using a community based approach , 2014, BMC Systems Biology.

[5]  Philippe Broët,et al.  Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients. , 2007, Blood.

[6]  N. Meinshausen,et al.  Stability selection , 2008, 0809.2932.

[7]  Gordon B Mills,et al.  Functional proteomic profiling of AML predicts response and survival. , 2009, Blood.

[8]  Paul M. Thompson,et al.  Analysis of sampling techniques for imbalanced data: An n=648 ADNI study , 2014, NeuroImage.

[9]  C. Wilke,et al.  A single determinant dominates the rate of yeast protein evolution. , 2006, Molecular biology and evolution.

[10]  K Wheatley,et al.  The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. , 1998, Blood.

[11]  Brunangelo Falini,et al.  Mutational landscape of AML with normal cytogenetics: biological and clinical implications. , 2013, Blood reviews.

[12]  Steven M Kornblau,et al.  Abnormal expression of FLI1 protein is an adverse prognostic factor in acute myeloid leukemia. , 2011, Blood.

[13]  David Haussler,et al.  ENCODE Data in the UCSC Genome Browser: year 5 update , 2012, Nucleic Acids Res..

[14]  Andrea Califano,et al.  Toward better benchmarking: challenge-based methods assessment in cancer genomics , 2014, Genome Biology.

[15]  Xuming He,et al.  Non-parametric quantification of protein lysate arrays , 2007, Bioinform..

[16]  N. D. Clarke,et al.  Towards a Rigorous Assessment of Systems Biology Models: The DREAM3 Challenges , 2010, PloS one.

[17]  Laura M. Heiser,et al.  A community effort to assess and improve drug sensitivity prediction algorithms , 2014, Nature Biotechnology.

[18]  Kevin R. Coombes,et al.  Variable slope normalization of reverse phase protein arrays , 2009, Bioinform..

[19]  Adam A. Margolin,et al.  Systematic Analysis of Challenge-Driven Improvements in Molecular Prognostic Models for Breast Cancer , 2013, Science Translational Medicine.

[20]  C. Bloomfield,et al.  The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. , 2009, Blood.

[21]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[22]  Asim Khwaja,et al.  Acute myeloid leukaemia , 2016, Nature Reviews Disease Primers.

[23]  H. Kantarjian,et al.  Acute myeloid leukemia , 2018, Methods in Molecular Biology.

[24]  Philipp A. Greif,et al.  The NPM1 Mutation Type Has No Impact on Survival in Cytogenetically Normal AML , 2014, PloS one.

[25]  Michael W. Parker,et al.  Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. , 2013, Blood.

[26]  R. Norel,et al.  The self-assessment trap: can we all be better than average? , 2011, Molecular systems biology.

[27]  Mei Zhang,et al.  Prognostic significance of NPM1 mutations in acute myeloid leukemia: A meta-analysis. , 2014, Molecular and clinical oncology.

[28]  Bob Löwenberg,et al.  Review Articles (434 articles) , 2008 .

[29]  D. Floreano,et al.  Revealing strengths and weaknesses of methods for gene network inference , 2010, Proceedings of the National Academy of Sciences.

[30]  Paola Fazi,et al.  Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. , 2005, The New England journal of medicine.

[31]  Patrick Goymer Genetics: Conserved by evolution, but altered in cancer , 2007, Nature Reviews Cancer.

[32]  Patrick Mayeux,et al.  Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia , 2010, Haematologica.

[33]  Diogo M. Camacho,et al.  Wisdom of crowds for robust gene network inference , 2012, Nature Methods.

[34]  Kevin R. Coombes,et al.  Highly Phosphorylated FOXO3A Is an Adverse Prognostic Factor in Acute Myeloid Leukemia , 2010, Clinical Cancer Research.

[35]  J. Dudley,et al.  Phylomedicine: an evolutionary telescope to explore and diagnose the universe of disease mutations. , 2011, Trends in genetics : TIG.

[36]  Xi Chen,et al.  Random survival forests for high‐dimensional data , 2011, Stat. Anal. Data Min..

[37]  Johann S. Hawe,et al.  Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression , 2014, Nature Biotechnology.

[38]  H. Gralnick,et al.  Proposals for the Classification of the Acute Leukaemias French‐American‐British (FAB) Co‐operative Group , 1976, British journal of haematology.

[39]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[40]  G. Mills,et al.  Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells , 2006, Molecular Cancer Therapeutics.

[41]  Keith A. Baggerly,et al.  Surface Adjustment of Reverse Phase Protein Arrays using Positive Control Spots , 2012, Cancer informatics.

[42]  Shuiwang Ji,et al.  SLEP: Sparse Learning with Efficient Projections , 2011 .