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Key Points Crowdsourcing is emerging as a novel framework to tackle scientific problems. A variant of crowdsourcing, scientific competitions known as 'Challenges', enables a rigorous validation of methods, promotes reproducibility and fosters community building. Challenges also accelerate scientific discovery by allowing large numbers of groups to work jointly on a problem. Integrating predictions from different methods submitted by participants to solve a Challenge provides a robust solution that is often better than the best individual solution, a phenomenon known as the 'wisdom of crowds'. The patterns of similar findings that emerge from several independent Challenges can provide useful insight into various key questions in genetics and genomics. Considerable resources are required to gain maximal insights into the diverse big data sets in biomedicine. In this Review, the authors discuss how crowdsourcing, in the form of collaborative competitions (known as Challenges), can engage the scientific community to provide the diverse expertise and methodological approaches that can robustly address some of the most pressing questions in genetics, genomics and biomedical sciences. The generation of large-scale biomedical data is creating unprecedented opportunities for basic and translational science. Typically, the data producers perform initial analyses, but it is very likely that the most informative methods may reside with other groups. Crowdsourcing the analysis of complex and massive data has emerged as a framework to find robust methodologies. When the crowdsourcing is done in the form of collaborative scientific competitions, known as Challenges, the validation of the methods is inherently addressed. Challenges also encourage open innovation, create collaborative communities to solve diverse and important biomedical problems, and foster the creation and dissemination of well-curated data repositories.

Current measures of health and disease are often insensitive, episodic, and subjective. Further, these measures generally are not designed to provide meaningful feedback to individuals. The impact of high-resolution activity data collected from mobile phones is only beginning to be explored. Here we present data from mPower, a clinical observational study about Parkinson disease conducted purely through an iPhone app interface. The study interrogated aspects of this movement disorder through surveys and frequent sensor-based recordings from participants with and without Parkinson disease. Benefitting from large enrollment and repeated measurements on many individuals, these data may help establish baseline variability of real-world activity measurement collected via mobile phones, and ultimately may lead to quantification of the ebbs-and-flows of Parkinson symptoms. App source code for these data collection modules are available through an open source license for use in studies of other conditions. We hope that releasing data contributed by engaged research participants will seed a new community of analysts working collaboratively on understanding mobile health data to advance human health. Design Type(s) observation design • time series design • repeated measure design Measurement Type(s) disease severity measurement Technology Type(s) Patient Self-Report Factor Type(s) Sample Characteristic(s) Homo sapiens Machine-accessible metadata file describing the reported data (ISA-Tab format)

Genetic information from individuals who do not succumb to disease may point to new therapies and ideas about wellness The genetics approach to uncovering the causes of disease has focused mainly on finding the underlying primary mutations, with diseased individuals playing the leading role in this discovery. But as health care begins to focus more on preventive therapies, an emphasis on understanding how individuals remain healthy—“resilient” to disease—may provide insights into disease pathogenesis and new treatments. This view underlies “The Resilience Project” ( www.resilienceproject.me ), an effort to search broadly for these apparently healthy people (see the photo). There are, indeed, individuals whose genetics indicate exceptionally high risk of disease, yet they never show any signs of the disorder. What are the genetic and environmental factors that buffer disease for them? How can such information be gathered and harnessed most efficiently and effectively?

Elucidating the first principles of synthetic lethality in cancer, including biological context, will assist clinical translation. Most cancer mutations, including those causing a loss of function, are not directly “druggable” with conventional small-molecule drugs or biologicals, such as antibodies. Thus, despite our growing knowledge of mutations that drive cancer progression, there remains a frustrating gap in translating this information into the development of targeted treatments that kill only cancer cells. An approach that exploits a concept from genetics called “synthetic lethality” could provide a solution. But it has been over 15 years since that framework was proposed ( 1 ). Does the synthetic lethality principle still have the potential for treating cancer?

The authors takes a systems-biology approach to the problems of personalized cancer medicine. They describe the challenges of moving to a discipline that is predictive, personalized, preventive and participatory and explore methods for overcoming these obstacles. Medicine will move from a reactive to a proactive discipline over the next decade—a discipline that is predictive, personalized, preventive and participatory (P4). P4 medicine will be fueled by systems approaches to disease, emerging technologies and analytical tools. There will be two major challenges to achieving P4 medicine—technical and societal barriers—and the societal barriers will prove the most challenging. How do we bring patients, physicians and members of the health-care community into alignment with the enormous opportunities of P4 medicine? In part, this will be done by the creation of new types of strategic partnerships—between patients, large clinical centers, consortia of clinical centers and patient-advocate groups. For some clinical trials it will necessary to recruit very large numbers of patients—and one powerful approach to this challenge is the crowd-sourced recruitment of patients by bringing large clinical centers together with patient-advocate groups.

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 .

Breast cancer is the most common malignancy in women and is responsible for hundreds of thousands of deaths annually. As with most cancers, it is a heterogeneous disease and different breast cancer subtypes are treated differently. Understanding the difference in prognosis for breast cancer based on its molecular and phenotypic features is one avenue for improving treatment by matching the proper treatment with molecular subtypes of the disease. In this work, we employed a competition-based approach to modeling breast cancer prognosis using large datasets containing genomic and clinical information and an online real-time leaderboard program used to speed feedback to the modeling team and to encourage each modeler to work towards achieving a higher ranked submission. We find that machine learning methods combined with molecular features selected based on expert prior knowledge can improve survival predictions compared to current best-in-class methodologies and that ensemble models trained across multiple user submissions systematically outperform individual models within the ensemble. We also find that model scores are highly consistent across multiple independent evaluations. This study serves as the pilot phase of a much larger competition open to the whole research community, with the goal of understanding general strategies for model optimization using clinical and molecular profiling data and providing an objective, transparent system for assessing prognostic models.

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. 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. 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. 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. 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.

Collection of high-dimensional, longitudinal digital health data has the potential to support a wide-variety of research and clinical applications including diagnostics and longitudinal health tracking. Algorithms that process these data and inform digital diagnostics are typically developed using training and test sets generated from multiple repeated measures collected across a set of individuals. However, the inclusion of repeated measurements is not always appropriately taken into account in the analytical evaluations of predictive performance. The assignment of repeated measurements from each individual to both the training and the test sets (“record-wise” data split) is a common practice and can lead to massive underestimation of the prediction error due to the presence of “identity confounding.” In essence, these models learn to identify subjects, in addition to diagnostic signal. Here, we present a method that can be used to effectively calculate the amount of identity confounding learned by classifiers developed using a record-wise data split. By applying this method to several real datasets, we demonstrate that identity confounding is a serious issue in digital health studies and that record-wise data splits for machine learning- based applications need to be avoided.

Treating messenger RNA transcript abundances as quantitative traits and mapping gene expression quantitative trait loci for these traits has been pursued in gene-specific ways. Transcript abundances often serve as a surrogate for classical quantitative traits in that the levels of expression are significantly correlated with the classical traits across members of a segregating population. The correlation structure between transcript abundances and classical traits has been used to identify susceptibility loci for complex diseases such as diabetes 1 and allergic asthma 2 . One study recently completed the first comprehensive dissection of transcriptional regulation in budding yeast 3 , giving a detailed glimpse of a genome-wide survey of the genetics of gene expression. Unlike classical quantitative traits, which often represent gross clinical measurements that may be far removed from the biological processes giving rise to them, the genetic linkages associated with transcript abundance affords a closer look at cellular biochemical processes. Here we describe comprehensive genetic screens of mouse, plant and human transcriptomes by considering gene expression values as quantitative traits. We identify a gene expression pattern strongly associated with obesity in a murine cross, and observe two distinct obesity subtypes. Furthermore, we find that these obesity subtypes are under the control of different loci.