Michael Hogarth

Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

pSCANNER: patient-centered Scalable National Network for Effectiveness Research

This article describes the patient-centered Scalable National Network for Effectiveness Research (pSCANNER), which is part of the recently formed PCORnet, a national network composed of learning healthcare systems and patient-powered research networks funded by the Patient Centered Outcomes Research Institute (PCORI). It is designed to be a stakeholder-governed federated network that uses a distributed architecture to integrate data from three existing networks covering over 21 million patients in all 50 states: (1) VA Informatics and Computing Infrastructure (VINCI), with data from Veteran Health Administrations 151 inpatient and 909 ambulatory care and community-based outpatient clinics; (2) the University of California Research exchange (UC-ReX) network, with data from UC Davis, Irvine, Los Angeles, San Francisco, and San Diego; and (3) SCANNER, a consortium of UCSD, Tennessee VA, and three federally qualified health systems in the Los Angeles area supplemented with claims and health information exchange data, led by the University of Southern California. Initial use cases will focus on three conditions: (1) congestive heart failure; (2) Kawasaki disease; (3) obesity. Stakeholders, such as patients, clinicians, and health service researchers, will be engaged to prioritize research questions to be answered through the network. We will use a privacy-preserving distributed computation model with synchronous and asynchronous modes. The distributed system will be based on a common data model that allows the construction and evaluation of distributed multivariate models for a variety of statistical analyses.

Validation: The New Challenge for Pathology

Modern pathologists have been challenged to “validate” mouse models of human cancer. Validation requires matching of morphological attributes of the model to human disease. Computers can assist in the validation process. However, adequate controlled, computer-readable vocabularies that can match terms do not currently exist in mouse pathology. Further, current standard diagnostic terminologies do not include the new concepts discussed here such as pathway pathology and mammary intraepithelial neoplasia. The terminologies must be revised and improved to meet the challenge. Human medicine has traditionally used “guilt-by-association” to validate interpretations of disease. Experimental pathology uses experimental verification exemplified by “test-by-transplantation.” Genetically Engineered Mice (GEM) develop unique tumor phenotypes bringing new structural-functional insights and reevaluation of concepts. Novel GEM-related tumors appear in all organ systems but mouse models of human breast cancer are prototypes. For example, mammary tumors induced by Mouse Mammary Tumor Virus (MMTV), chemical, radiation or other carcinogenic stimuli have limited phenotypes. These “spontaneous” or induced mammary tumors have never resembled human breast cancers. GEM tumors created with genes associated with human cancer are strikingly different. GEM tumors have unique histological phenotypes. Depending on the genes, the tumors may: 1) resemble MMTV-induced tumors, 2) display “signature” phenotypes, and 3) mimic human breast cancers. The phenotypes can be placed into structural and functional clusters with shared characteristics leading to the concepts of Pathway Pathology: tumor phenotype reflects the genotype.

Annotating scientific images: a concept-based approach

Data annotations are an important kind of metadata that occur in the form of externally assigned descriptions of particular features in Web accessible documents. Such metadata are eventually used in data retrieval tasks on heterogeneous, possible distributed Web-accessible documents. In this paper, we present the model and realization of an annotation framework that scientists can employ to semantically enrich different types of documents, primarily scientific images made available through an image repository. Although we employ ontology like structures, called concepts, for metadata schemes used in annotations, our primary focus is on how concepts are actually used to annotate images and regions of interest, respectively, that exhibit features of interest to a researcher. It turns out that the combined consideration of domain specific concepts and annotated regions in images provides interesting means to analyze the usage of metadata regarding certain correctness and plausibility criteria. We detail our annotation management framework in the context of the Human Brain Project in which Neuroscientists record their observations on specific brain structures, and share and exchange information through concept-based annotations associated with images.

Standards-based, open-source electronic health record systems: A desirable future for the U.S. health industry

Many healthcare systems are moving toward a fully electronic health record (EHR) in order to better manage patient care. Unfortunately, in the United States, many current EHR systems leave much to be desired. Among well-documented criticisms are that they tend to be inflexible, proprietary, nonintuitive, expensive, difficult to maintain and rarely interoperable across health systems. From the clinicians perspective, these flaws sometimes make having an EHR system seem no better than retaining a paper-based system. Open-source software, a great success in other information-intensive industries, is one possible solution to these problems, and may help integrate a functional EHR system into, and across, more health systems and clinics because of the greater potential for local customization. We believe that the advantages of an open-source EHR system outweigh the costs of a more traditional, proprietary EHR system, and recommend that more work be done to advance an interoperable open-source EHR system in the United States. Open-source EHR systems have the potential to improve healthcare in the United States as they have done in many other areas around the world.

Creating a mission-based reporting system at an academic health center.

The authors developed a Web-based mission-based reporting (MBR) system for their university’s (UC Davis’s) health system to report faculty members’ activities in research and creative work, clinical service, education, and community/university service. They developed the system over several years (1998–2001) in response to a perceived need to better define faculty members’ productivity for faculty development, financial management, and program assessment. The goal was to create a measurement tool that could be used by department chairs to counsel faculty on their performances. The MBR system provides measures of effort for each of the university’s four missions. Departments or the school can use the output to better define expenditures and allocations of resources. The system provides both a quantitative metric of times spent on various activities within each mission, and a qualitative metric for the effort expended. The authors report the process of developing the MBR system and making it applicable for both clinical and basic science departments, and the mixed success experienced in its implementation. The system appears to depict the activities of most faculty fairly accurately, and chairs of test departments have been generally enthusiastic. However, resistance to general implementation remains, chiefly due to concerns about reliability, validity, and time required for completing the report. The authors conclude that MBR can be useful but will require some streamlining and the elimination of other redundant reporting instruments. A well-defined purpose is required to motivate its use.

Implementing a mission-based reporting system at an academic health center: a method for mission enhancement.

Purpose To describe the utility of school-wide use of mission-based reporting (MBR) for medical school deans and department chairs. Method All faculty members in the University of California, Davis, School of Medicine reported their clinical, creative, teaching, and service activities for 2000–2001 to the MBR system. The authors report on school-wide and department MBR profiles, and profiles by rank and academic series. They validate MBR by comparing individual results with actual merit actions reviewed independently by the schools academic personnel committee. Results A total of 419 faculty members (85%) completed their MBR reports. The average faculty member spent considerably more than 50 hours per week fulfilling the missions of the school, and full professors and faculty members in academic series supported by state funds were the most productive in investigative and creative work. The teaching load was shared equally by all the academic ranks, although the clinician–scholars taught more than did faculty members in the other series. There was an inverse relationship between clinical load and academic rank, with the majority of the clinical work performed by junior faculty members. MBR results compared favorably with the merit review process, although MBR is not expected to replace the traditional peer review system. Conclusion The creation of these graphic profiles and summaries is a valuable feature of MBR that would not have been possible without such quantitative data. The profiles allow monitoring to ensure that workload conforms to established objectives for individuals, departments, academic ranks and series. Finally, the authors discuss future directions for their MBR system.

Leveraging State Cancer Registries to Measure and Improve the Quality of Cancer Care: A Potential Strategy for California and Beyond

Despite recent increased attention to healthcare performance and the burden of disease from cancer, measures of quality of cancer care are not readily available. In 2013, the California HealthCare Foundation convened an expert workgroup to explore the potential for leveraging data in the California Cancer Registry (CCR), one of the worlds largest population-based cancer registries, for measuring and improving the quality of cancer care. The workgroup assessed current registry operations, the value to be gained by linking CCR data with health insurance claims or encounter data and clinical data contained in health system electronic health records, and potential barriers to these linkages. The workgroup concluded that: 1) The CCR mandate should be expanded to include use of its data for quality of cancer care measurement and public reporting; and 2) a system should be developed to support linkage of registry data with both claims data and provider electronic health record data.

The Athena Breast Health Network: developing a rapid learning system in breast cancer prevention, screening, treatment, and care.

The term breast cancer covers many different conditions, whose clinical course ranges from indolent to aggressive. However, current practice in breast cancer prevention and care, and in breast cancer epidemiology, does not take into account the heterogeneity of the disease. A comprehensive understanding of the etiology and progression of different breast cancer subtypes would enable a more patient-centered approach to breast health care: assessing an individual’s risk of getting specific subtypes of the disease, providing risk-based screening and prevention recommendations, and, for those diagnosed with the disease, tailored treatment options based on risk and timing of progression and mortality. The Athena Breast Health Network is an initiative of the five University of California medical and cancer centers to prototype this approach and to enable the development of a rapid learning system—connecting risk and outcome information from a heterogeneous patient population in real time and using new knowledge from research to continuously improve the quality of care. The Network is based on integrating clinical and research processes to create a comprehensive approach to accelerating patient-centered breast health care. Since its inception in 2009, the Network has developed a multi-site, transdisciplinary collaboration that enables the learning system. The five-campus collaboration has implemented a shared informatics platform, standardized electronic patient intake questionnaires, and common biospecimen protocols, as well as new clinical programs and multi-center research projects. The Athena Breast Health Network can serve as a model of a rapid learning system that integrates epidemiologic, behavioral, and clinical research with clinical care improvements.

The Communication and Care Plan: A novel approach to patient-centered clinical information systems

The US health care system and its information access models are organized around institutions and providers. Patient-centered functionality is rarely present in prevailing information systems and, if present, it typically does not ideally support shared decision making about important treatment events. We sought to better understand the functional needs of providers and patients around the process of care plan decision making, and used this information to develop a prototype decision support tool, using women with newly diagnosed breast cancer as our clinical scenario. This paper describes the user-centered design process we undertook and the resulting prototype system, the Communication and Care Plan (CCP).