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Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Background:In contrast to pediatric Crohn's disease (CD), little is known in pediatric ulcerative colitis (UC) about the relationship between disease phenotype and serologic reactivity to microbial and other antigens. Aim:The aim of this study was to examine disease phenotype and serology in a well-characterized inception cohort of children newly diagnosed with UC during the PROTECT Study (Predicting Response to Standardized Pediatric Colitis Therapy). Methods:Patients were recruited from 29 participating centers. Demographic, clinical, laboratory, and serologic (pANCA, ASCA IgA/IgG, Anti-CBir1, and Anti-OmpC) data were obtained from children 4-17 years old with UC. Results:Sixty-five percent of the patients had positive serology for pANCA, with 62% less than 12 years old and 66% 12 years old or older. Perinuclear anti-neutrophil cytoplasmic antibodies did not correspond to a specific phenotype though pANCA ≥100, found in 19%, was strongly associated with pancolitis (P = 0.003). Anti-CBir1 was positive in 19% and more common in younger children with 32% less than 12 years old as compared with 14% 12 years old or older (P < 0.001). No association was found in any age group between pANCA and Anti-CBir1. Relative rectal sparing was more common in +CBir1, 16% versus 7% (P = 0.02). Calprotectin was lower in Anti-CBir1+ (Median [IQR] 1495 mcg/g [973-3333] vs 2648 mcg/g [1343-4038]; P = 0.04). Vitamin D 25-OH sufficiency was associated with Anti-CBir1+ (P = 0.0009). Conclusions:The frequency of pANCA in children was consistent with adult observations. High titer pANCA was associated with more extensive disease, supporting the idea that the magnitude of immune reactivity may reflect disease severity. Anti-CBir1+ was more common in younger ages, suggesting host-microbial interactions may differ by patient age.

This report documents the procedures for data cleaning and imputation for the 1993 Robert Wood Johnson Foundation Employer Health Insurance Survey. The survey was conducted in 10 states to provide state-level data on the employment-based health insurance market. RAND designed the survey under a grant from The Robert Wood Johnson Foundation's State Initiatives in Health Care Reform program.

This DataWatch reports key findings from the 1993 Robert Wood Johnson Foundation Employer Health Insurance Survey, through which more than 20,000 employers in ten states were interviewed. Our report contrasts the behavior of four size classes of small businesses (fewer than fifty workers) with that of all other businesses. We examine offer rates by business size; characteristics of employers and workers in businesses offering and not offering insurance; premiums, benefits, and medical underwriting; the extent of choice among plans; and self-insurance We discuss the implications of our findings for health policy.

The Military Health Services System (MHSS) provides health care to active-duty service members, military retirees, and their dependents. Over the past several years, the system has faced the twin challenges of downsizing in consonance with the rest of the Department of Defense (DoD) and of controlling escalating health care costs. These challenges cannot, however, be dealt with independently. Closing military treatment facilities (MITs) could drive non- active-duty beneficiaries to seek more expensive medical care from the civilian sector, care that is reimbursed by DoD through the Civilian Health and Medical Program of the Uniformed Services (CHAMPUS). In 1991, in response to a congressional request, the Director of Program Analysis and Evaluation (PA&E) undertook an evaluation of health care utilization and costs within the current system and of various possible alternatives to that system. PA&E turned to RAND's National Defense Research Institute (NDRl) for analytic support in responding to Congress. Specifically, we were asked to compare current utilization by military beneficiaries with use by civilians, to develop analytic cases to study alternatives to the current medical structure, and to assess costs and changes in utilization associated with these cases (with the exception of MIF costs, which are being assessed by the Institute for Defense Analyses). pg10. JMD

This Note documents a briefing about research on prior-service reservists that was designed to complement previous research about the behavior of non-prior service reservists. The research investigates accession into the reserves among two groups of individuals with prior military service: (1) those who served on active duty in the Army and (2) those who served in the Army Reserve or Army National Guard and left reserve service. The research then examines the attrition decision among persons from these two groups who do join (or rejoin) the Army Reserve or Army National Guard. It considers what prior- service personnel enter the reserves, when, why, and the match between their active and reserve occupational specialties. It also considers who leaves the reserves, when, why, and how attrition patterns differ by specialty. The results suggest that targeted recruiting may have more effect on attrition rates than do changes in compensation policies. However, affiliation bonuses appear to be an effective means of recruiting those leaving active service, and at least for the Army Reserve, in decreasing attrition among those who receive a bonus. (KR)

This report analyzes the separation decisions of prior-service reservists in the Army Reserve and the Army National Guard, the two components that recruit over 60 percent of all Selected Reserve prior-service accessions. The authors examine the effects of military compensation on attrition among prior-service reservists. They also investigate the ways separation patterns differ depending on the personal characteristics of individuals. In successive sections, the report (1) reviews the conceptual model of attrition that guides the empirical work and specifies the hypotheses that are tested with the data; (2) discusses the data available for modeling attrition, and the methods of analysis; (3) describes the variation in length of service among prior-service enlistees as a function of selected characteristics; and (4) presents results from a multivariate analysis of attrition. The study suggests that the rate of military pay can significantly affect the length of service of prior-service personnel. However, demographic characteristics have a much larger influence on attrition than economic factors; targeted recruiting may be more effective in retaining personnel for longer terms than changing compensation policies. (kr)

This report analyzes the accession behavior of enlistees who have had prior military service either on active duty or in reserve service. For two reasons, this report focuses on the accession behavior of prior service reservists who served in the Active Army or in the Army Reserve and Army National Guard. First, these reservists account for the largest number of separations; in addition, over 60 percent of prior enlisted accessions are to one of the two Selected Reserve Army components. Second, these components have also traditionally had relatively greater problems in meeting their end-strength requirements and with shortages in different skills, areas, and units. A primary objective of this report is to determine which policies appear to increase accessions among prior service personnel, with special emphasis on reserve pay and affiliation bonuses.

Choosing economically optimal health insurance coverage involves a trade-off between risk reduction and the overuse of health care. The economic purpose of insurance is to reduce financial uncertainty or risk - the more health insurance lowers the risk, the greater will be the increase in social well-being. But increases in health insurance also increase the amount of medical care demand, because insurance lowers the out-of-pocket cost of health care - the larger the demand response of medical care to cost sharing, the greater the decrease in social well-being, due to the purchase of too much health care. This study examines this trade-off empirically by estimating both the demand for health insurance and the demand for health services. It relies on data from a randomized controlled trial of the cost sharing's effects on the use of health services and on the health status for a general, nonelderly (under age 65) population., Based on data collected in the RAND Health Insurance Experiment. Prepared for the National Center for Health Service Research and Health Care Technology Assessment.

This paper was later published in the Journal of Econometrics., This report revises and expands a Rand report first issued in 1974. The first version critically reviewed the econometric literature on the demand for medical care. The present version revises both theoretical and empirical materials in the first version and considers a few additional studies that have appeared in the literature since 1974.

In the six years since the IPCe's Third Assessment Report (TAR), significant progress has been made in understanding past and recent climate change and in projecting future changes. These advances have arisen from large amounts of new data, more sophisticated analyses of data, improvements in the understanding and simulation of physical processes in climate models and more extensive exploration of uncertainty ranges in model results. The increased confidence in climate science provided by these developments is evident in this Working Group I contribution to the IPCe's Fourth Assessment Report. While this report provides new and important policyrelevant information on the scientific understanding of climate change, the complexity of the climate system and the multiple interactions that determine its behaviour impose limitations on our ability to understand fully the future course of Earth's global climate. There is still an incomplete physical understanding of many components of the climate system and their role in climate change. Key uncertainties include aspects of the roles played by clouds, the cryosphere, the oceans, land use and couplings between climate and biogeochemical cycles. The areas of science covered in this report continue to undergo rapid progress and it should be recognised that the present assessment reflects scientific understanding based on the peer-reviewed literature available in mid-2006.

The Working Group I contribution to the IPCC Fourth Assessment Report describes progress in understanding of the human and natural drivers of climate change, observed climate change, climate processes and attribution, and estimates of projected future climate change. It builds upon past IPCC assessments and incorporates new findings from the past six years of research. Scientific progress since the TAR is based upon large amounts of new and more comprehensive data, more sophisticated analyses of data, improvements in understanding of processes and their simulation in models, and more extensive exploration of uncertainty ranges.

This paper was later published in the Journal of Econometrics., This report revises and expands a Rand report first issued in 1974. The first version critically reviewed the econometric literature on the demand for medical care. The present version revises both theoretical and empirical materials in the first version and considers a few additional studies that have appeared in the literature since 1974.

The Working Group I contribution to the IPCC Fourth Assessment Report describes progress in understanding of the human and natural drivers of climate change, observed climate change, climate processes and attribution, and estimates of projected future climate change. It builds upon past IPCC assessments and incorporates new findings from the past six years of research. Scientific progress since the TAR is based upon large amounts of new and more comprehensive data, more sophisticated analyses of data, improvements in understanding of processes and their simulation in models, and more extensive exploration of uncertainty ranges.

In the six years since the IPCe's Third Assessment Report (TAR), significant progress has been made in understanding past and recent climate change and in projecting future changes. These advances have arisen from large amounts of new data, more sophisticated analyses of data, improvements in the understanding and simulation of physical processes in climate models and more extensive exploration of uncertainty ranges in model results. The increased confidence in climate science provided by these developments is evident in this Working Group I contribution to the IPCe's Fourth Assessment Report. While this report provides new and important policyrelevant information on the scientific understanding of climate change, the complexity of the climate system and the multiple interactions that determine its behaviour impose limitations on our ability to understand fully the future course of Earth's global climate. There is still an incomplete physical understanding of many components of the climate system and their role in climate change. Key uncertainties include aspects of the roles played by clouds, the cryosphere, the oceans, land use and couplings between climate and biogeochemical cycles. The areas of science covered in this report continue to undergo rapid progress and it should be recognised that the present assessment reflects scientific understanding based on the peer-reviewed literature available in mid-2006.