An evidence-based methodology for systematic evaluation of clinical outcome assessment measures for traumatic brain injury.

INTRODUCTION: The high failure rate of clinical trials in traumatic brain injury (TBI) may be attributable, in part, to the use of untested or insensitive measurement instruments. Of more than 1,000 clinical outcome assessment measures (COAs) for TBI, few have been systematically vetted to determine their performance within specific "contexts of use (COU)." As described in guidance issued by the U.S. Food and Drug Administration (FDA), the COU specifies the population of interest and the purpose for which the COA will be employed. COAs are commonly used for screening, diagnostic categorization, outcome prediction, and establishing treatment effectiveness. COA selection typically relies on expert consensus; there is no established methodology to match the appropriateness of a particular COA to a specific COU. We developed and pilot-tested the Evidence-Based Clinical Outcome assessment Platform (EB-COP) to systematically and transparently evaluate the suitability of TBI COAs for specific purposes. METHODS AND FINDINGS: Following a review of existing literature and published guidelines on psychometric standards for COAs, we developed a 6-step, semi-automated, evidence-based assessment platform to grade COA performance for six specific purposes: diagnosis, symptom detection, prognosis, natural history, subgroup stratification and treatment effectiveness. Mandatory quality indicators (QIs) were identified for each purpose using a modified Delphi consensus-building process. The EB-COP framework was incorporated into a Qualtrics software platform and pilot-tested on the Glasgow Outcome Scale-Extended (GOSE), the most widely-used COA in TBI clinical studies. CONCLUSION: The EB-COP provides a systematic methodology for conducting more precise, evidence-based assessment of COAs by evaluating performance within specific COUs. The EB-COP platform was shown to be feasible when applied to a TBI COA frequently used to detect treatment effects and can be modified to address other populations and COUs. Additional testing and validation of the EB-COP are warranted.

Bone microarchitecture, biomechanical properties, and advanced glycation end-products in the proximal femur of adults with type 2 diabetes.

Skeletal fragility is a major complication of type 2 diabetes mellitus (T2D), but there is a poor understanding of mechanisms underlying T2D skeletal fragility. The increased fracture risk has been suggested to result from deteriorated bone microarchitecture or poor bone quality due to accumulation of advanced glycation end-products (AGEs). We conducted a clinical study to determine whether: 1) bone microarchitecture, AGEs, and bone biomechanical properties are altered in T2D bone, 2) bone AGEs are related to bone biomechanical properties, and 3) serum AGE levels reflect those in bone. To do so, we collected serum and proximal femur specimens from T2D (n = 20) and non-diabetic (n = 33) subjects undergoing total hip replacement surgery. A section from the femoral neck was imaged by microcomputed tomography (microCT), tested by cyclic reference point indentation, and quantified for AGE content. A trabecular core taken from the femoral head was imaged by microCT and subjected to uniaxial unconfined compression tests. T2D subjects had greater HbA1c (+23%, p ≤ 0.0001), but no difference in cortical tissue mineral density, cortical porosity, or trabecular microarchitecture compared to non-diabetics. Cyclic reference point indentation revealed that creep indentation distance (+18%, p ≤ 0.05) and indentation distance increase (+20%, p ≤ 0.05) were greater in cortical bone from T2D than in non-diabetics, but no other indentation variables differed. Trabecular bone mechanical properties were similar in both groups, except for yield stress, which tended to be lower in T2D than in non-diabetics. Neither serum pentosidine nor serum total AGEs were different between groups. Cortical, but not trabecular, bone AGEs tended to be higher in T2D subjects (21%, p = 0.09). Serum AGEs and pentosidine were positively correlated with cortical and trabecular bone AGEs. Our study presents new data on biomechanical properties and AGEs in adults with T2D, which are needed to better understand mechanisms contributing to diabetic skeletal fragility.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability.

BACKGROUND: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. OBJECTIVES: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. METHODS: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. CONCLUSION: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

The Traumatic Brain Injury Endpoints Development (TED) Initiative: Progress on a Public-Private Regulatory Collaboration To Accelerate Diagnosis and Treatment of Traumatic Brain Injury.

The Traumatic Brain Injury Endpoints Development (TED) Initiative is a 5-year, Department of Defense-funded project that is working toward the ultimate goal of developing better designed clinical trials, leading to more precise diagnosis, and effective treatments for traumatic brain injury (TBI). TED is comprised of leading academic clinician-scientists, along with innovative industry leaders in biotechnology and imaging technology, patient advocacy organizations, and philanthropists, working collaboratively with regulatory authorities, specifically the U.S. Food and Drug Administration (FDA). The goals of the TED Initiative are to gain consensus and validation of TBI clinical outcome assessment measures and biomarkers for endorsement by global regulatory agencies for use in drug and device development processes. This article summarizes the Initiative's Stage I progress over the first 18 months, including intensive engagement with a number of FDA divisions responsible for review and validation of biomarkers and clinical outcome assessments, progression into the prequalification phase of the FDA's Medical Device Development Tool program for a candidate set of neuroimaging biomarkers, and receipt of the FDA's Recognition of Research Importance Letter and a Letter of Support regarding TBI. Other signal achievements relate to the creation of the TED Metadataset, harmonizing study measures across eight major TBI studies, and the leadership role played by TED investigators in the conversion of the NINDS TBI Common Data Elements to Clinical Data Interchange Standards Consortium standards. This article frames both the near-term expectations and the Initiative's long-term vision to accelerate approval of treatments for patients affected by TBI in urgent need of effective therapies.

The genetics of lipid storage and human lipodystrophies.

Life depends on securing sufficient energy intake to enable growth, movement, and reproduction. Throughout evolution, lifeforms have struggled to ensure adequate energy intake, and this remains a major challenge for many species. Modern humans are particularly well adapted to store surplus energy efficiently, but they are considerably less well adapted for coping with sustained access to energy-dense food. We briefly review the evolution of adipocytes and the metabolic consequences of suboptimal energy storage, focusing on insights derived from rare human monogenic disorders. From the evidence presented, we argue that a mismatch between the capacity for nutrient storage and the burden of excess energy intake is an important factor in the development of some forms of human insulin resistance.

Estimating the number of men who have sex with men by race/ethnicity at the county level in Texas.

This analysis presents a method for estimating the population of men who have sex with men (MSM) at the county and metropolitan area level in Texas. Surveillance data consistently demonstrate that MSM experience a high burden of HIV and other sexually transmitted infections (STIs). Numerous studies have shown that MSM are also vulnerable to many other health concerns such as suicide, substance abuse, domestic violence and assault, homelessness, and mental illness. However, compilation of rates of HIV, STIs, and other health issues is dependent on estimation of population denominators. In the absence of systematic, consistent, and direct assessment of sexual orientation and gender identity in national surveys, it is difficult to estimate the size of at-risk populations. Previous estimates at the national and state level have been calculated using varied methodologies. However, to date, statewide estimates at the county level have only been produced for the state of Florida. County-level and metropolitan area estimates of MSM population were produced using three modified models developed by Lieb et al. These models used data on population and same-sex households from the US Census, along with estimates of sexual behavior from the National Survey on Family Growth. These models produce an estimate of 599,683 MSM in Texas (6.4 % of the adult male population). Metropolitan areas with the highest percentage of MSM population include Dallas and Austin (10.3 and 9.8 %, respectively). County-level estimates of MSM population range from 1.0 to 12.9 %. These local estimates are critical to targeting vulnerable populations and effective allocation of resources for prevention and treatment programs.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease.

Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.

Adaptation and implementation of an evidence-based prevention counseling intervention in Texas.

HIV prevention counseling linked with testing has been shown to reduce high-risk behaviors and new sexually transmitted diseases in public clinic settings. However, few studies have been conducted evaluating the implementation of such models outside a research setting. This study sought to determine the extent to which the introduction of a standard protocol based on Project RESPECT improves the achievement of HIV prevention counseling goals of existing counseling and testing programs. Four prevention counseling programs contracting with the Texas Department of State Health Services completed a standardized 5-day training and implemented the protocols, counseling tools, and quality assurance (QA) procedures developed for the project. Introduction of the protocol was accomplished with existing program resources and significantly improved prevention counseling. Direct observation of counseling sessions demonstrated a significant improvement in attainment for eight of the nine counseling goals of initial sessions and for all counseling goals of follow-up sessions after the protocol was introduced. Client exit questionnaires reinforced this finding. Significant improvement was also found in use of counseling skills, with improvements in 6 of 10 skills observed in initial sessions and 4 of 10 skills in follow-up sessions. Challenges identified through semistructured interviews with counselors and supervisors included serving non-English-speaking and low-risk clients, mastery of the protocol, the amount of time required for QA, and implementation in settings with severe time constraints.

Formative assessment of use of behavioral data in HIV prevention: Texas.

A formative assessment was conducted with Texas HIV prevention community planning group (CPG) members, prevention provider staff, and supervisors of those staff to better understand how to enhance their use of epidemiologic and behavioral data in the selection and prioritization of prevention interventions. Semi-structured interviews, mail surveys, and content analysis of funding proposals were used to determine the current use of these data, their perceived value, and the most trusted sources for data. CPG members, prevention provider staff, and supervisors valued information from their peers and networking most, and made more use of socially available information than they did research or systematically collected assessment data. CPG members wanted more local data and data on specific sub-populations of interest. Prevention providers viewed the utility of behavioral data as limited, and were primarily concerned with the pragmatic aspects of fielding interventions; however, this group also expressed an interest in rapid community assessment methods and learning more about new and effective prevention interventions. These results led to the development of training and technical assistance materials.

Bridging data and decision making: development of techniques for improving the HIV prevention community planning process.

Assessments of community planning in Massachusetts and Texas were used to develop tools for increasing the use of data by HIV prevention community planning groups (CPGs) and prevention providers while also increasing participation of CPG members. Barriers to data use included organizational problems in CPGs (e.g., lack of clear procedures, distrust of peers and leadership) and technical assistance needs for CPG members and researchers who provide data. The absence of data relevant to local epidemics was another barrier. Specific linkages are provided between the assessments of these needs and the development of a technical assistance tools (e.g., websites, templates for data presentation, experiential involvement in data use) and strategies for organizational change in CPGs, as well as efforts to better use available data and create or identify new sources of local data.

After the innovation: outcomes from the Texas behavioral data project.

The Texas Department of Health and University of Texas Southwestern staff, using formative assessment data, developed a set of innovative methods and tools to increase the use of behavioral and epidemiologic data in decision-making about HIV prevention interventions by HIV prevention community planning groups (CPGs) and HIV prevention providers. Semistructured interviews, mail surveys, meeting observations, and content analysis of funding proposals were used to measure the results of the multifaceted intervention. Compared to baseline measures, CPG members reported that data played a more central and desired role in their decision-making. HIV prevention providers exposed to the project's materials were more likely to choose evidence-based interventions to conduct. The tools and structural intervention methods of this project were diffused and had an impact on the use of behavioral data by community planning groups and HIV prevention providers. The structural interventions were not sufficient without the additional effect of the trained peers acting as advocates and intervention innovators.

Improving the use of data for HIV prevention decision making: lessons learned.

HIV prevention community planning was developed to promote identification of local prevention priorities through a process that was evidence-based and provided community input. There are a variety of barriers to effective use of data in community planning which include characteristics of data (availability, timeliness, relevance to planning tasks), characteristics of planning group members and providers of data (e.g., skills in understanding and applying data), and social-organizational aspects of community-planning groups (CPGs). Lessons learned from this project illustrate how to create locally relevant sources of data, build data use skills of CPG members and data providers, and address social-organizational aspects of planning, while also better integrating community planning with implementation of prevention plans. Adaptation of tools and methods is discussed along with future considerations for research and planning practice.

Prenatal HIV testing in private OB-Gyn practices in Texas.

This study evaluates the prenatal human immunodeficiency virus (HIV) testing behaviors of private obstetrics and gynecology practitioners in Texas. A statewide telephone survey of 614 providers of prenatal care determined the level of HIV testing, how testing is offered, and patient acceptance of the test. Ninety-nine percent of the practices offered HIV testing to all their pregnant patients, and 96% of the practices included HIV testing in the routine panel of tests for pregnant patients. More than 95% of the practices reported that 10% or less of the women refused the test when offered it; 73% of the practices reported no refusals. Less than half of the practices, however, discussed HIV prevention topics, and only 29% of the practices referred high-risk pregnant patients for prevention counseling. Although private practices of obstetrics and gynecology report testing almost all their prenatal patients, survey results suggest that providers could improve their prevention and patient education practices.