Jonathan D. Rubright

How redesigning AD clinical trials might increase study partners’ willingness to participate

Background: Timely recruiting and retaining participants into Alzheimer disease (AD) clinical trials is a challenge. We used conjoint analysis to identify how alterations in attributes of clinical trial design improve willingness to participate: risk, home visits, car service, or increased chance of receiving intervention. Method: A total of 108 study partners of patients with very mild to severe stage AD rated willingness to allow their relative to participate in eight clinical trials that varied combinations of the four attributes. Results: The highest utility was for home visits (0.89) which essentially compensated for the disutility of high risk (−0.85). The combination of home visits and car service was redundant, with almost no increase in utility over home visits alone. Seventeen percent were willing to participate in a trial with no amenities; the addition of home visits increased predicted willingness to participate to 27%; low risk, home visits, and higher chance of active treatment increased predicted willingness to 60%. The value of reducing the hassles of travel correlated well with measures of AD severity (activities of daily living r = 0.41, p < 0.001; basic activities of daily living r = 0.38, p < 0.001; Neuropsychiatric Inventory severity p = 0.24, p = 0.01; Neuropsychiatric Inventory distress r = 0.23, p < 0.02). No association was found between degree of study partner burden and willingness to tolerate risk of an intervention. Conclusion: Clinical trials that reduce travel inconvenience may offset the disincentive of study features such as the risk of intervention and may also increase willingness to participate. Redesigning trials may also help recruit patients with more severe Alzheimer disease. Shorter recruitment periods and increased retention rates may offset costs of these changes. GLOSSARY: AD = Alzheimer disease; BLUP = best linear unbiased prediction; RAQ = Research Attitude Questionnaire.

Measuring How People View Biomedical Research: Reliability and Validity Analysis of the Research Attitudes Questionnaire

With increasing numbers of studies on research ethics and a need to improve the recruitment of research subjects, the ability to measure attitudes toward biomedical research has become important. The Research Attitudes Questionnaire is a significant predictor of the publics attitudes toward and willingness to participate in research, yet limited data are available on its psychometric properties. This study establishes the scales internal consistency and dimensionality using a large Internet-based sample from the United States. One item was removed due to a poor item-total correlation, and three additional items were removed which formed a reverse-wording measurement artifact factor. With improved internal consistency and dimensionality, the seven-item version has the advantages of shorter administration time and improved psychometric properties.

A Memory and Organizational Aid Improves Alzheimer Disease Research Consent Capacity: Results of a Randomized, Controlled Trial

OBJECTIVES Early and progressive cognitive impairments of patients with Alzheimer disease (AD) hinder their capacity to provide informed consent. Unfortunately, the limited research on techniques to improve capacity has shown mixed results. Therefore, the authors tested whether a memory and organizational aid improves the performance of patients with AD on measures of capacity and competency to give informed consent. DESIGN, SETTING, AND PARTICIPANTS Patients with AD randomly assigned to standard consent or standard plus a memory and organizational aid. INTERVENTION Memory and organizational aid summarized the content of information mandated under the informed consent disclosure requirements of the Common Rule at a sixth grade reading level. MEASUREMENTS Three psychiatrists without access to patient data independently reviewed MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) interview transcripts to judge whether the patient was capable of providing informed consent. The agreement of at least two of the three experts defined a participant as capable of providing informed consent. Secondary outcomes are MacCAT-CR measures of understanding, appreciation and reasoning, and comparison with cognitively normal older adult norms. RESULTS AD intervention and control groups were similar in terms of age, education, and cognitive status. The intervention group was more likely to be judged competent than control group and had higher scores on MacCAT-CR measure of understanding. The intervention had no effect on the measures of appreciation or reasoning. CONCLUSIONS A consent process that addresses the deficits in memory and attention of a patient with AD can improve capacity to give informed consent for early phase AD research. The results also validate the MacCAT-CR as an instrument to measure capacity, especially the understanding subscale. TRIAL REGISTRY ClinicalTrials.Gov#NCT00105612, http://clinicaltrials.gov/show/NCT00105612.

The Penn Parkinson's Daily Activities Questionnaire-15: Psychometric properties of a brief assessment of cognitive instrumental activities of daily living in Parkinson's disease *

INTRODUCTION To describe the psychometric properties of the Penn Parkinsons Daily Activities Questionnaire-15 (PDAQ-15), a 15-item measure of cognitive instrumental activities of daily living for Parkinsons disease (PD) patients derived from the original 50-item PDAQ. METHODS PDAQ-15 items were chosen by expert consensus. Knowledgeable informants of PD participants (n = 161) completed the PDAQ-15. Knowledgeable informants were defined as an individual having regular contact with the PD participant. PD participants were assigned a diagnosis of normal cognition, mild cognitive impairment, or dementia based on expert consensus. RESULTS PDAQ-15 scores correlated strongly with global cognition (Dementia Rating Scale-2, r = 0.71, p < 0.001) and a performance-based functional measure (Direct Assessment of Functional Status, r = 0.83; p < 0.001). PDAQ-15 scores accurately discriminated between non-demented PD participants (normal cognition/mild cognitive impairment) and PD with dementia (ROC curve area = 0.91), participants with and without any cognitive impairment (normal cognition versus mild cognitive impairment/dementia, ROC curve area = 0.85) and between participants with mild cognitive impairment and dementia (ROC curve area = 0.84). CONCLUSIONS The PDAQ-15 shows good discriminant validity across cognitive stages, correlates highly with global cognitive performance, and appears suitable to assess daily cognitive functioning in PD.

Why are Spousal Caregivers More Prevalent than Nonspousal Caregivers as Study Partners in AD Dementia Clinical Trials

Objectives:Most Alzheimer disease (AD) caregivers are not spouses and yet most AD dementia trials enroll spousal study partners. This study examines the association between caregiver relationship to the patient and willingness to enroll in an AD clinical trial and how caregiver burden and research attitudes modify willingness. Design:Interviews with 103 AD caregivers who met criteria for ability to serve as a study partner. Results:A total of 54% of caregivers were spouses or domestic partners and the remaining were adult children. Willingness to enroll a patient in a clinical trial was associated with being a spouse [odds ratio (OR)=2.53, P=0.01], increasing age (OR=1.39, P=0.01), and increasing scores on the Research Attitudes Questionnaire (OR=1.39, P<0.001). No measures of caregiver burden or patient health were significant predictors of willingness. In multivariate models both research attitudes (OR=1.37, P<0.001) and being a spouse, as opposed to an adult child, (OR=2.06, P=0.048) were independently associated with willingness to participate. Conclusions:Spousal caregivers had both a higher willingness to participate and a more positive attitude toward research. Caregiver burden had no association with willingness to participate. The strongest predictor of willingness was research attitudes.

Awareness of Mild Cognitive Impairment and Mild Alzheimer’s Disease Dementia Diagnoses Associated With Lower Self-Ratings of Quality of Life in Older Adults

Objective This study examined how awareness of diagnostic label impacted self-reported quality of life (QOL) in persons with varying degrees of cognitive impairment. Method Older adults (n = 259) with normal cognition, Mild Cognitive Impairment (MCI), or mild Alzheimers disease dementia (AD) completed tests of cognition and self-report questionnaires that assessed diagnosis awareness and multiple domains of QOL: cognitive problems, activities of daily living, physical functioning, mental wellbeing, and perceptions of ones daily life. We compared measures of QOL by cognitive performance, diagnosis awareness, and diagnostic group. Results Persons with MCI or AD who were aware of their diagnosis reported lower average satisfaction with daily life (QOL-AD), basic functioning (BADL Scale), and physical wellbeing (SF-12 PCS), and more difficulties in daily life (DEM-QOL) than those who were unaware (all p ≤ .007). Controlling for gender, those expecting their condition to worsen over time reported greater depression (GDS), higher stress (PSS), lower quality of daily life (QOL-AD, DEM-QOL), and more cognitive difficulties (CDS) compared to others (all p < .05). Discussion Persons aware of their diagnostic label-either MCI or AD-and its prognosis report lower QOL than those unaware of these facts about themselves. These relationships are independent of the severity of cognitive impairment.

Who Can Speak for the Emergently Ill? Testing a Method to Identify Communities and Their Leaders

OBJECTIVES The Food and Drug Administration (FDA) requires researchers to consult with the community prior to conducting research with exception from informed consent, but little is known about whether people support this and, if they do, who researchers should consult. We sought to determine if people could identify communities and leaders of those communities who researchers should consult with to represent their views about research that requires an exception from informed consent. METHODS We conducted a cross-sectional interview study using a convenience sample of patients seeking care in an urban emergency department (ED) to determine if people belonged to specific communities and, if they did, if they could identify communities and leaders appropriate for consultation. Descriptive statistics were used to represent our findings. RESULTS Most of the 262 participants approached for the study completed the interview (199; 76%). Of those interviewed, 122 (61%) were African American, 54 (27%) were white, 83 (42%) were male, and the mean (+/-standard deviation [SD]) age was 36.2 +/- 14.4 years. Most, (194; 97%), identified that they belonged to a community and most (177; 89%), said that researchers could consult at least one of their communities for consultation about an exception from informed consent study. Participants typically named geographic and religious-affiliated communities and leaders as appropriate for consultation. CONCLUSION Most participants identified a community and a leader of that community who researchers could consult about research with exception from informed consent. Geographic and faith-based organizations could play an important role in consultation.

Bayesian Prior Choice in IRT Estimation Using MCMC and Variational Bayes

This study investigated the impact of three prior distributions: matched, standard vague, and hierarchical in Bayesian estimation parameter recovery in two and one parameter models. Two Bayesian estimation methods were utilized: Markov chain Monte Carlo (MCMC) and the relatively new, Variational Bayesian (VB). Conditional (CML) and Marginal Maximum Likelihood (MML) estimates were used as baseline methods for comparison. Vague priors produced large errors or convergence issues and are not recommended. For both MCMC and VB, the hierarchical and matched priors showed the lowest root mean squared errors (RMSEs) for ability estimates; RMSEs of difficulty estimates were similar across estimation methods. For the standard errors (SEs), MCMC-hierarchical displayed the largest values across most conditions. SEs from the VB estimation were among the lowest in all but one case. Overall, VB-hierarchical, VB-matched, and MCMC-matched performed best. VB with hierarchical priors are recommended in terms of their accuracy, and cost and (subsequently) time effectiveness.

Fit for purpose and modern validity theory in clinical outcomes assessment

PurposeThe US Food and Drug Administration (FDA), as part of its regulatory mission, is charged with determining whether a clinical outcome assessment (COA) is “fit for purpose” when used in clinical trials to support drug approval and product labeling. In this paper, we will provide a review (and some commentary) on the current state of affairs in COA development/evaluation/use with a focus on one aspect: How do you know you are measuring the right thing? In the psychometric literature, this concept is referred to broadly as validity and has itself evolved over many years of research and application.ReviewAfter a brief introduction, the first section will review current ideas about “fit for purpose” and how it has been viewed by FDA. This section will also describe some of the unique challenges to COA development/evaluation/use in the clinical trials space. Following this, we provide an overview of modern validity theory as it is currently understood in the psychometric tradition. This overview will focus primarily on the perspective of validity theorists such as Messick and Kane whose work forms the backbone for the bulk of high-stakes assessment in areas such as education, psychology, and health outcomes.ConclusionsWe situate the concept of fit for purpose within the broader context of validity. By comparing and contrasting the approaches and the situations where they have traditionally been applied, we identify areas of conceptual overlap as well as areas where more discussion and research are needed.

Identifying an appropriate measurement modeling approach for the Mini-Mental State Examination.

The Mini-Mental State Examination (MMSE) is a 30-item, dichotomously scored test of general cognition. A number of benefits could be gained by modeling the MMSE in an item response theory (IRT) framework, as opposed to the currently used classical additive approach. However, the test, which is built from groups of items related to separate cognitive subdomains, may violate a key assumption of IRT: local item independence. This study aimed to identify the most appropriate measurement model for the MMSE: a unidimensional IRT model, a testlet response theory model, or a bifactor model. Local dependence analysis using nationally representative data showed a meaningful violation of the local item independence assumption, indicating multidimensionality. In addition, the testlet and bifactor models displayed superior fit indices over a unidimensional IRT model. Statistical comparisons showed that the bifactor model fit MMSE respondent data significantly better than the other models considered. These results suggest that application of a traditional unidimensional IRT model is inappropriate in this context. Instead, a bifactor model is suggested for future modeling of MMSE data as it more accurately represents the multidimensional nature of the scale. (PsycINFO Database Record