Promoting equity in clinical research: The role of social determinants of health.

OBJECTIVE: This study aims to investigate the association between social determinants of health (SDoH) and clinical research recruitment outcomes and recommends evidence-based strategies to enhance equity. MATERIALS AND METHODS: Data were collected from the internal clinical study manager database, clinical data warehouse, and clinical research registry. Study characteristics (e.g., study phase) and sociodemographic information were extracted. Median neighborhood income, distance from the study location, and Area Deprivation Index (ADI) were calculated. Mixed effect generalized regression was used for clustering effects and false discovery rate adjustment for multiple testing. A stratified analysis was performed to examine the impact in distinct medical departments. RESULTS: The study sample consisted of 3,962 individuals, with a mean age of 61.5 years, 53.6 % male, 54.2 % White, and 49.1 % non-Hispanic or Latino. Study characteristics revealed a variety of protocols across different departments, with cardiology having the highest percentage of participants (46.4 %). Industry funding was the most common (74.5 %), and digital advertising and personal outreach were the main recruitment methods (58.9 % and 90.8 %). DISCUSSION: The analysis demonstrated significant associations between participant characteristics and research participation, including biological sex, age, ethnicity, and language. The stratified analysis revealed other significant associations for recruitment strategies. SDoH is crucial to clinical research recruitment, and this study presents evidence-based solutions for equity and inclusivity. Researchers can tailor recruitment strategies to overcome barriers and increase participant diversity by identifying participant characteristics and research involvement status. CONCLUSION: The findings highlight the relevance of clinical research inequities and equitable representation of historically underrepresented populations. We need to improve recruitment strategies to promote diversity and inclusivity in research.

Sociotechnical feasibility of natural language processing-driven tools in clinical trial eligibility prescreening for Alzheimer's disease and related dementias.

BACKGROUND: Alzheimer's disease and related dementias (ADRD) affect over 55 million globally. Current clinical trials suffer from low recruitment rates, a challenge potentially addressable via natural language processing (NLP) technologies for researchers to effectively identify eligible clinical trial participants. OBJECTIVE: This study investigates the sociotechnical feasibility of NLP-driven tools for ADRD research prescreening and analyzes the tools' cognitive complexity's effect on usability to identify cognitive support strategies. METHODS: A randomized experiment was conducted with 60 clinical research staff using three prescreening tools (Criteria2Query, Informatics for Integrating Biology and the Bedside [i2b2], and Leaf). Cognitive task analysis was employed to analyze the usability of each tool using the Health Information Technology Usability Evaluation Scale. Data analysis involved calculating descriptive statistics, interrater agreement via intraclass correlation coefficient, cognitive complexity, and Generalized Estimating Equations models. RESULTS: Leaf scored highest for usability followed by Criteria2Query and i2b2. Cognitive complexity was found to be affected by age, computer literacy, and number of criteria, but was not significantly associated with usability. DISCUSSION: Adopting NLP for ADRD prescreening demands careful task delegation, comprehensive training, precise translation of eligibility criteria, and increased research accessibility. The study highlights the relevance of these factors in enhancing NLP-driven tools' usability and efficacy in clinical research prescreening. CONCLUSION: User-modifiable NLP-driven prescreening tools were favorably received, with system type, evaluation sequence, and user's computer literacy influencing usability more than cognitive complexity. The study emphasizes NLP's potential in improving recruitment for clinical trials, endorsing a mixed-methods approach for future system evaluation and enhancements.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

INTRODUCTION: The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. METHODS: The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. RESULTS: We observed a significant difference in Aß42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage. DISCUSSION: This suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity. HIGHLIGHTS: Some A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

Uncovering key clinical trial features influencing recruitment.

Background: Randomized clinical trials (RCT) are the foundation for medical advances, but participant recruitment remains a persistent barrier to their success. This retrospective data analysis aims to (1) identify clinical trial features associated with successful participant recruitment measured by accrual percentage and (2) compare the characteristics of the RCTs by assessing the most and least successful recruitment, which are indicated by varying thresholds of accrual percentage such as ≥ 90% vs ≤ 10%, ≥ 80% vs ≤ 20%, and ≥ 70% vs ≤ 30%. Methods: Data from the internal research registry at Columbia University Irving Medical Center and Aggregated Analysis of ClinicalTrials.gov were collected for 393 randomized interventional treatment studies closed to further enrollment. We compared two regularized linear regression and six tree-based machine learning models for accrual percentage (i.e., reported accrual to date divided by the target accrual) prediction. The outperforming model and Tree SHapley Additive exPlanations were used for feature importance analysis for participant recruitment. The identified features were compared between the two subgroups. Results: CatBoost regressor outperformed the others. Key features positively associated with recruitment success, as measured by accrual percentage, include government funding and compensation. Meanwhile, cancer research and non-conventional recruitment methods (e.g., websites) are negatively associated with recruitment success. Statistically significant subgroup differences (corrected p-value < .05) were found in 15 of the top 30 most important features. Conclusion: This multi-source retrospective study highlighted key features influencing RCT participant recruitment, offering actionable steps for improvement, including flexible recruitment infrastructure and appropriate participant compensation.

International Genetic Testing and Counseling Practices for Parkinson's Disease.

BACKGROUND: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing. OBJECTIVES: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations. METHODS: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership. RESULTS: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. CONCLUSIONS: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society.

Providing genetic testing and genetic counseling for Parkinson's disease to the community.

PURPOSE: To evaluate the feasibility and impact of offering genetic testing and counseling to patients with Parkinson's disease (PD), with the potential to enroll in gene-targeted clinical trials and improve clinical care. METHODS: A multicenter, exploratory pilot study at 7 academic hospital sites in the United States tracked enrollment and randomized participants to receive results and genetic counseling at local sites or by genetic counselors, remotely. Follow-up surveys measured participant/provider satisfaction, knowledge, and psychological impact. RESULTS: From September 5, 2019 to January 4, 2021, 620 participants were enrolled and 387 completed outcome surveys. There were no significant differences in outcomes between local and remote sites, with both arms reporting high knowledge and satisfaction scores (>80%). Notably, 16% of those tested had reportable PD gene variants (pathogenic/likely pathogenic/risk allele). CONCLUSION: Local clinicians, as well as genetic counselors, with educational support as needed, can effectively return genetic results for PD as we observed favorable outcome measures in both groups. Increasing access to PD genetic testing and counseling is urgent; this can inform future efforts to integrate genetic testing and counseling into clinical care for all those with PD.

Clinical research resource support for off-site research coordinators in intensive and specialty care units.

Clinical Research Coordinators (CRCs) are vital collaborators in a clinical research project. They often are the primary liaisons between investigators and human participants in studies and are involved in every aspect of many protocols, including participant recruitment, care (both usual medical care and specific study-related monitoring and procedures), data collection, specimen processing, and follow-up. The Clinical Translational Science Award program, which was created by the National Institutes of Health in 2006, has significantly expanded the venues in which Clinical Research Resource (CRR) - based CRCs are embedded. CRCs functioning in these areas, outside of the research-focused in-patient environment of the CRR, are designated as "off-site" CRCs. Many of these locations, such as intensive care units and emergency departments, require that CRCs interact regularly with healthcare providers whose primary functions are focused on providing optimal patient care rather than research and often involving very complex patients. These off-site CRCs require additional training and support outside of the usual research-oriented environment of the CRR. They are required to function within the context of the patient-care team while fostering implementation of collaborative research. This is a description of such a program specifically geared to off-site CRCs with the goal of enhancing the quality of research and experiences of CRCs.

Genetic Testing in Parkinson's Disease.

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Patterns of TDP-43 Deposition in Brains with LRRK2 G2019S Mutations.

OBJECTIVE: To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation. BACKGROUND: LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carriers. METHODS: Twelve brains with LRRK2 G2019S mutations were available for study from the New York Brain Bank at Columbia University; 11 of them had samples available for TDP-43 immunostaining. Clinical, demographic, and pathological data are reported for 11 brains with a LRRK2 G2019S mutation and compared to 11 brains without GBA1 or LRRK2 G2019S mutations with a pathologic diagnosis of Parkinson's disease (PD) or diffuse Lewy body disease. They were frequency matched by age, gender, parkinsonism age of onset, and disease duration. RESULTS: TDP-43 aggregates were present in 73% (n = 8) of brains with a LRRK2 mutation and 18% (n = 2) of brains without a LRRK2 mutation (P = 0.03). In one brain with a LRRK2 mutation, TDP-43 proteinopathy was the primary neuropathological change. CONCLUSIONS: Extranuclear TDP-43 aggregates are observed with greater frequency in LRRK2 G2019S autopsies compared to PD cases without a LRRK2 G2019S mutation. The association between LRRK2 and TDP-43 should be further explored. © 2023 International Parkinson and Movement Disorder Society.

A data-driven approach to optimizing clinical study eligibility criteria.

OBJECTIVE: Feasible, safe, and inclusive eligibility criteria are crucial to successful clinical research recruitment. Existing expert-centered methods for eligibility criteria selection may not be representative of real-world populations. This paper presents a novel model called OPTEC (OPTimal Eligibility Criteria) based on the Multiple Attribute Decision Making method boosted by an efficient greedy algorithm. METHODS: It systematically identifies the optimal criteria combination for a given medical condition with the optimal tradeoff among feasibility, patient safety, and cohort diversity. The model offers flexibility in attribute configurations and generalizability to various clinical domains. The model was evaluated on two clinical domains (i.e., Alzheimer's disease and Neoplasm of pancreas) using two datasets (i.e., MIMIC-III dataset and NewYork-Presbyterian/Columbia University Irving Medical Center (NYP/CUIMC) database). RESULTS: We simulated the process of automatically optimizing eligibility criteria according to user-specified prioritization preferences and generated recommendations based on the top-ranked criteria combination accordingly (top 0.41-2.75%) with OPTEC. Harnessing the power of the model, we designed an interactive criteria recommendation system and conducted a case study with an experienced clinical researcher using the think-aloud protocol. CONCLUSIONS: The results demonstrated that OPTEC could be used to recommend feasible eligibility criteria combinations, and to provide actionable recommendations for clinical study designers to construct a feasible, safe, and diverse cohort definition during early study design.

Clinical research staff perceptions on a natural language processing-driven tool for eligibility prescreening: An iterative usability assessment.

BACKGROUND: Participant recruitment is a barrier to successful clinical research. One strategy to improve recruitment is to conduct eligibility prescreening, a resource-intensive process where clinical research staff manually reviews electronic health records data to identify potentially eligible patients. Criteria2Query (C2Q) was developed to address this problem by capitalizing on natural language processing to generate queries to identify eligible participants from clinical databases semi-autonomously. OBJECTIVE: We examined the clinical research staff's perceived usability of C2Q for clinical research eligibility prescreening. METHODS: Twenty clinical research staff evaluated the usability of C2Q using a cognitive walkthrough with a think-aloud protocol and a Post-Study System Usability Questionnaire. On-screen activity and audio were recorded and transcribed. After every-five evaluators completed an evaluation, usability problems were rated by informatics experts and prioritized for system refinement. There were four iterations of system refinement based on the evaluation feedback. Guided by the Organizational Framework for Intuitive Human-computer Interaction, we performed a directed deductive content analysis of the verbatim transcriptions. RESULTS: Evaluators aged from 24 to 46 years old (33.8; SD: 7.32) demonstrated high computer literacy (6.36; SD:0.17); female (75 %), White (35 %), and clinical research coordinators (45 %). C2Q demonstrated high usability during the final cycle (2.26 out of 7 [lower scores are better], SD: 0.74). The number of unique usability issues decreased after each refinement. Fourteen subthemes emerged from three themes: seeking user goals, performing well-learned tasks, and determining what to do next. CONCLUSIONS: The cognitive walkthrough with a think-aloud protocol informed iterative system refinement and demonstrated the usability of C2Q by clinical research staff. Key recommendations for system development and implementation include improving system intuitiveness and overall user experience through comprehensive consideration of user needs and requirements for task completion.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Recruitment and retention of clinical trial participants: understanding motivations of patients with chronic pain and other populations.

This paper aims to present and discuss the issues, challenges, and strategies related to recruitment and retention in clinical trials involving participants with chronic pain. The randomized controlled clinical trial (RCT) is widely regarded as the gold standard for evaluating clinical interventions. However, it is crucial to acknowledge and address the challenges associated with recruiting and retaining participants. To prioritize the experience of the study population, targeted outreach strategies and a patient-centric approach are necessary. Researchers should consider incorporating recruitment and retention strategies during the study design phase. Implementing multi-pronged recruitment methods, leveraging relationships with community providers, and involving representatives of the patient population are helpful approaches. Effective communication and maintaining a professional environment are vital for optimizing engagement and supporting the successful execution of clinical trials involving participants with chronic pain.

Longitudinal Patterns of Cortical Atrophy on MRI in Patients With Alzheimer Disease With and Without Lewy Body Pathology.

BACKGROUND AND OBJECTIVES: Although Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) represent two different pathologies, they have clinical overlap, and there is a significant degree of co-occurrence of their neuropathological findings. Many studies have examined imaging characteristics in clinically diagnosed patients; however, there is a relative lack of longitudinal studies that have studied patients with pathological confirmation. We examined whether there were differences in longitudinal patterns of cortical atrophy between patients with both AD and DLB (AD/DLB) vs. those with AD alone. METHODS: We collected and analyzed clinical and neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database for patients who underwent autopsy. The rates of change in various neuropsychological assessments were not significantly different between AD/DLB and AD patients, and each group had neuropsychological outcomes consistent with disease progression. For our neuroimaging analysis, we used a linear mixed effects model to examine if there were longitudinal differences in cortical rates of atrophy between AD/DLB and AD patients. RESULTS: Autopsies and serial neuroimaging was available on 48 patients (24 AD, 24 AD/DLB). Patients with AD alone had significantly higher atrophy rates in the left cuneus, lateral occipital, and parahippocampal regions over time when compared to patients with concomitant DLB, after covarying for interval from imaging to autopsy, gender, and total estimated intracranial volume (eTIV). Site ID was included as a random effect to account for site differences. For these regions, the rate of decline over time in the AD/DLB group were less steep by a difference of 0.1887, 0.395, and 0.0989, respectively (p =.022, .006, and .006). The lattermost left cuneus volume measurement also positively correlated to Braak Lewy score (Pearson's product-moment correlation 0.37, p=.009), while the lattermost left parahippocampal volume measurement negatively correlated to Braak NFT score (Pearson's product-moment correlation -0.327, p=.02). DISCUSSION: AD patients had more significant atrophy in the left cuneus, lateral occipital, and parahippocampal regions when compared to AD/DLB patients. These regions are known to distinguish DLB and AD pathology cross-sectionally, but here are shown to distinguish longitudinal disease progression.

Association of Olfactory Performance With Motor Decline and Age at Onset in People With Parkinson Disease and the LRRK2 G2019S Variant.

BACKGROUND AND OBJECTIVES: There is clinical and phenotypic heterogeneity in LRRK2 G2019S Parkinson disease (PD), including loss of smell. Olfactory scores have defined subgroups of LRRK2 PD at baseline. We now extend this work longitudinally to better determine features associated with olfactory classes and to gain further insight into this heterogeneity. METHODS: Evaluation of 162 patients with LRRK2 PD and 198 patients with idiopathic PD (IPD) from the LRRK2 Ashkenazi Jewish Consortium was performed, with follow-up available for 92 patients with LRRK2 PD and 74 patients with IPD. Olfaction (University of Pennsylvania Smell Identification Test [UPSIT]), motor function (Unified Parkinson Disease Rating Scale), and cognition (Montreal Cognitive Assessment), as well as sleep, nonmotor, and mood, were measured. Gaussian mixture models were applied on the UPSIT percentile score to determine subgroups based on olfactory performance. Linear mixed effects models, using PD duration as the time scale, assessed the relationship between UPSIT subgroup membership and motor/cognitive change. RESULTS: Baseline olfaction was better in LRRK2 PD compared with IPD (mean UPSIT ± SD: 24.2 ± 8.8 vs 18.9 ± 7.6), with higher mean percentile scores (difference: 15.3 ± 11.6) (p < 0.001) and less frequent hyposmia (55.6% vs 85.4%; p < 0.001). Analysis suggested 3 classes among LRRK2 PD. Age at onset in LRRK2 PD was earlier in the worst olfaction group (group 1), compared with groups 2 and 3 (54.5 ± 11.1 vs 61.7 ± 9.3) (p = 0.012), and separately in the hyposmic group overall (55.0 ± 11.3 vs 61.7 ± 9.1) (p < 0.001). Longitudinal motor deterioration in LRRK2 PD was also significantly faster in the worst UPSIT group than the best UPSIT group (group 3 vs group 1: B = 0.31, SE = 0.35 vs B = 0.96, SE = 0.28) (rate difference = -0.65, SE = 0.29) (p = 0.03). However, olfactory group membership was not significantly associated with cognitive decline. DISCUSSION: In this large LRRK2 cohort with longitudinal analysis, we extend prior work demonstrating subgroups defined by olfaction in LRRK2 G2019S PD and show that the worst olfaction group has earlier age at PD onset and more rapid motor decline. This supports a subgroup of LRRK2 PD that might show more rapid change in a clinical trial of LRRK2-related agents and highlights the need to integrate careful phenotyping into allocation schema in clinical trials of LRRK2-related agents. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that worse olfactory scores were associated with an earlier age at symptomatic onset and a faster rate of motor deterioration in patients with LRRK2 PD.