A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10-4; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD

MHConstructor: a high-throughput, haplotype-informed solution to the MHC assembly challenge.

The extremely high levels of genetic polymorphism within the human major histocompatibility complex (MHC) limit the usefulness of reference-based alignment methods for sequence assembly. We incorporate a short-read, de novo assembly algorithm into a workflow for novel application to the MHC. MHConstructor is a containerized pipeline designed for high-throughput, haplotype-informed, reproducible assembly of both whole genome sequencing and target capture short-read data in large, population cohorts. To-date, no other self-contained tool exists for the generation of de novo MHC assemblies from short-read data. MHConstructor facilitates wide-spread access to high-quality, alignment-free MHC sequence analysis

Association of Menopause With Functional Outcomes and Disease Biomarkers in Women With Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: The impact of menopause on the brain is not well understood. Hormonal changes, including puberty and pregnancy, influence the onset and course of multiple sclerosis (MS). After menopause, a worsening of MS disease trajectory measured on the clinician-rated Expanded Disability Status Scale (EDSS) was reported in some, but not all, studies. Evaluating the association between menopause and more objective measures of CNS injury is warranted. This study sought to assess the trajectory of objective functional outcomes and disease biomarkers in women with MS before and after menopause in a longitudinal prospective observational cohort. METHODS: Data were collected prospectively from a longitudinally followed MS cohort, including the performance-based Multiple Sclerosis Functional Composite (MSFC) as the primary functional outcome and the paraclinical marker of neuronal injury serum neurofilament light chain (sNfL) as the primary biomarker outcome. Outcomes were analyzed using segmented linear mixed model regressions adjusted for age, BMI, and tobacco use, with a change in slope at the time of menopause, as the a priori inflection point. RESULTS: One hundred and eighty-four postmenopausal women met inclusion criteria. Participants were followed for a median of 13 years (interquartile range [IQR] = 4, range: 1-17). The median MS duration was 24 years (IQR = 13, range: 3-64), and the median EDSS score was 2.5 (IQR = 2, range: 0-8). The median age at natural menopause was 50 years (IQR = 5, range: 33-60); 17% of participants used any systemic menopausal hormone therapy. Menopause reflected an inflection point in MSFC worsening (slope difference 0.08, 95% CI 0.01, 0.14, p = 0.0163) and increase in serum neurofilament light chain (slope difference -0.95, 95% CI -1.74 to -0.16, p = 0.0194) while the opposite was found for EDSS (slope difference 0.05, 95% CI 0.01-0.09, p = 0.0200). Findings remained significant after adjustment for multiple covariates. When using additional nonlinear regression modeling, similar inflection points were found (within 3 years of the final menstrual period) for sNfL and EDSS but not MSFC. DISCUSSION: The menopausal transition may represent an inflection in accumulation of neuronal injury and functional decline in MS

TopoDB: a novel multifunctional management system for laboratory animal colonies

Abstract Animal models are widely employed in basic research to test mechanistic hypotheses in a complex biological environment as well as to evaluate the therapeutic potential of candidate compounds in preclinical settings. Rodents, and in particular mice, represent the most common in vivo models for their small size, short lifespan and possibility to manipulate their genome. Over time, a typical laboratory will develop a substantial number of inbred strains and transgenic mouse lines, requiring a substantial effort, in both logistic and economic terms, to maintain an animal colony for research purposes and to safeguard the integrity of results. To meet this need, here we present TopoDB, a robust and extensible web-based platform for the rational management of laboratory animals. TopoDB allows an easy tracking of individual animals within the colony and breeding protocols as well as the convenient storage of both genetic and phenotypic data generated in the different experiments. Altogether, these features facilitate and enhance the design of in vivo research, thus reducing the number of necessary animals and the housing costs. In summary, TopoDB represents a novel valuable tool in modern biomedical research. Database URL: https://github.com/UCSF-MS-DCC/TopoDB</jats:p

TopoDB: a novel multifunctional management system for laboratory animal colonies.

Animal models are widely employed in basic research to test mechanistic hypotheses in a complex biological environment as well as to evaluate the therapeutic potential of candidate compounds in preclinical settings. Rodents, and in particular mice, represent the most common in vivo models for their small size, short lifespan and possibility to manipulate their genome. Over time, a typical laboratory will develop a substantial number of inbred strains and transgenic mouse lines, requiring a substantial effort, in both logistic and economic terms, to maintain an animal colony for research purposes and to safeguard the integrity of results. To meet this need, here we present TopoDB, a robust and extensible web-based platform for the rational management of laboratory animals. TopoDB allows an easy tracking of individual animals within the colony and breeding protocols as well as the convenient storage of both genetic and phenotypic data generated in the different experiments. Altogether, these features facilitate and enhance the design of in vivo research, thus reducing the number of necessary animals and the housing costs. In summary, TopoDB represents a novel valuable tool in modern biomedical research. Database URL: https://github.com/UCSF-MS-DCC/TopoDB

TopoDB: a novel multifunctional management system for laboratory animal colonies.

Animal models are widely employed in basic research to test mechanistic hypotheses in a complex biological environment as well as to evaluate the therapeutic potential of candidate compounds in preclinical settings. Rodents, and in particular mice, represent the most common in vivo models for their small size, short lifespan and possibility to manipulate their genome. Over time, a typical laboratory will develop a substantial number of inbred strains and transgenic mouse lines, requiring a substantial effort, in both logistic and economic terms, to maintain an animal colony for research purposes and to safeguard the integrity of results. To meet this need, here we present TopoDB, a robust and extensible web-based platform for the rational management of laboratory animals. TopoDB allows an easy tracking of individual animals within the colony and breeding protocols as well as the convenient storage of both genetic and phenotypic data generated in the different experiments. Altogether, these features facilitate and enhance the design of in vivo research, thus reducing the number of necessary animals and the housing costs. In summary, TopoDB represents a novel valuable tool in modern biomedical research. Database URL: https://github.com/UCSF-MS-DCC/TopoDB

A Precision Medicine Tool for Patients With Multiple Sclerosis (the Open MS BioScreen): Human-Centered Design and Development (Preprint)

BACKGROUND Patients with multiple sclerosis (MS) face several challenges in accessing clinical tools to help them monitor, understand, and make meaningful decisions about their disease course. The University of California San Francisco MS BioScreen is a web-based precision medicine tool initially designed to be clinician facing. We aimed to design a second, openly available tool, Open MS BioScreen, that would be accessible, understandable, and actionable by people with MS. OBJECTIVE This study aimed to describe the human-centered design and development approach (inspiration, ideation, and implementation) for creating the Open MS BioScreen platform. METHODS We planned an iterative and cyclical development process that included stakeholder engagement and iterative feedback from users. Stakeholders included patients with MS along with their caregivers and family members, MS experts, generalist clinicians, industry representatives, and advocacy experts. Users consisted of anyone who wants to track MS measurements over time and access openly available tools for people with MS. Phase I (inspiration) consisted of empathizing with users and defining the problem. We sought to understand the main challenges faced by patients and clinicians and what they would want to see in a web-based app. In phase II (ideation), our multidisciplinary team discussed approaches to capture, display, and make sense of user data. Then, we prototyped a series of mock-ups to solicit feedback from clinicians and people with MS. In phase III (implementation), we incorporated all concepts to test and iterate a minimally viable product. We then gathered feedback through an agile development process. The design and development were cyclical—many times throughout the process, we went back to the drawing board. RESULTS This human-centered approach generated an openly available, web-based app through which patients with MS, their clinicians, and their caregivers can access the site and create an account. Users can enter information about their MS (basic level as well as more advanced concepts), visualize their data longitudinally, access a series of algorithms designed to empower them to make decisions about their treatments, and enter data from wearable devices to encourage realistic goal setting about their ambulatory activity. Agile development will allow us to continue to incorporate precision medicine tools, as these are validated in the clinical research arena. CONCLUSIONS After engaging intended users into the iterative human-centered design of the Open MS BioScreen, we will now monitor the adaptation and dissemination of the tool as we expand its functionality and reach. The insights generated from this approach can be applied to the development of a number of self-tracking, self-management, and user engagement tools for patients with chronic conditions. </sec

A Precision Medicine Tool for Patients With Multiple Sclerosis (the Open MS BioScreen): Human-Centered Design and Development

Background Patients with multiple sclerosis (MS) face several challenges in accessing clinical tools to help them monitor, understand, and make meaningful decisions about their disease course. The University of California San Francisco MS BioScreen is a web-based precision medicine tool initially designed to be clinician facing. We aimed to design a second, openly available tool, Open MS BioScreen, that would be accessible, understandable, and actionable by people with MS. Objective This study aimed to describe the human-centered design and development approach (inspiration, ideation, and implementation) for creating the Open MS BioScreen platform. Methods We planned an iterative and cyclical development process that included stakeholder engagement and iterative feedback from users. Stakeholders included patients with MS along with their caregivers and family members, MS experts, generalist clinicians, industry representatives, and advocacy experts. Users consisted of anyone who wants to track MS measurements over time and access openly available tools for people with MS. Phase I (inspiration) consisted of empathizing with users and defining the problem. We sought to understand the main challenges faced by patients and clinicians and what they would want to see in a web-based app. In phase II (ideation), our multidisciplinary team discussed approaches to capture, display, and make sense of user data. Then, we prototyped a series of mock-ups to solicit feedback from clinicians and people with MS. In phase III (implementation), we incorporated all concepts to test and iterate a minimally viable product. We then gathered feedback through an agile development process. The design and development were cyclical—many times throughout the process, we went back to the drawing board. Results This human-centered approach generated an openly available, web-based app through which patients with MS, their clinicians, and their caregivers can access the site and create an account. Users can enter information about their MS (basic level as well as more advanced concepts), visualize their data longitudinally, access a series of algorithms designed to empower them to make decisions about their treatments, and enter data from wearable devices to encourage realistic goal setting about their ambulatory activity. Agile development will allow us to continue to incorporate precision medicine tools, as these are validated in the clinical research arena. Conclusions After engaging intended users into the iterative human-centered design of the Open MS BioScreen, we will now monitor the adaptation and dissemination of the tool as we expand its functionality and reach. The insights generated from this approach can be applied to the development of a number of self-tracking, self-management, and user engagement tools for patients with chronic conditions. </jats:sec

Remote Observational Research for Multiple Sclerosis

Background and ObjectivesProspective, deeply phenotyped research cohorts monitoring individuals with chronic neurologic conditions, such as multiple sclerosis (MS), depend on continued participant engagement. The COVID-19 pandemic restricted in-clinic research activities, threatening this longitudinal engagement, but also forced adoption of televideo-enabled care. This offered a natural experiment in which to analyze key dimensions of remote research: (1) comparison of remote vs in-clinic visit costs from multiple perspectives and (2) comparison of the remote with in-clinic measures in cross-sectional and longitudinal disability evaluations.MethodsBetween March 2020 and December 2021, 207 MS cohort participants underwent hybrid in-clinic and virtual research visits; 96 contributed 100 “matched visits,” that is, in-clinic (Neurostatus-Expanded Disability Status Scale [NS-EDSS]) and remote (televideo-enabled EDSS [tele-EDSS]; electronic patient-reported EDSS [ePR-EDSS]) evaluations. Clinical, demographic, and socioeconomic characteristics of participants were collected.ResultsThe costs of remote visits were lower than in-clinic visits for research investigators (facilities, personnel, parking, participant compensation) but also for participants (travel, caregiver time) and carbon footprint (p&lt; 0.05 for each). Median cohort EDSS was similar between the 3 modalities (NS-EDSS: 2, tele-EDSS: 1.5, ePR-EDSS: 2, range 0.6.5); the remote evaluations were each noninferior to the NS-EDSS within ±0.5 EDSS point (TOST for noninferiority,p&lt; 0.01 for each). Furthermore, year to year, the % of participants with worsening/stable/improved EDSS scores was similar, whether each annual evaluation used NS-EDSS or whether it switched from NS-EDSS to tele-EDSS.DiscussionAltogether, the current findings suggest that remote evaluations can reduce the costs of research participation for patients, while providing a reasonable evaluation of disability trajectory longitudinally. This could inform the design of remote research that is more inclusive of diverse participants.</jats:sec