Mid-pass whole genome sequencing enables biomedical genetic studies of diverse populations.

BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.

Inequities in people with gout: a focus on Maori (Indigenous People) of Aotearoa New Zealand.

Health equity can be defined as the absence of systematic disparities in health between more and less advantaged social groups. Gout is one of the most common forms of arthritis and disproportionally affects Indigenous peoples, including Maori in Aotearoa New Zealand. Inequities in gout management are well documented and clearly evidenced in Indigenous populations. For example, while gout occurs at a younger age and is more severe in Maori, there is less regular dispensing of urate-lowering therapies. Indigenous peoples are also under-represented in clinical trials. Herein, we will review inequities in gout using Aoteoaroa New Zealand as an example. We will explore reasons for health inequities and challenges that need to be faced to achieve health equity.

Flare Rate Thresholds for Patient Assessment of Disease Activity States in Gout.

OBJECTIVE: To determine the relationship between gout flare rate and self-categorization into remission, low disease activity (LDA), and patient acceptable symptom state (PASS). METHODS: Patients with gout self-categorized as remission, LDA, and PASS, and reported number of flares over the preceding 6 and 12 months. Multinomial logistic regression was used to determine the association between being in each disease state (LDA and PASS were combined) and flare count, and self-reported current flare. A distribution-based approach and extended Youden index identified possible flare count thresholds for each state. RESULTS: Investigators from 17 countries recruited 512 participants. Remission was associated with a median recalled flare count of zero over both 6 and 12 months. Each recalled flare reduced the likelihood of self-perceived remission compared with being in higher disease activity than LDA/PASS, by 52% for 6 months and 23% for 12 months, and the likelihood of self-perceived LDA/PASS by 15% and 5% for 6 and 12 months, respectively. A threshold of 0 flares in preceding 6 and 12 months was associated with correct classification of self-perceived remission in 58% and 56% of cases, respectively. CONCLUSION: Flares are significantly associated with perceptions of disease activity in gout, and no flares over the prior 6 or 12 months is necessary for most people to self-categorize as being in remission. However, recalled flare counts alone do not correctly classify all patients into self-categorized disease activity states, suggesting that other factors may also contribute to self-perceived gout disease activity.

Tapering biologic therapy for people with rheumatoid arthritis in remission: A review of patient perspectives and associated clinical evidence.

OBJECTIVES: Biologic therapies have increased the control of disease activity in rheumatoid arthritis (RA). Questions remain about tapering biologics when remission is achieved in RA. The patient perspective has to be incorporated in pragmatic applications of tapering but is rarely accounted for in clinical studies of tapering. The aim of the present review was to summarize the evidence about RA patient perspectives on biologic tapering. METHODS: We provided a narrative summary of the currently small body of research on patient perspectives retrieved through systematic searches with an emphasis on seeking qualitative research. In addition, we provided an update on relevant clinical research and financial considerations that frame the findings on patient perspectives. RESULTS: Financial considerations around commencing/continuing on biologic therapies in RA vary internationally and have implications for patient perspectives. Recent clinical studies indicate that the benefit of tapering biologic therapy when in remission are predicted by drug concentration and aspects of disease activity, severity and duration. Three major concerns have been identified from studies of patient perspectives on biologic tapering: (a) disease relapse; (b) access to treatment in the case of disease flare when tapering; and (c) local motivation for dose reduction (i.e., driven by funding or health benefit). CONCLUSIONS: More research is needed on tapering biologics, and should include studies of patient perspectives as well as health economic evaluations. Patient decision aids are a potential way of applying clinical and patient-focused evidence to help all parties come to a decision, but require developmental research and pragmatic evaluation.

Assessment of the relationship between methotrexate polyglutamates in red blood cells and clinical response in patients commencing methotrexate for rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX, MTXGlu1) has not been established. In this study, we aim to explore the relationship between red blood cell (RBC) concentrations of MTX and its polyglutamate metabolites (MTXGlu(n); n = 2, 3, 4, 5) and clinical response in RA patients commencing MTX. METHODS: The binding activity of MTXGlu(n) to three putative enzymes involved in the MTX mechanism of action­dihydrofolate reductase, thymidylate synthase, and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase­was simulated. RBC MTXGlu(n) concentrations that gave the highest inhibition activity across all three enzymes were linked with the disease activity score DAS28-3v (C-reactive protein [CRP]). A population pharmacokinetic-pharmacodynamic model was developed to describe the relationship between RBC MTX polyglutamate concentrations and clinical response in 12 RA patients commencing MTX. RESULTS: The highest inhibition activity was with RBC MTXGlu(3-5). These polyglutamates were further evaluated for their relationship with DAS28-3v (CRP). Three of the 12 patients had a high DAS28-3v (CRP) at baseline (mean = 6.1) and showed a delayed response to MTX treatment. The remaining nine patients with a lower DAS28-3v (CRP) baseline (mean = 3.6) showed an immediate response. The developed MTX pharmacokinetic-pharmacodynamic model provided an acceptable description of the observed DAS28-3v (CRP) across all patients. CONCLUSIONS: The developed model describes a longitudinal relationship between RBC MTXGlu(3-5) concentrations and DAS28-3v (CRP) in patients with RA commencing MTX. Further work is required to determine whether measurement of RBC MTX polyglutamates might be useful for dose individualisation in patients with RA.