Markov Chain Monte Carlo in Genetics: Subphenotyping, Linkage Disequilibrium Modeling, and Fine Mapping.

The advance of modern genotyping and sequencing technologies makes large scale data available in different genetic studies. Meanwhile, MCMC algorithm provides powerful computational tools in handling these high-dimensional genetic data. In this dissertation, I demonstrate several MCMC applications in emerging genetic studies. In Chapter 2, I propose a method to identify genetically homogeneous subphenotypes of complex diseases. I assume that different disease subtypes, caused by different risk variants, behave uniquely in clinical characteristics (treated as covariates). I design an algorithm to identify these covariates to define genetically homogeneous subtypes. Conditional on these covariates, this algorithm calculate each affected individual’s posterior probability of belonging to each subtype. Using simulated data, I illustrate that my algorithm correctly identifies subtypes, such that affected individuals within each subtype group are likely to carry the same risk variants. I also evaluate whether stratifying on these estimated subtype memberships improves the power to detect phenotypic association at risk loci attributable to these subtypes. In Chapter 3, I introduce a novel algorithm to model the linkage disequilibrium (LD) between different genomic positions through shared genealogies. Compared to traditional hidden Markov models (HMM) which might over simplify the evolutionary process of sampled haplotypes, my method allows for more variations in prior probabilities about shared haplotype segments descend from particular ancestors, as well as more variations in population genetic parameters. Through this more careful model, our method improves the accuracy in haplotype reconstruction. Moreover, I propose a fine mapping algorithm based on this model to localize complex trait loci. My algorithm identifies disease causal loci accurately when traditional mapping approaches based on single marker tests have low power. In Chapter 4, I propose an approach to overcome the computational burden in fine mappings using our coalescent-based modeling. I first estimate a set of clusters of sampled haplotypes such that members within each cluster share one common ancestor. I then make inferences about genealogies of these clusters to localize candidate regions of disease-causing mutations. Using simulated data, I illustrate that this implementation enables my fine mapping approach in large samples with several tens of thousands of individuals.PHDBiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108872/1/zgeng_1.pd

A Practical Response Adaptive Block Randomization Design with Analytic Type I Error Protection

Response adaptive randomization is appealing in confirmatory adaptive clinical trials from statistical, ethical, and pragmatic perspectives, in the sense that subjects are more likely to be randomized to better performing treatment groups based on accumulating data. The Doubly Adaptive Biased Coin Design (DBCD) is a popular solution due to its asymptotic normal property of final allocations, which further justifies its asymptotic type I error rate control. As an alternative, we propose a Response Adaptive Block Randomization (RABR) design with pre-specified randomization ratios for the control and high-performing groups to robustly achieve desired final sample size per group under different underlying responses, which is usually required in industry-sponsored clinical studies. We show that the usual test statistic has a controlled type I error rate. Our simulations further highlight the advantages of the proposed design over the DBCD in terms of consistently achieving final sample allocations and of power performance. We further apply this design to a Phase III study evaluating the efficacy of two dosing regimens of adjunctive everolimus in treating tuberous sclerosis complex but with no previous dose-finding studies in this indication

Deep Historical Borrowing Framework to Prospectively and Simultaneously Synthesize Control Information in Confirmatory Clinical Trials with Multiple Endpoints

In current clinical trial development, historical information is receiving more attention as providing value beyond sample size calculation. Meta-analytic-predictive (MAP) priors and robust MAP priors have been proposed for prospectively borrowing historical data on a single endpoint. To simultaneously synthesize control information from multiple endpoints in confirmatory clinical trials, we propose to approximate posterior probabilities from a Bayesian hierarchical model and estimate critical values by deep learning to construct pre-specified decision functions before the trial conduct. Simulation studies and a case study demonstrate that our method additionally preserves power, and has a satisfactory performance under prior-data conflict

Efficacy and Safety of Adalimumab in Conjunction With Surgery in Moderate to Severe Hidradenitis Suppurativa:The SHARPS Randomized Clinical Trial

IMPORTANCE: Surgery is a mainstay in the management of hidradenitis suppurativa (HS). Adalimumab is the first drug approved for HS. OBJECTIVE: To investigate the efficacy and safety of adalimumab in combination with wide-excision surgery followed by secondary intention healing. DESIGN, SETTING, AND PARTICIPANTS: The Safety and Efficacy of Adalimumab for Hidradenitis Suppurativa Peri-Surgically (SHARPS) trial was a phase 4, randomized, double-blind, placebo-controlled study of adalimumab in conjunction with surgery. Patients were enrolled in 45 sites across 20 countries from July 18, 2016, to February 2, 2019, with the last patient visit on October 16, 2019. Eligible patients (aged 18-65 years) had moderate to severe HS that required radical surgery in an axillary or inguinal region and had 2 other anatomical regions affected, with 1 or more regions at Hurley stage II or III. Analysis was conducted in November 2019. INTERVENTIONS: Patients were randomized 1:1 to receive continuous adalimumab, 40 mg, or placebo during presurgery (12 weeks), perioperative (2 weeks), and postoperative (10 weeks) periods. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients achieving HS clinical response across all body regions at week 12. RESULTS: Overall, 103 patients were randomized to adalimumab and 103 to matching placebo. Among all patients, 51% (n = 106) were women, 94% (n = 193) were White, and the mean (SD) age was 37.6 (11.3) years. At week 12, significantly more patients receiving adalimumab (49 of 103 [48%]) vs placebo (35 of 103 [34%]; P = .049) achieved HS clinical response across all body regions (treatment difference, 14% [95% CI, 0%-27%]). Treatment-emergent adverse events were reported in 74 of 103 patients (72%) and 69 of 103 patients (67%) in the adalimumab and placebo groups, respectively. No increased risk of postoperative wound infection, complication, or hemorrhage was observed with adalimumab vs placebo. Two deaths occurred in the adalimumab group; neither was considered as having a reasonable possibility of relationship to study drug. CONCLUSIONS AND RELEVANCE: Adalimumab was efficacious in conjunction with wide-excision surgery followed by secondary intention healing, with no need to interrupt treatment prior to surgery. These data support further investigation of adalimumab as an adjuvant therapy to surgery in patients with moderate to severe HS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0280897

Examining Spatial Inequalities in Public Green Space Accessibility: A Focus on Disadvantaged Groups in England

Green spaces have been recognised for their positive impact on residents’ health and well-being. However, equitable access to these spaces remains a concern as certain social groups face barriers to reaching public green areas (PGS). Existing studies have explored the relationship between green spaces and vulnerable populations but have often overlooked the spatial variations in accessibility experienced by these groups. This research aimed to investigate the spatial association between green space accessibility and five key variables representing vulnerability: age, educational deprivation, health deprivation, crime rates, and housing barriers. Ordinary least squares and multi-scale geographically weighted regression (MGWR) techniques were employed to analyse the relationship between the nearest distance to public green spaces and the challenges experienced by vulnerable groups based on socioeconomic factors in England. The findings highlight disparities in open green space access for vulnerable groups, particularly older adults and individuals with limited education and housing accessibility, who are more likely to face restricted access to green spaces. There was a negative correlation found between health deprivation and the accessibility of green spaces, indicating people who suffer from the disease may live closer to green spaces. Surprisingly, although a positive association was observed between crime risk and distance to public green space in most areas, there were specific areas that exhibit a negative correlation between them. This study emphasises the importance of considering the perspectives of vulnerable groups in addressing PGS inequality and underscores the need for inclusive public green space planning and policy development

Achieving hidradenitis suppurativa response score is associated with significant improvement in clinical and patient-reported outcomes: Post hoc analysis of pooled data from PIONEER I and II

Hidradenitis Suppurativa Clinical Response (HiSCR), is a validated tool that has been used to assess the efficacy of adalimumab among patients with hidradenitis suppurativa. We evaluated the clinical meaning of HiSCR by relating it to patient-reported outcomes to give further context to its achievement in a post hoc analysis of integrated data from two phase 3 clinical trials (PIONEER I and II). Pooling placebo and active treatment arms, 39% of patients (245/629) achieved HiSCR at week 12. Irrespective of treatment, significantly (p < 0.05) more HiSCR responders than non-responders experienced clinically meaningful improvement in Dermatology Life Quality Index (60.5% vs 30.4%), Pain Numeric Rating Scale (46.9% vs 19.9%), hidradenitis suppurativa quality of life (49.4% vs 26.9%), work-related performance (52.6% vs 37.7%), and non-work-related performance (59.5% vs 33.3%). Clinically meaningful outcomes in hidradenitis suppurativa are more likely to be attained in patients achieving HiSCR level improvement

Efficacy and Safety of Risankizumab for the Treatment of Hidradenitis Suppurativa: A Phase 2, Randomized, Placebo-Controlled Trial

Introduction: Hidradenitis suppurativa (HS) is a chronic, immune-mediated skin condition characterized by inflammatory lesions that can cause pain, impaired physical activity, and reduced quality of life. This study evaluated the efficacy and safety of risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit, for the treatment of HS. Methods: This phase II multicenter, randomized, placebo-controlled, double-blind study investigated the efficacy and safety of risankizumab in patients with moderate-to-severe HS. Patients were randomized 1:1:1 to receive subcutaneous risankizumab 180 mg; risankizumab 360 mg; or placebo at weeks 0, 1, 2, 4, and 12. Patients initially randomized to placebo received blinded risankizumab 360 mg at weeks 16, 17, and 18; patients initially randomized to risankizumab received blinded matching placebo at the same time points. From weeks 20–60, all patients received open-label risankizumab 360 mg every 8 weeks. The primary endpoint was the achievement of HS Clinical Response (HiSCR) at week 16. Safety was assessed by monitoring of treatment-emergent adverse events (TEAEs). Results: A total of 243 patients were randomized (risankizumab 180 mg, n = 80; risankizumab 360 mg, n = 81; placebo, n = 82). HiSCR was achieved by 46.8% of patients with risankizumab 180 mg, 43.4% with risankizumab 360 mg, and 41.5% with placebo at week 16. The primary endpoint was not met, and the study was terminated early. Incidence of TEAEs, severe TEAEs, TEAEs considered possibly related to study drug, and TEAEs leading to discontinuation of study drug were generally low and comparable across treatment groups. Conclusion: Risankizumab does not appear to be an efficacious treatment for moderate-to-severe HS. Future studies to understand the complex molecular mechanisms underlying HS pathogenesis and develop improved therapies are warranted. Trial Registration: ClinicalTrials.gov identifier: NCT03926169

Efficacy, safety, usability, and acceptability of risankizumab 150 mg formulation administered by prefilled syringe or by an autoinjector for moderate to severe plaque psoriasis

Background Risankizumab is approved for treatment of moderate to severe plaque psoriasis. Availability of a patient-controlled single self-injection of risankizumab may improve adherence and long-term management of psoriasis. Objective To investigate efficacy, safety, and usability of a new risankizumab 150 mg/mL formulation administered as a single subcutaneous injection via prefilled syringe (PFS) or autoinjector (AI). Methods Efficacy, safety, usability, and acceptability of risankizumab 150 mg/mL PFS or AI were investigated in adults with moderate to severe psoriasis in two phase 3 studies. Study 1 was a multicenter, randomized, double-blinded, placebo-controlled study that investigated 150 mg/mL risankizumab PFS; study 2 was a multicenter, single-arm, open-label study that investigated 150 mg/mL risankizumab AI. Results At week 16, risankizumab 150 mg/mL demonstrated efficacy vs. placebo (Psoriasis Area and Severity Index ≥90% improvement (PASI 90), 62.9% vs. 3.8%; static Physician Global Assessment (sPGA) 0/1, 78.1% vs. 9.6%; both p< .001) in study 1; in study 2, PASI 90 and sPGA 0/1 were 66.7%, and 81.5%, respectively. All patients successfully self-administered study treatments via PFS or AI. Acceptability of self-injection was high in both studies. Efficacy and safety of risankizumab 150 mg/mL were comparable with results from previous risankizumab phase 3 studies using the 90 mg/mL formulation. Conclusions The efficacy, safety, and usability of 150 mg/mL risankizumab delivered as a single PFS or AI injection support use of this new formulation in patients with moderate to severe plaque psoriasis. Clinical trials NCT03875482 and NCT038750

Efficacy and Safety of Risankizumab for the Treatment of Hidradenitis Suppurativa: A Phase 2, Randomized, Placebo-Controlled Trial

IntroductionHidradenitis suppurativa (HS) is a chronic, immune-mediated skin condition characterized by inflammatory lesions that can cause pain, impaired physical activity, and reduced quality of life. This study evaluated the efficacy and safety of risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit, for the treatment of HS.MethodsThis phase II multicenter, randomized, placebo-controlled, double-blind study investigated the efficacy and safety of risankizumab in patients with moderate-to-severe HS. Patients were randomized 1:1:1 to receive subcutaneous risankizumab 180&nbsp;mg; risankizumab 360&nbsp;mg; or placebo at weeks&nbsp;0, 1, 2, 4, and 12. Patients initially randomized to placebo received blinded risankizumab 360&nbsp;mg at weeks&nbsp;16, 17, and 18; patients initially randomized to risankizumab received blinded matching placebo at the same time points. From weeks&nbsp;20-60, all patients received open-label risankizumab 360&nbsp;mg every 8&nbsp;weeks. The primary endpoint was the achievement of HS Clinical Response (HiSCR) at week&nbsp;16. Safety was assessed by monitoring of treatment-emergent adverse events (TEAEs).ResultsA total of 243 patients were randomized (risankizumab 180&nbsp;mg, n = 80; risankizumab 360&nbsp;mg, n = 81; placebo, n = 82). HiSCR was achieved by 46.8% of patients with risankizumab 180&nbsp;mg, 43.4% with risankizumab 360&nbsp;mg, and 41.5% with placebo at week&nbsp;16. The primary endpoint was not met, and the study was terminated early. Incidence of TEAEs, severe TEAEs, TEAEs considered possibly related to study drug, and TEAEs leading to discontinuation of study drug were generally low and comparable across treatment groups.ConclusionRisankizumab does not appear to be an efficacious treatment for moderate-to-severe HS. Future studies to understand the complex molecular mechanisms underlying HS pathogenesis and develop improved therapies are warranted.Trial registrationClinicalTrials.gov identifier: NCT03926169

Effect of risankizumab on patient-reported outcomes in moderate to severe psoriasis : the UltIMMa-1 and UltIMMa-2 randomized clinical trials

IMPORTANCE Demonstrating the value of therapies from a patient's perspective is increasingly important for patient-centered care. OBJECTIVE To compare patient-reported outcomes (PROs) with risankizumab vs ustekinumab and placebo in psoriasis symptoms, health-related quality of life (HRQL), and mental health among patients with moderate to severe psoriasis. DESIGN, SETTING, AND PARTICIPANTS The UltIMMa-1 and UltIMMa-2 studies were replicate 52-week phase 3, randomized, multisite, double-blind, placebo-controlled and active comparator-controlled trials conducted in 139 sites (including hospitals, academic medical centers, clinical research units, and private practices) globally in Asia-Pacific, Japan, Europe, and North America. Adults (>= 18 years) with moderate to severe chronic plaque psoriasis with body surface area (BSA) involvement of 10% or more, Psoriasis Area Severity Index (PASI) scores of 12 or higher, and static Physician's Global Assessment (sPGA) scores of 3 or higher were included. INTERVENTIONS In each trial, patients were randomly assigned (3:1:1) to 150 mg of risankizumab, 45 mg or 90 mg of ustekinumab (weight-based per label) for 52 weeks, or matching placebo for 16 weeks followed by risankizumab. MAIN OUTCOMES AND MEASURES Integrated data from 2 trials were used to compare Psoriasis Symptom Scale (PSS) (total score and item scores for pain, redness, itchiness, and burning), Dermatology Life Quality Index (DLQI), 5-level EuroQoL-5D (EQ-5D-5L), and Hospital Anxiety and Depression Scale (HADS), at baseline, week 16, and week 52. RESULTS A total of 997 patients with moderate to severe chronic plaque psoriasis were analyzed. Across all arms, the mean age was 47.2 to 47.8 years and 68.3% (136/199 for ustekinumab) to 73.0% (146/200 for placebo) were men. Patients' characteristics and PROs were comparable across all treatment arms at baseline (n = 598, 199, 200 for risankizumab, ustekinumab, and placebo, respectively). At week 16, a significantly greater proportion of patients treated with risankizumab than those treated with ustekinumab or placebo achieved PSS = 0, indicating no psoriasis symptoms (30.3% [181/598], 15.1% [30/199], 1.0% [2/200], bothP < .001), and DLQI = 0 or 1 indicating no impact on skin-related HRQL (66.2%, 44.7%, 6.0%,P < .001). Significantly greater proportions of patients treated with risankizumab achieved minimally clinically important difference (MCID) than ustekinumab or placebo for DLQI (94.5% [516/546], 85.1% [149/175], 35.6% [64/180]; bothP < .001), EQ-5D-5L (41.7% [249/597] vs 31.5% [62/197],P = .01; vs 19.0% [38/200],P < .001), and HADS (anxiety: 69.1% [381/551] vs 57.1% [104/182],P = .004; vs 35.9% [66/184],P < .001; depression: 71.1% [354/598] vs 60.4% [96/159],P = .01; vs 37.1% [59/159],P < .001). At week 52, improvements in patients treated with risankizumab compared with those treated with ustekinumab were sustained for PSS, DLQI, and EQ-5D-5L. CONCLUSIONS AND RELEVANCE Risankizumab significantly improved symptoms of moderate to severe psoriasis, improved HRQL, and reduced psychological distress compared with ustekinumab or placebo