A Likelihood Based Approach to the Assessment of Large Sample Convergence and Model Based Clustering.

The likelihood is a function of model parameter(s) and data using a pre-defined probability density function (pdf). Thus, the likelihood can be viewed as model-data combination that can be utilized to address questions of interest. The relative likelihood function is the likelihood function scaled by its mode so as to have its maximum at one. Unlike likelihood functions, relative likelihood functions have attracted little attention and use by statisticians. The proposed dissertation work explores the properties and applications of relative likelihood functions in examining the large-sample convergence properties of maximum likelihood estimator (MLE) and in relation to clustering. The dissertation consists of three chapters. The first chapter presents a simulation based approach to examine the relationship between sample size and the asymptotic behavior of the MLE. The convergence of the observed relative likelihood function (RLF) to the asymptotic relative likelihood function (RLF) is assessed for different sample sizes using two measures of convergence; difference in areas and dissimilarity in shape. The proposed approach has been applied to data from the literature as well as to data simulated from different exponential family distributions. The second chapter proposes a novel clustering approach based on the observed RLFs. Observations in the dataset are assumed to follow a known distribution and observed RLFs are obtained. The observed RLFs are further scaled by the inverse of the asymptotic variation (Fisher Information) evaluated at the mode of the likelihood functions. The weighted RLFs reflect information based similarity among observations in the data. A data matrix is then developed by evaluating the weighted RLFs at different values in the parameter space. The data matrix allows for direct application of standard clustering algorithms such as k-means algorithm. This clustering approach was applied to simulated dataset based on real data and to datasets simulated from known distributions. The third chapter examines the proposed RLF based clustering approach to a publicly available gene expression dataset consisting of 70 gene expression profiles used to classify patients into prognostic groups. The agreement between the RLF clustering results and previous classification is also presented. The clusters obtained are also examined in relation to differences in two clinical features – time to overall survival; and time to metastases

A Geo-Stratified Analysis of Associations Between Socio-Economic Factors and Diabetes Risk

Introduction. In 2019, diabetes was the seventh leading cause of death in the United States. The association between diabetes risk and socio-economic factors in the United States has been examined primarily at the national level; little is known about this association at the regional level. This study examines and compares the association between diabetes risk and previously established socio-economic factors across four geographic regions (South, Midwest, West, and Northwest). Methods. We analyzed the 2014 Behavioral Risk Factor Surveillance System (BRFSS) data stratified by four geographic regions of the United States. The risk estimates of diabetes associated with previously established socio-economic factors as well as diabetes prevalence were compared across four geographic regions. Results. There was marked variation in association between diabetes risk and previously established risk factors across the four geographic regions. In the South, rural residency was associated with increased diabetes risk, whereas in the other geographic regions rural residency had a protective effect. In the South, the diabetes risk for males was 22% higher compared to females in the South, whereas the risk for males was 41% higher than females in the Northeast. Independently, age had the strongest discriminative ability to distinguish between a person with diabetes and a person without diabetes, whereas ethnicity, race and sex had the weakest discriminative abilities. Conclusions. Our findings suggest a higher prevalence of diabetes by race/ethnicity (Non-Hispanic Black and Hispanic) and income across all four regions. While rural residency is highest in the South, but protective in other regions. Overall, we found age and income provide the highest predictive ability for diabetes risk.  This study highlights differences in diabetes prevalence in association between previously established socio-economic variables and diabetes risk across four geographic regions. These findings could help public health professionals and policy makers in understanding the dynamic relationship between diabetes and risk factors at the regional level

Active vs Traditional Methods of Recruiting Children for a Clinical Trial in Rural Primary Care Clinics: A Cluster-Randomized Clinical Trial

Importance: To our knowledge, there are no published randomized clinical trials of recruitment strategies. Rigorously evaluated successful recruitment strategies for children are needed. Objective: To evaluate the feasibility of 2 recruitment methods for enrolling rural children through primary care clinics to assess whether either or both methods are sufficiently effective for enrolling participants into a clinical trial of a behavioral telehealth intervention for children with overweight or obesity. Design, setting, and participants: This cluster-randomized clinical trial of 2 recruitment methods was conducted at 4 primary care clinics in 4 separate states. Each clinic used both recruitment methods in random order. Clinic eligibility criteria included at least 40% pediatric patients with Medicaid coverage and at least 100 potential participants. Eligibility criteria for children included a rural home address, age 6 to 11 years, and body mass index at or above the 85th percentile. Recruitment began February 3, 2020, and randomization of participants occurred on August 17, 2020. Data were analyzed from October 3, 2021, to April 21, 2022. Interventions: Two recruitment methods were assessed: the active method, for which a list of potential participants seen within the past year at each clinic was generated through the electronic health record and consecutively approached by research staff based on visit date to the clinic, and the traditional method, for which recruitment included posters, flyers, social media, and press release. Clinics were randomized to the order in which the 2 methods were implemented in 4-week periods, followed by a 4-week catch-up period using the method found most effective in previous periods. Main outcomes and measures: For each recruitment method, the number and proportion of randomized children among those who were approached was calculated. Results: A total of 104 participants were randomized (58 girls [55.8%]; mean age, 9.3 [95% CI, 9.0-9.6] years). Using the active method, 535 child-parent dyads were approached and 99 (18.5% [95% CI, 15.3%-22.1%]) were randomized. Using the traditional method, 23 caregivers expressed interest, and 5 (21.7% [95% CI, 7.5%-43.7%]) were randomized. All sites reached full enrollment using the active method and no sites achieved full enrollment using the traditional method. Mean time to full enrollment was 26.3 (range, 21.0-31.0) days. Conclusions and relevance: This study supports the use of the active approach with local primary care clinics to recruit children with overweight and obesity from rural communities into clinical trials

Safety and Tolerability of Carboplatin and Paclitaxel in Cancer Patients with HIV (AMC-078), an AIDS Malignancy Consortium (AMC) Study

Patients with cancer and HIV are an underserved population. Paclitaxel and carboplatin is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. This pilot trial evaluated the safety of full dose paclitaxel and carboplatin in people living with HIV and cancer

Safety and Efficacy of Brentuximab Vedotin in Combination with AVD in Stage II-IV HIV-Associated Classical Hodgkin Lymphoma: Results of the Phase 2 Study, AMC 085

Introduction: Patients (pts) with HIV have a 6-fold increased risk of developing classic Hodgkin lymphoma (cHL) over the general population. The outcome of frontline therapy for HIV-associated cHL (HIV-cHL) using doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is similar to the non-HIV population. However, pts with advanced stage cHL continue to have a 30% chance of refractory/relapsed disease with ABVD. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that selectively induces apoptosis of CD30+ cells. The FDA approved BV with AVD (BV-AVD) after the Echelon-1 (E1) study for advanced stage disease demonstrated improved modified progression free survival (mPFS) at 2 years compared with standard ABVD: 82% vs. 77%. Pts with HIV were excluded from both relapsed/refractory and frontline BV trials. Here we present the final results of the phase 2 trial of BV-AVD in previously untreated HIV-associated cHL, an AIDS Malignancy Consortium/LYSA collaboration (ClinicalTrials.gov ID: NCT01771107). Methods: Forty-one pts were treated on days 1 and 15 of 6, 28 day cycles, with 1.2mgs/kg of BV in combination with doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD). Eligibility criteria included untreated cHL stage II-IV, CD4 + T-cell counts ≥50 cells/mm3, and initiation of combined antiretroviral therapy (cART) at least 1 week prior to therapy. Ritonavir, zidovidine, cobisistat, and other strong CYP3A4 or P-glycoprotein inhibitors were excluded with a washout of at least 1 week being required. Hematopoietic growth factor was mandated. The primary objective was 2 year PFS. The sample size was based on providing an estimate of the PFS with a 95% CI +/- 10% under the assumption of a 2 year progression free survival (PFS) estimate of 85%. Secondary objectives included toxicity, effects on CD4/CD8 + T-cells, HIV-1 viral load, prognostic significance of post C2 and end of treatment PET-CT. Results: Forty-one pts (93% men) were treated with a median age of 48y (range 24-67). Pts presented with stage II (17%), III (27%), and IV (56%) disease. Two year PFS estimate in the overall population (N=41) was 86% (95% CI: .74, .98). The 2-year overall survival (OS) estimate was 92% (95% CI: 0.83, 1.0) with 3 deaths at the time of analysis, including 1 which was a treatment related death (Figure 1A). For pts with advanced disease (N=34), the 2-year PFS estimate was 87% (95% CI: 0.76, 0.99) with an OS estimate of 90% (95% CI: 0.8, 1.00) (Figure 1B). Safety profiles were quite similar to the BV-AVD arm in the E1 study of the pts who received growth factor. Neuropathy was higher in our study compared to E1, (49% vs. 29% for any grade, P=0.01; 9.8% vs. 5% for G3/4, p=0.06). G3 Neutropenia was greater in AMC 085 compared to E1 BV-AVD arm with growth factor: 57% vs. 29% (p<0.01). The outcomes between this study and E1 with respect to serious adverse events due to infection (33% vs. 44%) or febrile neutropenia (11% vs. 15%) during therapy were similar. Two pts were removed from study for violating inclusion criteria by taking ritonavir, a strong CYP 3A4 inhibitor since enrollment. One developed febrile neutropenia and G4 pancreatitis cycle 1 day 7 while the second developed febrile neutropenia prior to cycle 2. A third pt discontinued ritonavir 2 days prior to enrollment and developed a prolonged G3 neuropathy. The median CD4 and CD8+ T-cell counts at diagnosis were 289 cells/mm3 (range 32-818) and 486 cells/mm3 (range 26-1780), respectively. Of evaluable pts an increase in CD4 and CD8+ T-cell counts were noted just 1 month after therapy to 545 cell/mm3 (range161-2130) and 745 cell/mm3 (range 132-3106) noted by cycle 2 day 1. Sixty-nine % had undetectable viral loads at baseline. For those with detectable viral loads at diagnosis, the median viral load was 52 copies/ml (range 22-15,706). HIV-1 viral loads declined during therapy. PET/CT data demonstrated 3/32 pts were PET positive after cycle 2. One of 29 pts was PET/CT positive by end of cycle 6 deemed to be a false positive based on benign biopsy and follow up. Conclusions: BV-AVD in stage II-IV HIV-cHL was efficacious although neutropenia and neuropathy were increased compared to the non-HIV population. The 2-year PFS estimate was 86% for the entire cohort and 87% for advanced stage HIV-cHL. Major interactions with strong CYP3A4 inhibitors lead to toxicity and must be avoided. The etiology of the CD4 increase is under investigation and may have implications for future therapy. Disclosures Rudek: Cullinan Apollo: Research Funding; Taiho: Research Funding; RenovoRX: Research Funding; Celgene: Research Funding. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. OffLabel Disclosure: Brentuximab Vedotin has been approved for the upfront treatment of advanced stage cHL in combination with AVD though not specifically approved for use in patients infected with HIV or stage 2 cHL

Brentuximab vedotin with AVD for stage II–IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial

International audienceBackground: Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin–AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. Methods: We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II–IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per μL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. Findings: Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16–38). 34 (83%) of 41 patients presented with stage III–IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71–94) and the overall survival was 92% (78–97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. Interpretation: Brentuximab vedotin–AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. Funding: National Institutes of Health and National Cancer Institute