Selection of the optimal personalized treatment from multiple treatments with right-censored multivariate outcome measures.

We propose a novel personalized concept for the optimal treatment selection for a situation where the response is a multivariate vector that could contain right-censored variables such as survival time. The proposed method can be applied with any number of treatments and outcome variables, under a broad set of models. Following a working semiparametric Single Index Model that relates covariates and responses, we first define a patient-specific composite score, constructed from individual covariates. We then estimate conditional means of each response, given the patient score, correspond to each treatment, using a nonparametric smooth estimator. Next, a rank aggregation technique is applied to estimate an ordering of treatments based on ranked lists of treatment performance measures given by conditional means. We handle the right-censored data by incorporating the inverse probability of censoring weighting to the corresponding estimators. An empirical study illustrates the performance of the proposed method in finite sample problems. To show the applicability of the proposed procedure for real data, we also present a data analysis using HIV clinical trial data, that contained a right-censored survival event as one of the endpoints.

Stepwise Proportional Weighting Algorithm for Single-Race Population Estimation Using Hawai'i Census Data.

Many health and health disparities studies require population prevalence information of various race groups, but the estimation of single-race population sizes using the US Census data has been challenging. For each Census race group, Census only provides the counts of those reported being single race ("race alone") and those reported of that specific race regardless of whether the individuals were multiracial or not ("race alone or in (any) combination"). The issue of how to classify Census multiracial individuals is especially important for the state of Hawai'i due to its large multiracial population. The current study developed the Stepwise Proportional Weighting Algorithm (SPWA) for single-race population estimation using US Census data for major race groups in the Census and their nested detailed races. Additionally, given that "partial Native Hawaiian" has often been treated as "Native Hawaiian" in health disparities studies in Hawai'i, the algorithm can also adjust for the unique partial Native Hawaiian race categorization. This paper describes the estimation process with the SPWA and demonstrates its ability to estimate single-races for the 5 most common race groups in Hawai'i. This new methodology addresses an important concern regarding how to classify multiracial individuals to strengthen health and health disparities research in Hawai'i.

Age and Sex Distributions of 31 Common Racial Groups in Hawai'i: A Shiny Web Application.

Hawai'i is the most ethnically diverse state with the highest proportion of multiracial individuals in the United States. The Stepwise Proportional Weighting Algorithm (SPWA) was developed to bridge the categorization of multiracial Census data into single-race population estimates for common races in Hawai'i. However, these estimates have not been publicly available. A Shiny web application, the Hawai'i Single-Race Categorization Tool, was developed as a user friendly research tool to obtain the age and sex distributions of single-race estimates for common racial groups in Hawai'i. The Categorization Tool implements the SPWA and presents the results in tabular and graphic formats, stratified by sex and age. It also allows the categorization of partial Native Hawaiians as Native Hawaiians in the population estimation. Using this tool, the current paper reports population estimates and distributions for 31 common racial groups using Hawai'i Census 2010 data. Among the major Census races, Asian had the largest population (631 881; 46.5%) in Hawai'i, followed by White (431 635; 31.7%) and Native Hawaiian and Other Pacific Islander (227 588; 16.7%). Among Census detailed races within Asian, Filipino had the largest population estimate (244 730; 18.0%), followed by Japanese (227 165; 16.7%) and Chinese (103 600; 7.6%). Native Hawaiian accounted for 12.3% of the Hawai'i population (166 944). After recategorizing part-Native Hawaiians as Native Hawaiians, Native Hawaiian increased by 150.0%, with the greatest increase among the young. This publicly available tool would be valuable for race-related resource allocation, policy development, and health disparities research in Hawai'i.

Racial/Ethnic Disparities in the Alzheimer's Disease Link with Cardio and Cerebrovascular Diseases, Based on Hawaii Medicare Data.

Background: There is an expanding body of literature implicating heart disease and stroke as risk factors for Alzheimer's disease (AD). Hawaii is one of the six majority-minority states in the United States and has significant racial health disparities. The Native-Hawaiians/Pacific-Islander (NHPI) population is well-known as a high-risk group for a variety of disease conditions. Objective: We explored the association of cardiovascular disease with AD development based on the Hawaii Medicare data, focusing on racial disparities. Methods: We utilized nine years of Hawaii Medicare data to identify subjects who developed heart failure (HF), ischemic heart disease (IHD), atrial fibrillation (AF), acute myocardial infarction (AMI), stroke, and progressed to AD, using multistate models. Propensity score-matched controls without cardiovascular disease were identified to compare the risk of AD after heart disease and stroke. Racial/Ethnic differences in progression to AD were evaluated, accounting for other risk factors. Results: We found increased risks of AD for AF, HF, IHD, and stroke. Socioeconomic (SE) status was found to be critical to AD risk. Among the low SE group, increased AD risks were found in NHPIs compared to Asians for all conditions selected and compared to whites for HF, IHD, and stroke. Interestingly, these observations were found reversed in the higher SE group, showing reduced AD risks for NHPIs compared to whites for AF, HF, and IHD, and to Asians for HF and IHD. Conclusions: NHPIs with poor SE status seems to be mostly disadvantaged by the heart/stroke and AD association compared to corresponding whites and Asians.

Perceived Barriers and Benefits of COVID-19 Testing among Pacific Islanders on Guam.

Pacific Islanders residing in the U.S. Affiliated Pacific Islands have had among the highest COVID-19-associated morbidity and mortality rates in the U.S. To reduce this disparity, we conducted a study to increase the reach and uptake of COVID-19 testing in Guam. Participants, who completed a pre-survey on demographics, health status, history of COVID-19 testing and vaccination, access to COVID-19 testing, sources of COVID-19 information, and knowledge and attitudes towards COVID-19 test results and transmission, were invited to attend an online educational session about COVID-19 testing and transmission and to complete a post-survey. There were significant positive changes between pre- and post-survey in knowledge and perceptions about COVID-19 testing and transmission, but changes were not necessarily due to exposure to the educational session. Compared to CHamoru participants (n = 380), Other Micronesians (n = 90) were significantly less knowledgeable about COVID-19 transmission and testing, were significantly more likely to not want to know if they had COVID-19, were more likely to believe if they did have COVID-19 there was not much that could be done for them, and that they would have difficulty in getting the needed healthcare. This study is another example of disparities in health knowledge and perceptions of certain Pacific Islander groups.

Impact of antiretroviral therapy intensification with C-C motif chemokine receptor 5 antagonist maraviroc on HIV-associated neurocognitive impairment.

OBJECTIVES: Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute to neuro-inflammation. The CCR5 antagonist maraviroc (MVC) has been suggested to improve HIV-associated neurocognitive impairment (NCI). DESIGN: A double-blind, placebo-controlled, 48-week, randomized study of MVC vs. placebo in people with HIV (PWH) on stable antiretroviral therapy (ART) for more than one year in Hawaii and Puerto Rico with plasma HIV RNA less than 50 copies/ml and at least mild NCI defined as an overall or domain-specific neuropsychological z (NPZ) score less than -0.5. METHODS: Study participants were randomized 2 : 1 to intensification of ART with MVC vs. placebo. The primary endpoint was change in global and domain-specific NPZ modeled from study entry to week 48. Covariate adjusted treatment comparisons of average changes in cognitive outcome were performed using winsorized NPZ data. Monocyte subset frequencies and chemokine expression as well as plasma biomarker levels were assessed. RESULTS: Forty-nine participants were enrolled with 32 individuals randomized to MVC intensification and 17 to placebo. At baseline, worse NPZ scores were seen in the MVC arm. Comparison of 48-week NPZ change by arm revealed no differences except for a modest improvement in the Learning and Memory domain in the MVC arm, which did not survive multiplicity correction. No significant changes between arms were seen in immunologic parameters. CONCLUSION: This randomized controlled study found no definitive evidence in favor of MVC intensification among PWH with mild cognitive difficulties.

Increased transmigration of intermediate monocytes associated with atherosclerotic burden in people with HIV on antiretroviral therapy.

This study evaluated the association between the transmigration of monocyte subpopulations that contributes to atherosclerosis development, along with surrogate biomarkers of inflammation and atherosclerosis, through carotid intima-media thickness (cIMT) measurements of 72 people with HIV (PWH) on suppressive antiretroviral therapy (ART). We found that the transmigration of intermediate monocytes was positively correlated with D-dimer and cIMT, suggesting that intermediate monocytes may have a greater propensity to promote cardiovascular disease (CVD) in PWH on ART.

Limited English Proficiency, Postoperative Complications, and Interpreter Use in Vascular Surgery Patients in Hawai'i.

A retrospective cohort analysis of inpatient and outpatient vascular surgery cases from 2014 to 2018 was conducted to analyze the relationship between limited English proficiency (LEP) and undesirable postoperative outcomes, and to evaluate interpreter use as part of culturally and linguistically appropriate services (CLAS). Propensity score matching and logistic regression models were used to examine the association of English proficiency with postoperative outcomes and chart review was done to examine CLAS provision. Of the 959 cases, 57 (6%) were LEP and had noticeably worse health status before surgery than non-LEP. The 57 cases include 51 patients who had a single vascular surgery and 3 patients who had 2 vascular surgeries (different medical encounter/visit). There was no statistically significant difference in postoperative outcomes between patients with LEP and without LEP. Males with LEP were significantly less likely than females to receive CLAS (P=.008). On the day of vascular surgery and/or the day informed surgical consent was obtained, 16% of patients with LEP received access to interpreters; 25% had no documentation about interpreter provision, and 59% had mixed language access (family, staff, or interpreter). The provision of interpreters might be influenced by providers' perceived ability to communicate with patients with LEP without an interpreter, ease of obtaining an interpreter, availability of family or ad-hoc interpreters, and patients' preferences. Future research should examine reasons for frequent use of untrained individuals and inform strategies to implement language services in line with national standards.

Optimal Personalized Treatment Selection with Multivariate Outcome Measures in a Multiple Treatment Case.

In this work we propose a novel method for individualized treatment selection when there are correlated multiple treatment responses. For the K treatment (K ≥ 2) scenario, we compare quantities that are suitable indexes based on outcome variables for each treatment conditional on patient-specific scores constructed from collected covariate measurements. Our method covers any number of treatments and outcome variables, and it can be applied for a broad set of models. The proposed method uses a rank aggregation technique that takes into account possible correlations among ranked lists to estimate an ordering of treatments based on treatment performance measures such as the smooth conditional mean. The method has the flexibility to incorporate patient and clinician preferences into the optimal treatment decision on an individual case basis. A simulation study demonstrates the performance of the proposed method in finite samples. We also present data analyses using HIV clinical trial data to show the applicability of the proposed procedure for real data.

Characterization of the primary antibody response to Plasmodium falciparum antigens in infants living in a malaria-endemic area.

BACKGROUND: The primary antibody (Ab) response to Plasmodium falciparum is a critical step in developing immunity to malaria. Information on the initial Ab responses of babies in malaria-endemic areas is incomplete, in part, because babies receive maternal IgG via transplacental-transfer and usually become infected before maternal IgG wanes. The study aimed to identify the primary IgM and IgG Ab responses to malarial antigens in Cameroonian babies. METHODS: Infants (n = 70) living in a high malaria transmission area were followed from birth throughout the first year of life (mean 341 ± 42 days, an average of 8.5 time points per infant). Malaria infection was assessed by microscopy and PCR, and IgM and IgG antibodies (Abs) were measured using a multiplex immunoassay to AMA1, EBA-175, MSP1-42, MSP2, MSP3, RESA, LSA1, and CSP. RESULTS: The half-life of maternal IgG varied among the antigens, ranging from 0.7 to 2.5 months. The first infection of 41% of the babies was sub-microscopic and only 11 to 44% of the babies produced IgM to the above antigens; however, when the first infection was detected by microscopy, 59-82% of the infants made IgM Abs to the antigens. Infants were able to produce IgM even when maternal IgG was present, suggesting maternal Abs did not suppress the baby's initial Ab response. Using longitudinal regression models that incorporated time-varying covariates, infants were found to produce IgG Ab to only AMA-1 when the first infection was sub-microscopic, but they produced IgG Abs to MSP1-42 (3D7, FVO), AMA1 (3D7, FVO) MSP2-FC27, MSP3, RESA, and LSA1, but not MSP 2-3D7, EBA-175, and CSP during their first slide-positive infection. Notably, the primary and secondary IgG responses were short-lived with little evidence of boosting. CONCLUSIONS: The primary Ab response of babies who had maternal IgG was similar to that reported for primary infections in malaria-naïve adults.

Quantiles based personalized treatment selection for multivariate outcomes and multiple treatments.

In this work, we propose a method for individualized treatment selection when there are correlated multiple responses for the K treatment ( K≥2 ) scenario. Here we use ranks of quantiles of outcome variables for each treatment conditional on patient-specific scores constructed from collected covariate measurements. Our method covers any number of treatments and outcome variables using any number of quantiles and it can be applied for a broad set of models. We propose a rank aggregation technique for combining several lists of ranks where both these lists and elements within each list can be correlated. The method has the flexibility to incorporate patient and clinician preferences into the optimal treatment decision on an individual case basis. A simulation study demonstrates the performance of the proposed method in finite samples. We also present illustrations using two different datasets from diabetes and HIV-1 clinical trials to show the applicability of the proposed procedure for real data.

Quality Improvement Projects as Training Tools for Family Medicine Residents and Faculty.

Quality improvement (QI) is part of the future of medicine. However, QI concepts are often poorly understood by physicians. Although teaching QI is required in resident training, an effective QI curriculum is difficult to design due to competing demands from clinic schedules and required rotations. The objective of this project was to teach family medicine residents the basic concepts of QI and practical implementation skills based on use of a clinic population, electronic medical record (EMR) system, and Plan-Do-Study-Act (PDSA) cycles. To do this, the Family Medicine residents and faculty at the University of Hawai`i participated in a QI curriculum to improve diabetes care from October 2018 to February 2019 with 5 sessions consisting of lectures, videos, discussions about QI data for diabetes patients, and group activities. Residents and faculty used quality measures pulled from the EMR and PDSA cycles to discuss, select, and implement QI projects for diabetes patients. Pre- and post-tests measured participants' baseline and end QI knowledge and skills. All 18 residents and 12 faculty in the program participated in the curriculum. The pre- and post-test comparisons showed significant improvement in knowledge of QI concepts and the comfort level among residents showing a 59% average improvement in knowledge questions and a 57% average improvement in comfort level in implementing a QI project (Table 4). This study shows that a 5-session QI curriculum based on EMR and PDSA cycles successfully increased family medicine residents' and faculty's knowledge of QI concepts and skills.

Multi-Response Based Personalized Treatment Selection with Data from Crossover Designs for Multiple Treatments.

In this work we propose a novel method for treatment selection based on individual covariate information when the treatment response is multivariate and data are available from a crossover design. Our method covers any number of treatments and it can be applied for a broad set of models. The proposed method uses a rank aggregation technique to estimate an ordering of treatments based on ranked lists of treatment performance measures such as smooth conditional means and conditional probability of a response for one treatment dominating others. An empirical study demonstrates the performance of the proposed method in finite samples.

Immunologic Change over 72 Weeks Following Raltegravir- Versus Efavirenz-Based Therapy in HIV/HCV-Coinfected Individuals in Vietnam.

The impact of HIV antiretroviral therapy (ART) on immune dysregulation associated with hepatitis C virus (HCV)/HIV coinfection is incompletely understood. We serially assessed monocyte activation (neopterin, sCD14, and sCD163) and T cell activation (HLA-DR, CD38) and immune exhaustion [program cell death protein 1 (PD1), TIGIT] in HIV/HCV-coinfected individuals who participated in a randomized trial performed in Vietnam designed to assess the hepatotoxicity of raltegravir (RAL)- versus efavirenz (EFV)-based therapy when used as first-time ART in combination with tenofovir disoproxil fumarate and emtricitabine. Baseline pre-ART values were compared with those from ART-naive HIV-monoinfected and HIV-seronegative individuals. Before ART, HIV/HCV-coinfected individuals had higher levels of neopterin, sCD14, and sCD163, and increased frequencies of CD38+HLA-DR+, PD1+, and TIGIT+ CD4 and CD8 T cells compared with ART-naive HIV-monoinfected or HIV-seronegative individuals (all p < .01). Most parameters did not normalize despite 72 weeks of ART. In particular sCD163 persisted at high levels. Improvement over 72 weeks in fibrosis as assessed by FibroScan® correlated with reductions in plasma sCD163 and in the frequencies of T cell activation, single PD1+, TIGIT+, and dual PD1+TIGIT+ CD8 T cells. A nonsignificant tendency toward more favorable effects on monocyte and T cell immune activation and on T cell exhaustion were seen with RAL-compared with EFV-based therapy. The initiation of ART in HIV/HCV-coinfected individuals is associated with incomplete improvement in monocyte and T cell immune activation and exhaustion, which was associated with some corresponding improvement in liver fibrosis.

Correction: Mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells is decreased in chronic HIV and correlates with immune dysregulation.

[This corrects the article DOI: 10.1371/journal.pone.0231761.].

Racial/ethnic differences in health-related quality of life among Hawaii adult population.

BACKGROUND: This study examined racial/ethnic differences in health-related quality of life (HRQOL) among adults and identified variables associated with HRQOL by race/ethnicity. METHODS: This study was conducted under a cross-sectional design. We used the 2011-2016 Hawaii Behavioral Risk Factor Surveillance System data. HRQOL were assessed by four measures: self-rated general health, physically unhealthy days, mentally unhealthy days, and days with activity limitation. Distress was defined as fair/poor for general health and 14 days or more for each of the other three HRQOL measures. We conducted multivariable logistic regressions with variables guided by Anderson's behavioral model on each distress measure by race/ethnicity. RESULTS: Among Hawaii adults, 30.4% were White, 20.9% Japanese, 16.8% Filipino, 14.6% Native Hawaiian and Pacific Islander (NHPI), 5.9% Chinese, 5.2% Hispanics, and 6.2% Other. We found significant racial/ethnic differences in the HRQOL measures. Compared to Whites, Filipinos, Japanese, NHPIs, and Hispanics showed higher distress rates in general health, while Filipinos and Japanese showed lower distress rates in the other HRQOL measures. Although no variables were consistently associated with all four HRQOL measures across all racial/ethnic groups, history of diabetes were significantly associated with general health across all racial/ethnic groups and history of depression was associated with at least three of the HRQOL measure across all racial/ethnic groups. CONCLUSIONS: This study contributes to the literature on disparities in HRQOL and its association with other variables among diverse racial/ethnic subgroups. Knowing the common factors for HRQOL across different racial/ethnic groups and factors specific to different racial/ethnic groups will provide valuable information for identifying future public health priorities to improve quality of life and reduce health disparities.

Short Communication: Carotid Artery Plaque Burden in HIV Is Associated with Soluble Mediators and Monocytes.

Maximum carotid plaque thickness (MCPT) measures the largest plaque thickness in the carotid artery and reflects atherosclerosis plaque burden. MCPT may be a better predictor of cardiovascular disease than carotid artery intima-media thickness (cIMT) because it identifies potential unstable arterial atherosclerosis plaques. We assessed the relationships of monocyte and T cell populations and plasma soluble mediators with MCPT measures. We performed a cross-sectional and small follow-up analysis in people living with HIV (PLWH) aged >40 years on stable antiretroviral therapy (ART) >6 months. MCPT was acquired by high-resolution B-mode ultrasound. Existing monocyte subsets and T cell activation frequencies were determined by flow cytometry and plasma mediators of inflammation and apolipoproteins were measured by Luminex assay. One hundred twenty-five ART-treated PLWH, 88% male, 55% Caucasian, with a median age of 51 years, median CD4 count of 477 cells/µL (Q1: 325, Q3: 612), 84% undetectable plasma HIV RNA (<50 copies/mL). Twenty-five PLWH had detectable carotid plaque. MCPT correlated with monocyte chemoattractant protein-1 (MCP-1; r = 0.487, p = .016), tumor necrosis factor-α (TNF-α; r = 0.474 p = .019), soluble vascular cell adhesion molecule-1 (sVCAM-1; r = 0.472, p = .020), apolipoprotein B6 (ApoB6; r = -0.473, p = .019), and interleukin-6 (IL-6; r = 0.455, p = .025). In a multivariable regression model, MCP-1, TNF-α, and sVCAM-1 remained significant after adjustment for age. Carotid plaque burden was associated with increased inflammatory, monocyte, and endothelial measures, including MCP-1, TNF-α, and sVCAM-1 levels. Further investigation on the evolution or severity of plaque burden in this population is warranted.

Personalized treatment plans with multivariate outcomes.

In this work, we propose a novel method for individualized treatment selection when the treatment response is multivariate. Our method covers any number of treatments and it can be applied for a broad set of models. The proposed method uses a Mahalanobis-type distance measure to establish an ordering of treatments based on treatment performance measures. Our investigation in this work deals with means of responses conditional on lower dimensional composite scores based on covariates where these scores are built using single index models to approximate mean responses against patient covariates. Smoothed estimates of such conditional means are combined to construct an estimate of the aforementioned distance measure, which is then used to estimate the optimal treatment. An empirical study demonstrates the performance of the proposed method in finite samples. We also present a data analysis using an HIV clinical trial data to show the applicability of the proposed procedure for real data.

Mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells is decreased in chronic HIV and correlates with immune dysregulation.

BACKGROUND: Cellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation. METHODS: PLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels. RESULTS: PLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA <50 copies/mL (84.6%). Median CI level was lower in PLWH compared with the HIV-seronegative group (65.5 vs 155.0 optical density/µg protein x 103, p <0.0001). There was no significant difference in median CIV levels. Lower OXPHOS levels correlated with lower CD4% and CD4/CD8 ratio. On multivariable linear regression adjusted for age, current use of zidovudine/didanosine, and HIV RNA (detectable versus undetectable), lower OXPHOS levels were significantly associated with higher MPO, SAA, SAP, and sVCAM, and higher frequencies of intermediate (CD14++CD16+) monocytes and TIGIT+TIM3+ CD4 T-cell (p<0.01). CONCLUSION: CI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted.