Variable-Dependent Partial Dimension Reduction

Sufficient dimension reduction reduces the dimension of a regression model without loss of information by replacing the original predictor with its lower-dimensional linear combinations. Partial (sufficient) dimension reduction arises when the predictors naturally fall into two sets X and W, and pursues a partial dimension reduction of X. Though partial dimension reduction is a very general problem, only very few research results are available when W is continuous. To the best of our knowledge, none can deal with the situation where the reduced lower-dimensional subspace of X varies with W. To address such issue, we in this paper propose a novel variable-dependent partial dimension reduction framework and adapt classical sufficient dimension reduction methods into this general paradigm. The asymptotic consistency of our method is investigated. Extensive numerical studies and real data analysis show that our variable-dependent partial dimension reduction method has superior performance compared to the existing methods

Variable-Dependent Partial Dimension Reduction

Sufficient dimension reduction reduces the dimension of a regression model without loss of information by replacing the original predictor with its lower-dimensional linear combinations. Partial (sufficient) dimension reduction arises when the predictors naturally fall into two sets X and W, and pursues a partial dimension reduction of X. Though partial dimension reduction is a very general problem, only very few research results are available when W is continuous. To the best of our knowledge, none can deal with the situation where the reduced lower-dimensional subspace of X varies with W. To address such issue, we in this paper propose a novel variable-dependent partial dimension reduction framework and adapt classical sufficient dimension reduction methods into this general paradigm. The asymptotic consistency of our method is investigated. Extensive numerical studies and real data analysis show that our variable-dependent partial dimension reduction method has superior performance compared to the existing methods

Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P \u3c 0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity. Antineoplastic, antiviral, analgesic, antibiotic, and antimycobacterial drugs were the top 5 drug classes with the highest ROR values. Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms, the top 4 drugs (ROR values \u3e18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P \u3c 0.0001), suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity. Univariate logistic regression analysis showed that reports of liver injury were 2.2 (odds ratio: 2.2, 95% CI 2.12–2.26) times more likely to be associated with older patient age, as compared with reports involving patients less than 65 years of age. Compared to males, female patients were 37% less likely (odds ratio: 0.63, 95% CI 0.61–0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms. Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity, it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives, more clinically relevant animal models, and better clinical biomarkers may provide a better translation of drug-induced mitochondrial toxicity risk assessment from animals to humans. Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI, and this should be further investigated in real-world studies with robust designs

Association of Baseline Viral Serology and Sirolimus Regimens With Kidney Transplant Outcomes

Background: The risks for transplant outcomes associated with baseline viral serostatus in kidney transplant recipients (KTR) on sirolimus have not been widely studied. Methods: We performed a cohort-study of 61 590 adult KTR in 2000 to 2013. We used Cox regression models to determine the adjusted hazard ratio (aHR) of patient death, death-censored graft loss and posttransplant malignancy associated with the baseline serostatus (+ or −: hepatitis B core [HBc], hepatitis C virus [HCV], Epstein-Barr virus [EBV], or cytomegalovirus [CMV]) in KTR on sirolimus (SRL) + mycophenolate (MPA) or SRL + tacrolimus (Tac), relative to the control-regimen: Tac + MPA. Results: Compared with Tac + MPA, SRL + MPA, and SRL + Tac were associated with higher risks of 5-year mortality (aHR, 1.41; 95% CI, 1.23-1.60 and aHR, 1.59; 95% CI, 1.38-1.83, respectively) and death-censored graft loss (aHR, 1.41; 95% CI, 1.24-1.60 and aHR, 1.38; 95% CI, 1.21-1.57, respectively). In KTR with negative pretransplant EBV, CMV, HBc, or HCV serostatus, SRL + MPA not SRL + Tac was associated with a lower risk of posttransplant malignancy compared with control (aHR, 0.27; 95% CI, 0.10-0.72; aHR, 0.61; 95% CI, 0.43-0.88; aHR, 0.79; 95% CI, 0.64-0.97; and aHR, 0.80; 95% CI, 0.65-0.98, respectively, for SRL + MPA and aHR, 0.98: 95% CI, 0.52-1.80; aHR, 0.69; 95% CI, 0.46-1.06; aHR, 0.83; 95% CI, 0.66-1.06 and aHR, 0.85; 95% CI, 0.67-1.07, respectively, for SRL + Tac). In KTR with positive serostatus to any of the above viruses, SRL + MPA or SRL + Tac was not associated with a different malignancy risk compared with control. Conclusions: Compared with Tac + MPA, SRL regimens were associated with higher risks for patient death and graft loss, although SRL + MPA was associated with a lower risk for posttransplant malignancy in kidney allograft recipients with negative pretransplant HBc, HCV, EBV, or CMV serology

Outcomes in Human Immunodeficiency Virus Infected Recipients of Heart and Lung Transplants

Background: With the advent of combined antiretroviral therapy (cART), growing evidence has shown human immunodeficiency virus (HIV) may no longer be an absolute contraindication for solid organ transplantation. This study compares outcomes of heart transplantations between HIV‐positive and HIV‐negative recipients using SRTR transplant registry data. Methods: Patient survival, overall graft survival and death‐censored graft survival were compared between HIV‐positive and HIV‐negative recipients. Multivariate Cox regression and Cox regression with a disease risk score (DRS) methodology were used to estimate the adjusted hazard ratios among heart transplant recipients (HTRs). Results: In total, 35 HTRs with HIV+ status were identified. No significant differences were found in patient survival (88% vs 77%; P = 0.1493), overall graft survival (85% vs 76%; P = 0.2758), and death‐censored graft survival (91% vs 91%; P = 0.9871) between HIV‐positive and HIV‐negative HTRs in 5‐year follow‐up. No significant differences were found after adjusting for confounders. Conclusions: This study supports the use of heart transplant procedures in selected HIV‐positive patients. This study suggests that HIV‐positive status is not a contraindication for life‐saving heart transplant as there were no differences in graft, patient survival

A Claims Analysis of the Utilization of Tramadol for Acute Pain in Patients Prescribed Buprenorphine/Naloxone for Opioid Use Disorder

Objective: To determine the prevalence of tramadol prescribing among commercially insured adults receiving medication assisted therapy (MAT) with buprenorphine/naloxone. Design: We conducted a cross-sectional descriptive study to evaluate the use of tramadol among patients prescribed buprenorphine/suboxone for MAT. Setting: This study utilized data from 2010 to 2013 Optum Clinformatics Data Mart (OptumInsight, Eden Prairie, MN). This cohort is an administrative health claims database from a large national insurer. This data included pharmacy and medical care utilization and information describing patient enrollment. Patients, Participants: Patients were 12 to 64 years of age and had complete and available medical, pharmacy and administrative records in the Optum Clinformatics Data Mart during study period. Main Outcome Measures: Patients who received at least one paid claim for buprenorphine/naloxone from 2010 to 2013 and also received at least one overlapping pharmacy dispensing for tramadol were identified for analysis. We determined if the concurrent buprenorphine/naloxone and tramadol dispensings were from the same or a different prescriber. Results: In this analysis of 18,734 U.S. commercially insured patients receiving MAT with buprenorphine/naloxone, we identified 1,198 (6.4%) patients who received at least one overlapping dispensing for tramadol during a four-year period spanning 2010 through 2013. Among these patients, 266 (1.42%) were co-prescribed buprenorphine/naloxone and tramadol from the same provider. Conclusions: These results suggest that the use of tramadol among patients receiving buprenorphine/naloxone is not uncommon. Further study is warranted to further determine the benefits and risks associated with the use of tramadol for pain management among patients prescribed buprenorphine/naloxone

Comparison of Utilization and Clinical Outcomes for Belatacept- and Tacrolimus- Based Immunosuppression in Renal Transplant Recipients

The performance of belatacept in a real clinical setting has not been reported. A retrospective cohort study was conducted using registry data comparing 1-year clinical outcomes between belatacept- and tacrolimus-treated adult kidney transplant recipients (KTRs) from January 6, 2011, through January 12, 2014. Of 50 244 total patients, 417 received belatacept plus tacrolimus, 458 received belatacept alone, and 49 369 received tacrolimus alone at discharge. In the overall study cohort, belatacept alone was associated with a higher risk of 1-year acute rejection, with the highest rates associated with non–lymphocyte-depleting induction (adjusted hazard ratio 2.65, 95% confidence interval 1.90–3.70, p \u3c 0.0001). There was no significant difference in rejection rates between belatacept plus tacrolimus and tacrolimus alone. In KTRs who met inclusion criteria for the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial–Extended Criteria Donors (BENEFIT-EXT), 1-year kidney function was higher with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (mean estimated GFR 65.6, 60.4 and 54.3 mL/min per 1.73 m2, respectively; p \u3c 0.001). The incidence of new-onset diabetes after transplantation was significantly lower with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (1.7%, 2.2%, and 3.8%, respectively; p = 0.01). Despite improved graft function and metabolic complications with belatacept alone, it may be advisable to add short-term tacrolimus in the first year after transplant and to consider lymphocyte-depleting induction in patients with high rejection risk, as the risk–benefit ratio allows

Estimating the Direct Costs of Outpatient Opioid Prescriptions: A Retrospective Analysis of Data from the Rhode Island Prescription Drug Monitoring Program

Background: Overuse and misuse of prescription opioids is associated with increased morbidity and mortality, and places a significant cost burden on health systems. Objective: To estimate annual state-wide spending for prescription opioids in Rhode Island. Methods: A cross-sectional study of opioids dispensed from retail pharmacies using data from the Rhode Island (R.I.) Prescription Drug Monitoring Program (PDMP) was performed. The study sample consisted of 651,227 opioid prescriptions dispensed to 197,062 patients between January 1, 2015 to December 31, 2015. The mean, median and total cost of opioid utilization was estimated using both prescription dispensings and patients as units of analysis. A generalized linear model with gamma distribution with an identity link function and separately with a log link function were used to estimate the annual adjusted average prescription opioid cost and to examine potential predictors of total annual expenditure, respectively. Results: The estimated annual expenditure for opioid prescriptions in R.I. for 2015 was $44,271,827. The average and median cost of an opioid prescription were$67.98 (standard deviation [SD] $210.91) and$21.08 (interquartile range [IQR]: $7.65,$47.51), respectively. Prescriptions for branded opioid products accounted for $17,380,279.05, which was about 39.3% of overall spending, although only 6% of all opioids dispensed were for brand-name drugs. On average, patients aged 45-54 and 55-64 years had overall adjusted spending for opioids that were 1.53 (95% confidence interval [CI]: 1.49, 1.57) and 1.75 (95% CI: 1.71, 1.80) times higher than patients age 65 years and older, respectively. Per patient Medicaid and Medicare average annual spending for opioid prescriptions were 1.19 (95% CI: 1.16, 1.22) and 2.01 (95% CI: 1.96, 2.06) times higher than commercial insurance spending, respectively. Annual opioid prescription spending was 2.01 (95% CI: 1.98, 2.04) and 1.50 (95% CI: 1.45, 1.55) times higher among patients who also had at least one benzodiazepine or sympathomimetic stimulant dispensing, respectively. Average total spending for prescription opioids per patient increased with the average daily dosage; from 3-fold for patients using 50-90 MME daily to 22-fold for those receiving 90 or more MME daily compared to those receiving less than 50 MME daily. Conclusion: This study provides the first estimate of the state-wide direct cost burden of prescription opioid use using PDMP data and standardized pricing benchmarks. Total annual cost increased with age up to 65 years, mean daily dose, and concurrent use of benzodiazepines or stimulants. Commercial insurance bears the majority of the cost of prescription opioid use but cost per patient is highest among Medicare beneficiaries. In addition to reducing harms associated with opioid overuse and misuse, substantial cost savings could be realized by reducing unnecessary opioid utilization especially among middle aged adults

Association of Gestational Opioid Exposure and Risk of Major and Minor Congenital Malformations

Importance: The rapid increase of opioid-related overdoses and deaths has become a public health concern in the US. Use of prescription opioids in pregnant women has increased; results from teratogenicity studies remain controversial. Objective: To evaluate the association between maternal prescription opioid use (excluding opioid use disorders) during pregnancy and the incidence of congenital malformations. Design, Setting, and Participants: This retrospective population-based cohort study evaluated linked Rhode Island Medicaid claims and vital statistics data of live births from January 1, 2008, to December 31, 2016. Data analysis was conducted from May 1, 2019, to May 31, 2020. Women who had a live birth during the study period, but no cancer or opioid use disorder, were followed up from 3 months before pregnancy to the end of pregnancy. Exposures: Data on the mother’s prescription opioid exposure were obtained through pharmacy claims and exposure was defined as dispensing of at least 1 prescription opioid during the first, second, or third trimester. Main Outcomes and Measures: The primary outcome was overall major or minor congenital malformations, defined as 1 or more major or minor congenital malformation. Secondary outcomes were defined as 10 specific categories of congenital malformations classified by organ systems using International Classification of Diseases diagnosis codes. Results: Of 12 424 included pregnancies, 891 mothers (7.2%) received prescription opioids during pregnancy and 3153 infants (25.4%) were diagnosed with major or minor congenital malformations. Comparing prescription opioid exposure vs nonexposure, no excess risk was observed for major birth defects in infants with opioid exposure in trimester 1 (adjusted relative risk [aRR], 1.40; 95% CI, 0.84-2.34), and higher risks were found for overall minor birth defects in trimester 3 (aRR, 1.26; 95% CI, 1.04-1.53) and minor birth defects in the musculoskeletal system in trimester 2 (aRR, 1.50; 95% CI, 1.10-2.03) and trimester 3 (aRR, 1.65; 95% CI, 1.23-2.22). Significant dose responses in selected minor malformations and effects of specific opioids were also identified. Hydrocodone in trimester 2 (aRR, 3.01; 95% CI, 1.80-5.03) and oxycodone in trimester 3 (aRR, 2.43; 95% CI, 1.37-4.02) were associated with plagiocephaly, polydactyly, and other specified congenital deformities of the hip. Conclusions and Relevance: The findings of this study suggest a higher risk of minor congenital malformations associated with use of prenatal prescription opioids in trimester 3, which seems to be dose-dependent. Further investigation is needed to establish causality and explore the physiologic plausibility of the association