Intensive blood pressure (BP) treatment can avert cardiovascular disease (CVD) events but can cause some serious adverse events. We sought to develop and validate risk models for predicting absolute ...risk difference (increased risk or decreased risk) for CVD events and serious adverse events from intensive BP therapy. A secondary aim was to test if the statistical method of elastic net regularization would improve the estimation of risk models for predicting absolute risk difference, as compared to a traditional backwards variable selection approach.
Cox models were derived from SPRINT trial data and validated on ACCORD-BP trial data to estimate risk of CVD events and serious adverse events; the models included terms for intensive BP treatment and heterogeneous response to intensive treatment. The Cox models were then used to estimate the absolute reduction in probability of CVD events (benefit) and absolute increase in probability of serious adverse events (harm) for each individual from intensive treatment. We compared the method of elastic net regularization, which uses repeated internal cross-validation to select variables and estimate coefficients in the presence of collinearity, to a traditional backwards variable selection approach. Data from 9,069 SPRINT participants with complete data on covariates were utilized for model development, and data from 4,498 ACCORD-BP participants with complete data were utilized for model validation. Participants were exposed to intensive (goal systolic pressure < 120 mm Hg) versus standard (<140 mm Hg) treatment. Two composite primary outcome measures were evaluated: (i) CVD events/deaths (myocardial infarction, acute coronary syndrome, stroke, congestive heart failure, or CVD death), and (ii) serious adverse events (hypotension, syncope, electrolyte abnormalities, bradycardia, or acute kidney injury/failure). The model for CVD chosen through elastic net regularization included interaction terms suggesting that older age, black race, higher diastolic BP, and higher lipids were associated with greater CVD risk reduction benefits from intensive treatment, while current smoking was associated with fewer benefits. The model for serious adverse events chosen through elastic net regularization suggested that male sex, current smoking, statin use, elevated creatinine, and higher lipids were associated with greater risk of serious adverse events from intensive treatment. SPRINT participants in the highest predicted benefit subgroup had a number needed to treat (NNT) of 24 to prevent 1 CVD event/death over 5 years (absolute risk reduction ARR = 0.042, 95% CI: 0.018, 0.066; P = 0.001), those in the middle predicted benefit subgroup had a NNT of 76 (ARR = 0.013, 95% CI: -0.0001, 0.026; P = 0.053), and those in the lowest subgroup had no significant risk reduction (ARR = 0.006, 95% CI: -0.007, 0.018; P = 0.71). Those in the highest predicted harm subgroup had a number needed to harm (NNH) of 27 to induce 1 serious adverse event (absolute risk increase ARI = 0.038, 95% CI: 0.014, 0.061; P = 0.002), those in the middle predicted harm subgroup had a NNH of 41 (ARI = 0.025, 95% CI: 0.012, 0.038; P < 0.001), and those in the lowest subgroup had no significant risk increase (ARI = -0.007, 95% CI: -0.043, 0.030; P = 0.72). In ACCORD-BP, participants in the highest subgroup of predicted benefit had significant absolute CVD risk reduction, but the overall ACCORD-BP participant sample was skewed towards participants with less predicted benefit and more predicted risk than in SPRINT. The models chosen through traditional backwards selection had similar ability to identify absolute risk difference for CVD as the elastic net models, but poorer ability to correctly identify absolute risk difference for serious adverse events. A key limitation of the analysis is the limited sample size of the ACCORD-BP trial, which expanded confidence intervals for ARI among persons with type 2 diabetes. Additionally, it is not possible to mechanistically explain the physiological relationships explaining the heterogeneous treatment effects captured by the models, since the study was an observational secondary data analysis.
We found that predictive models could help identify subgroups of participants in both SPRINT and ACCORD-BP who had lower versus higher ARRs in CVD events/deaths with intensive BP treatment, and participants who had lower versus higher ARIs in serious adverse events.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Heterogeneous treatment effects (HTEs), or systematic differences in treatment effectiveness among participants with different observable features, may be important when applying trial results to ...clinical practice. Current methods suffer from a potential for false detection of HTEs due to imbalances in covariates between candidate subgroups.
We introduce a new method, matching plus classification and regression trees (mCART), that yields balance in covariates in identified HTE subgroups. We compared mCART to a classical method (logistic regression LR with backwards covariate selection using the Akaike information criterion ) and two machine-learning approaches increasingly applied to HTE detection (random forest RF and gradient RF) in simulations with a binary outcome with known HTE subgroups. We considered an N = 200 phase II oncology trial where there were either no HTEs (1A) or two HTE subgroups (1B) and an N = 6000 phase III cardiovascular disease trial where there were either no HTEs (2A) or four HTE subgroups (2B). Additionally, we considered an N = 6000 phase III cardiovascular disease trial where there was no average treatment effect but there were four HTE subgroups (2C).
In simulations 1A and 2A (no HTEs), mCART did not identify any HTE subgroups, whereas LR found 2 and 448, RF 5 and 2, and gradient RF 5 and 24, respectively (all false positives). In simulation 1B, mCART failed to identify the two true HTE subgroups whereas LR found 4, RF 6, and gradient RF 10 (half or more of which were false positives). In simulations 2B and 2C, mCART captured the four true HTE subgroups, whereas the other methods found only false positives. All HTE subgroups identified by mCART had acceptable treated vs. control covariate balance with absolute standardized differences less than 0.2, whereas the absolute standardized differences for the other methods typically exceeded 0.2. The imbalance in covariates in identified subgroups for LR, RF, and gradient RF indicates the false HTE detection may have been due to confounding.
Covariate imbalances may be producing false positives in subgroup analyses. mCART could be a useful tool to help prevent the false discovery of HTE subgroups in secondary analyses of randomized trial data.
Tumor-infiltrating lymphocytes (TIL) in pretreatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte ...counts are associated with lower breast cancer-specific mortality (BCM) and overall mortality (OM) in TNBC.
Data on treatments and diagnostic tests from electronic medical records of two health care systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline
mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM, and OM. For a subgroup with TIL data available, we explored the relationship between TILs and peripheral lymphocyte counts.
A total of 1,463 stage I-III TNBC patients were diagnosed from 2000 to 2014; 1,113 (76%) received neoadjuvant/adjuvant chemotherapy within 1 year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/μL). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM HR = 0.23; 95% confidence interval (CI), 0.16-0.35 and BCM (HR = 0.19; CI, 0.11-0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (
= 70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy.
Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment.
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Near-Far Matching in R: The nearfar Package Rigdon, Joseph; Baiocchi, Michael; Basu, Sanjay
Journal of statistical software,
2018, Letnik:
86, Številka:
CS-5
Journal Article
Recenzirano
Odprti dostop
Estimating the causal treatment effect of an intervention using observational data is difficult due to unmeasured confounders. Many analysts use instrumental variables (IVs) to introduce a ...randomizing element to observational data analysis, potentially reducing bias created by unobserved confounders. Several persistent problems in the field have served as limitations to IV analyses, particularly the prevalence of "weak" IVs, or instrumental variables that do not effectively randomize individuals to the intervention or control group (leading to biased and unstable treatment effect estimates), as well as IV-based estimates being highly model dependent, requiring parametric adjustment for measured confounders, and often having high mean squared errors in the estimated causal effects. To overcome these problems, the study design method of "near-far matching" has been devised, which "filters" data from a cohort by simultaneously matching individuals within the cohort to be "near" (similar) on measured confounders and "far" (different) on levels of an IV. To facilitate the application of near-far matching to analytical problems, we introduce the R package
and illustrate its application to both a classical example and a simulated dataset. We illustrate how the package can be used to "strengthen" a weak IV by adjusting the "near-ness" and "far-ness" of a match, reduce model dependency, enable nonparametric adjustment for measured confounders, and lower mean squared error in estimated causal effects. We additionally illustrate how to utilize the
package when analyzing either continuous or binary treatments, how to prioritize variables in the match, and how to calculate
statistics of IV strength with or without adjustment for measured confounders.
•The contribution of POPs to type 1 diabetes (T1D) remains poorly known.•We investigated the link between POPs and T1D in youth and the effects of POPs on β-cell.•p,p’-DDE, p,p’-DDT, trans-nonachlor, ...and PCB-153 were associated with T1D with normal insulin sensitivity.•p,p’-DDE and PCB-153 cause dysfunction and destruction of β-cells in vitro.•Our findings suggest that POPs may play a role in T1D.
Diabetes affects millions of people worldwide with a continued increase in incidence occurring within the pediatric population. The potential contribution of persistent organic pollutants (POPs) to diabetes in youth remains poorly known, especially regarding type 1 diabetes (T1D), generally the most prevalent form of diabetes in youth.
We investigated the associations between POPs and T1D in youth and studied the impacts of POPs on pancreatic β-cell function and viability in vitro.
We used data and plasma samples from the SEARCH for Diabetes in Youth Case Control Study (SEARCH-CC). Participants were categorized as Controls, T1D with normal insulin sensitivity (T1D/IS), and T1D with insulin resistance (T1D/IR). We assessed plasma concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides and estimated the odds of T1D through multivariable logistic regression. In addition, we performed in vitro experiments with the INS-1E pancreatic β-cells. Cells were treated with PCB-153 or p,p’-DDE at environmentally relevant doses. We measured insulin production and secretion and assessed the mRNA expression of key regulators involved in insulin synthesis (Ins1, Ins2, Pdx1, Mafa, Pcsk1/3, and Pcsk2), glucose sensing (Slc2a2 and Gck), and insulin secretion (Abcc8, Kcnj11, Cacna1d, Cacna1b, Stx1a, Snap25, and Sytl4). Finally, we assessed the effects of PCB-153 and p,p’-DDE on β-cell viability.
Among 442 youths, 112 were controls, 182 were classified with T1D/IS and 148 with T1D/IR. The odds ratios (OR) of T1D/IS versus controls were statistically significant for p,p’-DDE (OR 2.0, 95% confidence interval (CI) 1.0, 3.8 and 2.4, 95% CI 1.2, 5.0 for 2nd and 3rd tertiles, respectively), trans-nonachlor (OR 2.5, 95% CI 1.3, 5.0 and OR 2.3, 95% CI 1.1, 5.1 for 2nd and 3rd tertiles, respectively), and PCB-153 (OR 2.3, 95% CI 1.1, 4.6 for 3rd tertile). However, these associations were not observed in participants with T1D/IR. At an experimental level, treatment with p,p’-DDE or PCB-153, at concentrations ranging from 1 × 10-15 M to 5 × 10-6 M, impaired the ability of pancreatic β-cells to produce and secrete insulin in response to glucose. These failures were paralleled by impaired Ins1 and Ins2 mRNA expression. In addition, among different targeted genes, PCB-153 significantly reduced Slc2a2 and Gck mRNA expression whereas p,p’-DDE mainly affected Abcc8 and Kcnj11. While treatment with PCB-153 or p,p’-DDE for 2 days did not affect β-cell viability, longer treatment progressively killed the β-cells.
These results support a potential role of POPs in T1D etiology and demonstrate a high sensitivity of pancreatic β-cells to POPs.
Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation that often manifests as Epstein‐Barr virus (EBV)‐associated B cell lymphomas. Current treatments ...for PTLD have limited efficacy and can be associated with graft rejection or systemic toxicities. The mTOR inhibitor, rapamycin, suppresses tumor growth of EBV+ B cell lymphoma cells in vitro and in vivo; however, the efficacy is limited and clinical benefits of mTOR inhibitors for PTLD are variable. Here, we show constitutive activation of multiple nodes within the PI3K/Akt/mTOR pathway in EBV+ PTLD‐derived cell lines. Inhibition of either PI3K or Akt, with specific inhibitors CAL‐101 and MK‐2206, respectively, diminished growth of EBV+ B cell lines from PTLD patients in a dose‐dependent manner. Importantly, rapamycin combined with CAL‐101 or MK‐2206 had a synergistic effect in suppressing cell growth as determined by IC50 isobolographic analysis and Loewe indices. Moreover, these combinations were significantly more effective than rapamycin alone in inhibiting tumor xenograft growth in NOD‐SCID mice. Finally, both CAL‐101 and MK‐2206 also prolonged survival of heterotopic cardiac allografts in C57BL/6 mice. Thus, combination therapy with rapamycin and a PI3K inhibitor, or an Akt inhibitor, can be an efficacious treatment for EBV‐associated PTLD, while simultaneously promoting allograft survival.
Inhibitors of PI3K and Akt synergize with the mTOR inhibitor rapamycin to suppress growth of posttransplant Epstein‐Barr virus B cell lymphomas in vitro and in vivo, and promote allograft survival.
Diabetes affects multiple systems in complex manners. Diabetic foot ulcers (DFUs) are a result of diabetes‐induced microarterial vessel disease and peripheral neuropathy. The presence of ...arteriosclerosis‐induced macroarterial disease can further complicate DFU pathophysiology. Recent studies suggest that mesenchymal stromal cell therapies can enhance tissue regeneration. This phase I study was designed to determine the safety and explore the efficacy of local injections of autologous adipose‐derived stromal vascular fraction (SVF) cells to treat nonhealing DFUs greater than 3 cm in diameter. Sixty‐three patients with type 2 diabetes with chronic DFU—all amputation candidates—were treated with 30 × 106 SVF cells injected in the ulcer bed and periphery and along the pedal arteries. Patients were seen at 6 and 12 months to evaluate ulcer closure. Doppler ultrasounds were performed in a subset of subjects to determine vascular structural parameters. No intervention‐related serious adverse events were reported. At 6 months, 51 subjects had 100% DFU closure, and 8 subjects had ≥75% closure. Three subjects had early amputations, and one subject died. At 12 months, 50 subjects had 100% DFU healing and 4 subjects had ≥85% healing. Five subjects died between the 6‐ and 12‐month follow‐up visits. No deaths were intervention related. Doppler studies in 11 subjects revealed increases in peak systolic velocity and pulsatility index in 33 of 33 arteries, consistent with enhanced distal arterial runoff. These results indicate that SVF can be safely used to treat chronic DFU, with evidence of efficacy (wound healing) and mechanisms of action that include vascular repair and/or angiogenesis.
Experimental design and outcomes.
It is important for physicians to learn how to provide culturally sensitive care. Cultural humility is defined as a lifelong process with a goal of fixing power imbalances and creating institutional ...accountability through learning about another's culture as well as performing self-exploration about one's own beliefs, identities, and biases. One way to teach cultural humility in medicine is simulation. However, there are no peer-reviewed published studies that examine whether the skin tone or gender of the high-fidelity simulation manikins (HFSM) used by emergency medicine (EM) residency programs reflects the US population nor whether high-fidelity simulation is used to teach cultural humility. We aimed to address that gap in the literature. Our primary objective was to evaluate what proportion of EM residency programs use HFS to teach cultural humility. Our secondary objective was to evaluate whether the skin tone and gender breakdown of the EM residency program HFSM is representative of the US population.
We conducted a simple random sample of 80 EM residency programs to characterize HFSM and cultural humility training. Selected programs were emailed a questionnaire. Key outcomes included HFSM skin tone and gender and whether cultural humility was taught via HFSM. We calculated point and interval estimates for the proportion of dark-, medium-, and light-toned skin and the proportion of female and male manikins. Confidence intervals were employed to test the null hypothesis that dark/medium/light skin tone was 20/20/60 and that the female/male ratio was 50/50. Both ratios were extrapolated from the US Census data.
Our response rate was 74% (59/80). Fifty-five of 59 EM residency programs that had manikins (0.93, 95% confidence interval CI 0.88-0.99) reported data on a total of 348 manikins. Thirty-nine of the 55 programs with manikins reported using HFS to teach cultural humility (0.71, 95% CI 0.60-0.82). Proportions of light-, medium-, and dark-toned manikins were 0.52 (0.43-0.62), 0.38 (0.29-0.47), and 0.10 (0.07-0.14), respectively. Proportions of male and female HFSM were 0.69 (0.64-0.76) and 0.31 (0.24-0.36), respectively. The null hypotheses that skin tone follows a 60/20/20 split and gender follows a 50/50 split were rejected, as not all confidence intervals contained these hypothesized values.
While most EM residency programs surveyed use high-fidelity simulation to teach cultural humility, the manikins do not reflect either the skin tone or gender of the US population.
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