Guidance on Individualized Treatment Rule Estimation in High Dimensions

Individualized treatment rules, cornerstones of precision medicine, inform patient treatment decisions with the goal of optimizing patient outcomes. These rules are generally unknown functions of patients' pre-treatment covariates, meaning they must be estimated from clinical or observational study data. Myriad methods have been developed to learn these rules, and these procedures are demonstrably successful in traditional asymptotic settings with moderate number of covariates. The finite-sample performance of these methods in high-dimensional covariate settings, which are increasingly the norm in modern clinical trials, has not been well characterized, however. We perform a comprehensive comparison of state-of-the-art individualized treatment rule estimators, assessing performance on the basis of the estimators' accuracy, interpretability, and computational efficacy. Sixteen data-generating processes with continuous outcomes and binary treatment assignments are considered, reflecting a diversity of randomized and observational studies. We summarize our findings and provide succinct advice to practitioners needing to estimate individualized treatment rules in high dimensions. All code is made publicly available, facilitating modifications and extensions to our simulation study. A novel pre-treatment covariate filtering procedure is also proposed and is shown to improve estimators' accuracy and interpretability

A generalization of moderated statistics to data adaptive semiparametric estimation in high-dimensional biology

The widespread availability of high-dimensional biological data has made the simultaneous screening of numerous biological characteristics a central statistical problem in computational biology. While the dimensionality of such datasets continues to increase, the problem of teasing out the effects of biomarkers in studies measuring baseline confounders while avoiding model misspecification remains only partially addressed. Efficient estimators constructed from data adaptive estimates of the data-generating distribution provide an avenue for avoiding model misspecification; however, in the context of high-dimensional problems requiring simultaneous estimation of numerous parameters, standard variance estimators have proven unstable, resulting in unreliable Type-I error control under standard multiple testing corrections. We present the formulation of a general approach for applying empirical Bayes shrinkage approaches to asymptotically linear estimators of parameters defined in the nonparametric model. The proposal applies existing shrinkage estimators to the estimated variance of the influence function, allowing for increased inferential stability in high-dimensional settings. A methodology for nonparametric variable importance analysis for use with high-dimensional biological datasets with modest sample sizes is introduced and the proposed technique is demonstrated to be robust in small samples even when relying on data adaptive estimators that eschew parametric forms. Use of the proposed variance moderation strategy in constructing stabilized variable importance measures of biomarkers is demonstrated by application to an observational study of occupational exposure. The result is a data adaptive approach for robustly uncovering stable associations in high-dimensional data with limited sample sizes

A nonparametric framework for treatment effect modifier discovery in high dimensions

Heterogeneous treatment effects are driven by treatment effect modifiers, pre-treatment covariates that modify the effect of a treatment on an outcome. Current approaches for uncovering these variables are limited to low-dimensional data, data with weakly correlated covariates, or data generated according to parametric processes. We resolve these issues by developing a framework for defining model-agnostic treatment effect modifier variable importance parameters applicable to high-dimensional data with arbitrary correlation structure, deriving one-step, estimating equation and targeted maximum likelihood estimators of these parameters, and establishing these estimators' asymptotic properties. This framework is showcased by defining variable importance parameters for data-generating processes with continuous, binary, and time-to-event outcomes with binary treatments, and deriving accompanying multiply-robust and asymptotically linear estimators. Simulation experiments demonstrate that these estimators' asymptotic guarantees are approximately achieved in realistic sample sizes for observational and randomized studies alike. This framework is applied to gene expression data collected for a clinical trial assessing the effect of a monoclonal antibody therapy on disease-free survival in breast cancer patients. Genes predicted to have the greatest potential for treatment effect modification have previously been linked to breast cancer. An open-source R package implementing this methodology, unihtee, is made available on GitHub at https://github.com/insightsengineering/unihtee

Rat endopeptidase-24.18 α subunit is secreted into the culture medium as a zymogen when expressed by COS-1 cells

AbstractEndopeptidase-24.18 (EC 3.4.24.18, E-24.18) is an oligomeric Zn-ectoenzyme. The α and β submits have been cloned from both rat and mouse kidneys. The primary structure of these subunits revealed that they both contain the consensus Zn binding site and that they are members of the astacin family. Analysis of the hydropathy plot also suggested that they are anchored by a C-terminal hydrophobic domain. In order to verify the mode of anchoring of the rat E-24.18 α subunit and to test the functionality of the astacin-like domain in the α subunit when expressed alone, COS-1 cells were transfected with a cloned cDNA for rat α subunit. Despite the presence of its putative transmembrane domain, the α subunit was not anchored in the plasma membrane but rather secreted as a dimer into the culture medium. When the enzymatic activity of the secreted recombinant protein was tested in the azocasein degradation assay, the α subunit was found to be inactive. Activity could, however, be revealed after mild trypsin digestion. This activity was abolished by replacing the Glu-157 in the active site by Val. Taken together our results suggest that the α subunit of Endopeptidase-24.18 contains a latent astacin-like Zn metallopeptidase activity which could be secreted as a soluble enzyme by kidney and intestine

Beneficial effects of reconstituted high-density lipoprotein (rHDL) on circulating CD34+ cells in patients after an acute coronary syndrome

Background: High-density lipoproteins (HDL) favorably affect endothelial progenitor cells (EPC). Circulating progenitor cell level and function are impaired in patients with acute coronary syndrome (ACS). This study investigates the short-term effects of reconstituted HDL (rHDL) on circulating progenitor cells in patients with ACS. Methods and Findings: The study population consisted of 33 patients with recent ACS: 20 patients from the ERASE trial (randomized to receive 4 weekly intravenous infusions of CSL-111 40 mg/kg or placebo) and 13 additional patients recruited as controls using the same enrolment criteria. Blood was collected from 16 rHDL (CSL-111)-treated patients and 17 controls at baseline and at 6–7 weeks (i.e. 2–3 weeks after the fourth infusion of CSL-111 in ERASE). CD34+ and CD34+/kinase insert domain receptor (KDR+) progenitor cell counts were analyzed by flow cytometry. We found preserved CD34+ cell counts in CSL-111-treated subjects at follow-up (change of 1.6%), while the number of CD34+ cells was reduced (-32.9%) in controls (p = 0.017 between groups). The level of circulating SDF-1 (stromal cell-derived factor-1), a chemokine involved in progenitor cell recruitment, increased significantly (change of 21.5%) in controls, while it remained unchanged in CSL-111-treated patients (p = 0.031 between groups). In vitro exposure to CSL-111 of early EPC isolated from healthy volunteers significantly increased CD34+ cells, reduced early EPC apoptosis and enhanced their migration capacity towards SDF-1. Conclusions: The relative increase in circulating CD34+ cells and the low SDF-1 levels observed following rHDL infusions in ACS patients point towards a role of rHDL in cardiovascular repair mechanisms

Clinical and MRI outcomes 10 years after repair of massive posterosuperior rotator cuff tears

BACKGROUND: Massive rotator cuff tears are challenging to treat, with few or no studies on long-term outcomes of repair. The purpose of this study was to report 10-year outcomes following repair of massive posterosuperior rotator cuff tears, with and without extension into the subscapularis, and to determine prognostic factors that could influence clinical scores and retear rates. METHODS: The records of 234 patients who underwent repair of a massive posterosuperior rotator cuff tear at a total of 15 centers were retrieved. Patients were asked to return for evaluation at 10 years; 78 patients could not be contacted, 7 had died, and 19 had undergone a reoperation. A total of 130 patients (68% men) with a mean age (and standard deviation) of 56.1 ± 7.7 years (range, 26 to 79 years) were evaluated clinically, and 102 of them were also evaluated using magnetic resonance imaging (MRI). The tear was confined to the supraspinatus and infraspinatus tendons in 94 shoulders and also involved the superior portion of the subscapularis in 36 shoulders. Univariable and multivariable regressions were performed to determine whether 10-year total Constant-Murley scores and repair integrity were associated with patient characteristics, tear patterns, or repair techniques. RESULTS: In the study cohort, complications were noted in 14 shoulders (11%) (stiffness in 10 and infection in 4). For the 130 shoulders evaluated clinically, the mean total Constant-Murley score improved from 53.1 ± 15.9 (range, 14 to 83) preoperatively to 78.5 ± 11.3 (range, 36 to 98) at 10 years. Of the 102 shoulders evaluated using MRI, 32 had a retear (Sugaya type IV or V). Of the 19 shoulders that underwent a reoperation (excluded from the study cohort), 9 had a retear. The overall prevalence of retears was 34%. Multivariable regression analysis revealed a significant association between the 10-year Constant-Murley score and preoperative retraction of the infraspinatus tendon, but no association between retears and any of the variables. Involvement of the subscapularis had no significant effect on preoperative or postoperative Constant-Murley scores or retear rates. CONCLUSIONS: Patients who had repair of a massive posterosuperior rotator cuff tear maintained considerable improvements in clinical and radiographic outcomes at 10 years. Partial concomitant tears of the subscapularis did not affect the total postoperative Constant-Murley scores or retear rates

How the greater tuberosity affects clinical outcomes after reverse shoulder arthroplasty for proximal humeral fractures

BACKGROUND: Our purpose was to evaluate the clinical and radiologic outcomes of reverse shoulder arthroplasty for proximal humeral fractures in a large cohort of elderly patients and compare the results in the case of tuberosity excision, failed fixation, or anatomic healing. METHODS: In this retrospective multicenter study, 420 patients underwent review and radiography with a minimum follow-up period of 12 months. The patients were divided into 3 groups according to the status of the greater tuberosity (GT) on the last anteroposterior radiographs: anatomic GT healing (group A, n = 169); GT resorption, malunion, or nonunion (group B, n = 131); and GT excision (group C, n = 120). Complications were recorded; shoulder function, active mobility, and subjective results were assessed. RESULTS: At a mean follow-up of 28 months, the mean Simple Shoulder Value in group A (75%) outperformed the results found in groups B (69%, P < .001) and C (56%, P < .001). Overall, the mean adjusted Constant-Murley score was significantly higher in group A (93% ± 22%) than in group B (82% ± 22%) and group C (80% ± 24%) (P < .001), but there was no difference between groups B and C (P = .88). Anterior active elevation and external rotation were significantly better in group A than in groups B and C (P < .001). The instability rate was significantly higher in group C (n = 15 [12.5%], P < .001) than in group A (n = 2) or group B (n = 3). CONCLUSION: In elderly patients who have undergone a reverse shoulder arthroplasty for acute proximal humeral fractures, anatomic tuberosity healing improves objective and subjective outcomes. GT excision is associated with the worst functional results and increases the risk of postoperative shoulder instability