ABSTRACT
There has been growing research interest in developing methodology to evaluate the health care providers' performance with respect to a patient outcome. Random and fixed effects models are traditionally used for such a purpose. We propose a new method, using a fusion penalty to cluster health care providers based on quasi-likelihood. Without any priori knowledge of grouping information, our method provides a desirable data-driven approach for automatically clustering health care providers into different groups based on their performance. Further, the quasi-likelihood is more flexible and robust than the regular likelihood in that no distributional assumption is needed. An efficient alternating direction method of multipliers algorithm is developed to implement the proposed method. We show that the proposed method enjoys the oracle properties; namely, it performs as well as if the true group structure were known in advance. The consistency and asymptotic normality of the estimators are established. Simulation studies and analysis of the national kidney transplant registry data demonstrate the utility and validity of our method.
Subject(s)
Biometry , Health Personnel , Cluster Analysis , Likelihood Functions , Humans , Health Personnel/statistics & numerical data , Biometry/methods , Kidney Transplantation , AlgorithmsABSTRACT
Healthcare quality measures are statistics that serve to evaluate healthcare providers and identify those that need to improve their care. Before using these measures in clinical practice, developers and reviewers assess measure reliability, which describes the degree to which differences in the measure values reflect actual variation in healthcare quality, as opposed to random noise. The Inter-Unit Reliability (IUR) is a popular statistic for assessing reliability, and it describes the proportion of total variation in a measure that is attributable to between-provider variation. However, Kalbfleisch, He, Xia, and Li (2018) [Health Services and Outcomes Research Methodology, 18, 215-225] have argued that the IUR has a severe limitation in that some of the between-provider variation may be unrelated to quality of care. In this paper, we illustrate the practical implications of this limitation through several concrete examples. We show that certain best-practices in measure development, such as careful risk adjustment and exclusion of unstable measure values, can decrease the sample IUR value. These findings uncover potential negative consequences of discarding measures with IUR values below some arbitrary threshold.
ABSTRACT
In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
Subject(s)
Cytosol , Mitochondria , Prohibitins , RNA, Double-Stranded , RNA, Mitochondrial , Humans , Cytosol/metabolism , Mitochondria/metabolism , RNA, Double-Stranded/metabolism , RNA, Mitochondrial/metabolism , RNA, Mitochondrial/genetics , Cell Line, Tumor , Repressor Proteins/metabolism , Repressor Proteins/genetics , RNA Transport , Exoribonucleases/metabolism , Exoribonucleases/genetics , Voltage-Dependent Anion Channel 1/metabolism , Voltage-Dependent Anion Channel 1/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Mitochondrial ProteinsABSTRACT
OBJECTIVE: This study was undertaken to delineate 21-year sex-specific trends in recurrence and postrecurrence mortality. METHODS: Between 2000 and 2020, first-ever ischemic stroke (IS) patients, ascertained from the population-based BASIC (Brain Attack Surveillance in Corpus Christi) project in South Texas, were followed for recurrent stroke and all-cause mortality until December 31, 2020. Multivariable regression models with an interaction between calendar year and sex were used to estimate sex-specific trends and sex differences in recurrence and postrecurrence mortality. RESULTS: Of the 6,057 IS patients (median age = 69 years, 49.8% women), 654 (10.8%) had a recurrence and 399 (47.7%) had postrecurrence mortality during 5 years of follow-up. In 2000, women had 2.5% higher albeit non-statistically significant 5-year risk of recurrence than men in absolute scale. With the trend declining in women by 7.6% (95% confidence interval [CI] = -10.8 to -4.5%) and in men by 3.6% (95% CI = -6.5% to -0.7%), the risk at the end of the study period was 1.5% (95% CI = -0.3% to 3.6%) lower among women than men. For postrecurrence mortality, the risk was 10.2% lower among women in 2000, but the sex difference was 3.3% by the end of the period, which was due to a larger overall increase in the risk among women than men over the entire time period. INTERPRETATION: The declines in recurrent stroke suggest successful secondary stroke prevention, especially in women. However, the continued high postrecurrence mortality among both sexes at the end of study period emphasizes the need for ongoing interventions to improve prognosis in those who have had recurrent cerebrovascular events. ANN NEUROL 2024;96:332-342.
Subject(s)
Recurrence , Sex Characteristics , Stroke , Humans , Female , Male , Aged , Middle Aged , Texas/epidemiology , Stroke/mortality , Stroke/epidemiology , Aged, 80 and over , Sex Factors , Population Surveillance/methods , Ischemic Stroke/mortality , Ischemic Stroke/epidemiologyABSTRACT
Identification of splice sites is a critical step in pre-messenger RNA (pre-mRNA) splicing because the definition of the exon/intron boundaries controls what nucleotides are incorporated into mature mRNAs. The intron boundary with the upstream exon is initially identified through interactions with the U1 small nuclear ribonucleoprotein (snRNP). This involves both base-pairing between the U1 snRNA and the pre-mRNA as well as snRNP proteins interacting with the 5' splice site (5'ss)/snRNA duplex. In yeast, this duplex is buttressed by two conserved protein factors, Yhc1 and Luc7. Luc7 has three human paralogs (LUC7L, LUC7L2, and LUC7L3), which play roles in alternative splicing. What domains of these paralogs promote splicing at particular sites is not yet clear. Here, we humanized the zinc finger (ZnF) domains of the yeast Luc7 protein in order to understand their roles in splice site selection using reporter assays, transcriptome analysis, and genetic interactions. Although we were unable to determine a function for the first ZnF domain, humanization of the second ZnF domain to mirror that found in LUC7L or LUC7L2 resulted in altered usage of nonconsensus 5'ss. In contrast, the corresponding ZnF domain of LUC7L3 could not support yeast viability. Further, humanization of Luc7 can suppress mutation of the ATPase Prp28, which is involved in U1 release and exchange for U6 at the 5'ss. Our work reveals a role for the second ZnF of Luc7 in splice site selection and suggests that different ZnF domains may have different ATPase requirements for release by Prp28.
Subject(s)
Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Zinc Fingers , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , RNA, Small Nuclear/genetics , RNA, Small Nuclear/metabolism , RNA Splicing Factors/metabolism , RNA Splicing Factors/genetics , RNA Splice Sites , Humans , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , RNA Splicing , RNA Precursors/genetics , RNA Precursors/metabolism , Alternative Splicing , Ribonucleoprotein, U1 Small Nuclear/metabolism , Ribonucleoprotein, U1 Small Nuclear/genetics , Introns/geneticsABSTRACT
PURPOSE: Surveillance, Epidemiology, and End Results (SEER) cancer registries provides information about survival duration and cause of death for cancer patients. Baseline demographic and tumor characteristics such as age, sex, race, year of diagnosis, and tumor stage can inform the expected survival time of patients, but their associations with survival may not be constant over the post-diagnosis period. METHODS: Using SEER data, we examined if there were time-varying associations of patient and tumor characteristics on survival, and we assessed how these relationships differed across 14 cancer sites. Standard Cox proportional hazards models were extended to allow for time-varying associations and incorporated into a competing-risks framework, separately modeling cancer-specific and other-cause deaths. For each cancer site and for each of the five factors, we estimated the relative hazard ratio and absolute hazard over time in the presence of competing risks. RESULTS: Our comprehensive consideration of patient and tumor characteristics when estimating time-varying hazards showed that the associations of age, tumor stage at diagnosis, and race/ethnicity with risk of death (cancer-specific and other-cause) change over time for many cancers; characteristics of sex and year of diagnosis exhibit some time-varying patterns as well. Stage at diagnosis had the largest associations with survival. CONCLUSION: These findings suggest that proportional hazards assumptions are often violated when examining patient characteristics on cancer survival post-diagnosis. We discuss several interesting results where the relative hazards are time-varying and suggest possible interpretations. Based on the time-varying associations of several important covariates on survival after cancer diagnosis using a pan-cancer approach, the likelihood of the proportional hazards assumption being met or corresponding interpretation should be considered in survival analyses, as flawed inference may have implications for cancer care and policy.
ABSTRACT
Advancements in quantum system lifetimes and control have enabled the creation of increasingly complex quantum states, such as those on multiple bosonic cavity modes. When characterizing these states, traditional tomography scales exponentially with the number of modes in both computational and experimental measurement requirement, which becomes prohibitive as the system size increases. Here, we implement a state reconstruction method whose sampling requirement instead scales polynomially with system size, and thus mode number, for states that can be represented within such a polynomial subspace. We demonstrate this improved scaling with Wigner tomography of multimode entangled W states of up to 4 modes on a 3D circuit quantum electrodynamics (cQED) system. This approach performs similarly in efficiency to existing matrix inversion methods for 2 modes, and demonstrates a noticeable improvement for 3 and 4 modes, with even greater theoretical gains at higher mode numbers.
ABSTRACT
Sutureless anastomotic devices present several advantages over traditional suture anastomosis, including expanded global access to microvascular surgery, shorter operation and ischemic times, and reduced costs. However, their adaptation for arterial use remains a challenge. This review aims to provide a comprehensive overview of sutureless anastomotic approaches that are either FDA-approved or under investigation. These approaches include extraluminal couplers, intraluminal devices, and methods assisted by lasers or vacuums, with a particular emphasis on tissue adhesives. We analyze these devices for artery compatibility, material composition, potential for intimal damage, risks of thrombosis and restenosis, and complications arising from their deployment and maintenance. Additionally, we discuss the challenges faced in the development and clinical application of sutureless anastomotic techniques. Ideally, a sutureless anastomotic device or technique should eliminate the need for vessel eversion, mitigate thrombosis through either biodegradation or the release of antithrombotic drugs, and be easily deployable for broad use. The transformative potential of sutureless anastomotic approaches in microvascular surgery highlights the necessity for ongoing innovation to expand their applications and maximize their benefits.
ABSTRACT
We show that adding noise before publishing data effectively screens [Formula: see text]-hacked findings: spurious explanations produced by fitting many statistical models (data mining). Noise creates "baits" that affect two types of researchers differently. Uninformed [Formula: see text]-hackers, who are fully ignorant of the true mechanism and engage in data mining, often fall for baits. Informed researchers, who start with an ex ante hypothesis, are minimally affected. We show that as the number of observations grows large, dissemination noise asymptotically achieves optimal screening. In a tractable special case where the informed researchers' theory can identify the true causal mechanism with very few data, we characterize the optimal level of dissemination noise and highlight the relevant trade-offs. Dissemination noise is a tool that statistical agencies currently use to protect privacy. We argue this existing practice can be repurposed to screen [Formula: see text]-hackers and thus improve research credibility.
ABSTRACT
United States federal agencies evaluate healthcare providers to identify, flag, and potentially penalize those that deliver low-quality care compared to national expectations. In practice, evaluation metrics are inevitably impacted by unobserved confounding factors, which reduce flagging accuracy and cause the statistics to be overdispersed relative to the theoretical null distributions. In response to this issue, several authors have proposed individualized empirical null (IEN) methods to estimate an appropriate null distribution for each provider's evaluation statistic while taking into account the provider's effective size. However, existing IEN methods require that the statistics asymptotically follow normal distributions, which often does not hold in applications with small providers or misspecified models. In this article, we develop an IEN framework for exact hypothesis tests that accounts for the impact of unobserved confounding without making any asymptotic assumptions. Simulations show that the proposed IEN method has greater flagging accuracy compared to conventional approaches. We apply these methods to evaluate dialysis facilities and transplant centers that are monitored by the Centers for Medicare and Medicaid Services.
Subject(s)
Quality of Health Care , Humans , United States , Models, Statistical , Computer Simulation , Centers for Medicare and Medicaid Services, U.S. , Renal DialysisABSTRACT
The manipulation of quantum states of light has resulted in significant advancements in both dark matter searches and gravitational wave detectors. Current dark matter searches operating in the microwave frequency range use nearly quantum-limited amplifiers. Future high frequency searches will use photon counting techniques to evade the standard quantum limit. We present a signal enhancement technique that utilizes a superconducting qubit to prepare a superconducting microwave cavity in a nonclassical Fock state and stimulate the emission of a photon from a dark matter wave. By initializing the cavity in an |n=4⟩ Fock state, we demonstrate a quantum enhancement technique that increases the signal photon rate and hence also the dark matter scan rate each by a factor of 2.78. Using this technique, we conduct a dark photon search in a band around 5.965 GHz (24.67 µeV), where the kinetic mixing angle ε≥4.35×10^{-13} is excluded at the 90% confidence level.
ABSTRACT
Bloodstream infections (BSIs) account for 18% of bacterial infections in the first year after solid organ transplantation (SOT). Enterococcus accounts for up to 20% of BSIs in this population, with vancomycin-resistant enterococcus (VRE) posing a particular risk. This is a retrospective, case-control study of adult liver and kidney transplant recipients between 01/01/2016 and 06/30/2021 that characterizes the epidemiology and outcomes of enterococcal BSIs in liver and kidney transplantations at a single institution. Subjects with an enterococcal BSI within the first 6 months post-transplant were compared to those with non-enterococcal BSIs in the same period. We identified 26 subjects with enterococcal BSIs and 28 controls with non-enterococcal BSIs (n = 54; 10.3%). Cases were mostly liver transplant recipients (n = 20; 77%) with a median MELD at transplant of 33 (range 14-43); controls included 14 KT recipients (50%). Groups differed significantly (all p < .05) by factors including perioperative transfusion requirements, need for reoperation, and number of interventions post-transplant. Cases had a median time of 25.5 days to infection and controls 100.5 days (p < .0001). There were no differences in 1-year mortality between the groups. Enterococcus faecium was the predominant species of Enterococcus (n = 23; 88.5%), with a majority (91.3%) of the isolates being VRE. In our liver and kidney transplants, enterococcal BSIs occurred early among liver transplant recipients. The high incidence of VRE among E. faecium isolates in this population warrants further investigation into the optimal approach to empiric antimicrobials for bacteremia in the early post-transplant period.
Subject(s)
Bacteremia , Gram-Positive Bacterial Infections , Kidney Transplantation , Vancomycin-Resistant Enterococci , Adult , Humans , Anti-Bacterial Agents/therapeutic use , Kidney Transplantation/adverse effects , Retrospective Studies , Case-Control Studies , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/epidemiology , Gram-Positive Bacterial Infections/etiology , Bacteremia/etiology , Bacteremia/microbiology , Liver , Risk FactorsABSTRACT
Identification of splice sites is a critical step in pre-mRNA splicing since definition of the exon/intron boundaries controls what nucleotides are incorporated into mature mRNAs. The intron boundary with the upstream exon is initially identified through interactions with the U1 snRNP. This involves both base pairing between the U1 snRNA and the pre-mRNA as well as snRNP proteins interacting with the 5' splice site/snRNA duplex. In yeast, this duplex is buttressed by two conserved protein factors, Yhc1 and Luc7. Luc7 has three human paralogs (LUC7L, LUC7L2, and LUC7L3) which play roles in alternative splicing. What domains of these paralogs promote splicing at particular sites is not yet clear. Here, we humanized the zinc finger domains of the yeast Luc7 protein in order to understand their roles in splice site selection using reporter assays, transcriptome analysis, and genetic interactions. While we were unable to determine a function for the first zinc finger domain, humanization of the second zinc finger domain to mirror that found in LUC7L or LUC7L2 resulted in altered usage of nonconsensus 5' splice sites. In contrast, the corresponding zinc finger domain of LUC7L3 could not support yeast viability. Further, humanization of Luc7 can suppress mutation of the ATPase Prp28, which is involved in U1 release and exchange for U6 at the 5' splice site. Our work reveals a role for the second zinc finger of Luc7 in splice site selection and suggests that different zinc finger domains may have different ATPase requirements for release by Prp28.
ABSTRACT
Recurrent events such as hospitalisations are outcomes that can be used to monitor dialysis facilities' quality of care. However, current methods are not adequate to analyse data from many facilities with multiple hospitalisations, especially when adjustments are needed for multiple time scales. It is also controversial whether direct or indirect standardisation should be used in comparing facilities. This study is motivated by the need of the Centers for Medicare and Medicaid Services to evaluate US dialysis facilities using Medicare claims, which involve almost 8,000 facilities and over 500,000 dialysis patients. This scope is challenging for current statistical software's computational power. We propose a method that has a flexible baseline rate function and is computationally efficient. Additionally, the proposed method shares advantages of both indirect and direct standardisation. The method is evaluated under a range of simulation settings and demonstrates substantially improved computational efficiency over the existing R package survival. Finally, we illustrate the method with an important application to monitoring dialysis facilities in the U.S., while making time-dependent adjustments for the effects of COVID-19.
ABSTRACT
BACKGROUND AND OBJECTIVES: During acute hospitalizations, physicians often focus on the stroke patient and not family who may be traumatized by this sudden change to their loved one. We investigated long-term psychological distress among family surrogate decision makers for Mexican American (MA) and non-Hispanic White (NHW) severe stroke patients. Previous work in other diseases suggested worse psychological outcomes in MA than NHW caregivers. METHODS: This was a population-based, prospective cohort study in Nueces County, TX. Stroke patient participants and their surrogate decision makers were enrolled soon after any stroke between April, 2016, and October, 2020, if surrogates had made decisions about life-sustaining treatments. Surrogates completed validated measures of posttraumatic stress, National Stressful Events Survey for Posttraumatic Stress Disorder Short Scale; anxiety, Generalized Anxiety Disorder-7; and depression, Patient Health Questionnaire-8 at discharge, 3, 6, and 12 months. Ethnic differences were assessed with multilevel linear mixed models, sequentially adjusted for prespecified patient and surrogate demographic, socioeconomic, and clinical covariates. RESULTS: There were 301 family surrogates for 241 severe stroke patients. The mean follow-up was 315 days. High scores on measures of psychological distress ranged between 17% and 28% of surrogates. One or more high levels of the psychological outcomes were found in 17%-43% of surrogates; 2 or more were found in 12%-27%; and all 3 were found in 5%-16% of surrogates. All psychological outcomes were worse among MAs on unadjusted analyses. In fully adjusted models, posttraumatic stress remained worse among MAs (0.36, 95% CI 0.17-0.56); ethnic differences were attenuated and no longer significant in the final model for anxiety (0.59, 95% CI -0.55 to 1.74) and depression (0.97, 95% CI -0.25 to 2.19). The trajectory for depression did differ by ethnicity (interaction p = 0.03), with depression score improving more rapidly over time among NHWs than MAs. Advance care plans did not seem to confound any ethnic differences. DISCUSSION: Psychological distress is common among family surrogate decision makers in the year after stroke and may be worse among MAs. Efforts are needed to support family members of all ethnic groups after severe stroke.
Subject(s)
Caregivers , Psychological Distress , Stroke , Humans , Decision Making , Ethnicity , Mexican Americans , Prospective Studies , Stroke/epidemiology , White , Caregivers/psychologyABSTRACT
"Xanthogranulomatous epithelial tumor" (XGET) and "keratin-positive giant cell-rich soft tissue tumor" (KPGCT), two recently described mesenchymal neoplasms, likely represent different aspects of a single entity. Both tumors are composed of only a small minority of tumor cells surrounded by large numbers of non-neoplastic inflammatory cells and histiocytes, suggesting production of a paracrine factor with resulting "landscape effect," as seen in tenosynovial giant cell tumor. Recent evidence suggests that the paracrine factor in XGET/KPGCT may be CSF1, as in tenosynovial giant cell tumor. We hypothesized that CSF1 is overexpressed in XGET/KPGCT. To test our hypothesis, we performed quantitative real time PCR (qPCR) for CSF1 expression and CSF1 RNAscope chromogenic in situ hybridization (CISH) on 6 cases of XGET/KPGCT. All cases were positive with CSF1 CISH and showed increased expression of CSF1 by qPCR. Our findings provide additional evidence that the CSF1/CSF1R pathway is involved in the pathogenesis of XGET/KPGCT. These findings suggest a possible role for CSF1R inhibition in the treatment of unresectable or metastatic XGET/KPGCT.
Subject(s)
Carcinoma , Giant Cell Tumor of Tendon Sheath , Giant Cell Tumors , Soft Tissue Neoplasms , Humans , Macrophage Colony-Stimulating Factor/genetics , Keratins , Giant Cell Tumors/metabolism , Giant Cell Tumors/pathology , Soft Tissue Neoplasms/pathology , Giant Cells/pathologyABSTRACT
Formins are large, multidomain proteins that nucleate new actin filaments and accelerate elongation through a processive interaction with the barbed ends of filaments. Their actin assembly activity is generally attributed to their eponymous formin homology (FH) 1 and 2 domains; however, evidence is mounting that regions outside of the FH1FH2 stretch also tune actin assembly. Here, we explore the underlying contributions of the tail domain, which spans the sequence between the FH2 domain and the C terminus of formins. Tails vary in length from â¼0 to >200 residues and contain a number of recognizable motifs. The most common and well-studied motif is the â¼15-residue-long diaphanous autoregulatory domain. This domain mediates all or nothing regulation of actin assembly through an intramolecular interaction with the diaphanous inhibitory domain in the N-terminal half of the protein. Multiple reports demonstrate that the tail can enhance both nucleation and processivity. In this study, we provide a high-resolution view of the alternative splicing encompassing the tail in the formin homology domain (Fhod) family of formins during development. While four distinct tails are predicted, we found significant levels of only two of these. We characterized the biochemical effects of the different tails. Surprisingly, the two highly expressed Fhod-tails inhibit processive elongation and diminish nucleation, while a third supports activity. These findings demonstrate a new mechanism of modulating actin assembly by formins and support a model in which splice variants are specialized to build distinct actin structures during development.
Subject(s)
Actins , Drosophila Proteins , Actin Cytoskeleton/metabolism , Actins/metabolism , Drosophila melanogaster , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , AnimalsABSTRACT
BACKGROUND: Multiple treatment options are available for the management of psoriasis, but clinical response varies among individual patients and no biomarkers are available to facilitate treatment selection for improved patient outcomes. OBJECTIVES: To utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis. METHODS: We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1942 genotyped patients with psoriasis. We examined 6 502 658 genetic markers to model their associations with response to six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomics, transcriptomics and a longitudinal clinical cohort to provide biological implications for the topmost signals associated with drug response. RESULTS: Two novel markers were revealed to be associated with treatment response: rs1991820 (P = 1.30 × 10-6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P = 2.94 × 10-6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (P = 1.0 × 10-12) and CD200 (P = 5.4 × 10-6). We demonstrated that KLK7 expression was increased in the psoriatic epidermis, as shown by immunohistochemistry, as well as single-cell RNA sequencing, and its responsiveness to anti-TNF treatment was highlighted. By inhibiting the expression of KLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF. CONCLUSIONS: Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7.
Subject(s)
Psoriasis , Humans , Kallikreins/genetics , Kallikreins/therapeutic use , Pharmacogenetics , Pharmacogenomic Testing , Psoriasis/drug therapy , Psoriasis/genetics , Psoriasis/pathology , Retrospective Studies , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/geneticsABSTRACT
PURPOSE: Soft tissue sarcomas (STS) are rare mesenchymal neoplasms that frequently show complex chromosomal aberrations such as amplifications or deletions of DNA sequences or even whole chromosomes. We recently found that gain of chromosome (chr) 8 is associated with worse overall survival (OS) in STS as a group. We therefore aimed to investigate the overall copy number profile of rhabdomyosarcoma (RMS) to evaluate for prognostic signatures. METHODS: Fluorescence in situ hybridization (FISH) testing was performed on a cohort of STS to assess for chr8 gain. Copy number variation (CNV) data from the National Cancer Institute were analyzed to assess for prognostically significant CNV aberrations in FOXO1 fusion-negative (FN)- versus fusion-positive (FP)-RMS. FISH testing was performed on a cohort of FN-RMS to assess for chr3q loss and correlate with outcomes. RESULTS: Chr8 gain is a highly prevalent CNV in embryonal RMS and shows slightly improved prognosis. Meanwhile, loss of chr3q was associated with worse outcome in FN-RMS compared with FP-RMS. CONCLUSION: The pathogenesis of STS including FN-RMS remains poorly understood, emphasizing the need for new therapeutic advances and adequate risk stratification. Our data demonstrate that loss of chr3q is associated with poor OS in FN-RMS, supporting it as an important tool for risk stratification.
Subject(s)
DNA Copy Number Variations , Rhabdomyosarcoma , Humans , In Situ Hybridization, Fluorescence , Prognosis , Rhabdomyosarcoma/diagnosis , Rhabdomyosarcoma/genetics , ChromosomesABSTRACT
In addition to applications in meta-analysis, funnel plots have emerged as an effective graphical tool for visualizing the detection of health care providers with unusual performance. Although there already exist a variety of approaches to producing funnel plots in the literature of provider profiling, limited attention has been paid to elucidating the critical relationship between funnel plots and hypothesis testing. Within the framework of generalized linear models, here we establish methodological guidelines for creating funnel plots specific to the statistical tests of interest. Moreover, we show that the test-specific funnel plots can be created merely leveraging summary statistics instead of individual-level information. This appealing feature inhibits the leak of protected health information and reduces the cost of inter-institutional data transmission. Two data examples, one for surgical patients from Michigan hospitals and the other for Medicare-certified dialysis facilities, demonstrate the applicability to different types of providers and outcomes with either individual- or summary-level information.