Publications by authors named "Yulun Liu"

29 Publications

  • Page 1 of 1

EEG phase-amplitude coupling to stratify encephalopathy severity in the developing brain.

Comput Methods Programs Biomed 2021 Dec 20;214:106593. Epub 2021 Dec 20.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States. Electronic address:

Background: Neonatal hypoxic ischemic encephalopathy (HIE) is difficult to classify within the narrow therapeutic window of hypothermia. Neurophysiological biomarkers are needed for timely differentiation of encephalopathy severity within the short therapeutic window for initiation of hypothermia therapy.

Methods: A novel analysis of mean Phase Amplitude Coupling index, PAC, of amplitudes high frequencies (12-30 Hz) coupled with phases of low (1,2 Hz) frequencies was calculated from the 6 h EEG recorded during the first day of life. PAC values were compared to identify differences between mild versus higher-grade HIE, respectively, for each of the EEG electrodes. A receiver operating characteristic curve was generated to examine the performance of PAC.

Results: 38 newborns with different HIE grades were enrolled in the first 6 h of life. Threshold PAC 0.001 at Fz, O1, O2, P3, and P4 had AUC >0.9 to differentiate HIE severity and predict the persistence of moderate to severe encephalopathy that requires treatment with hypothermia.

Conclusion: PAC is a promising biomarker to identify mild from higher severity of HIE after birth.
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http://dx.doi.org/10.1016/j.cmpb.2021.106593DOI Listing
December 2021

The natural history of non-functioning pituitary adenomas: A meta-analysis of conservatively managed tumors.

J Clin Neurosci 2022 Jan 10;95:134-141. Epub 2021 Dec 10.

UT Southwestern Medical School, Department of Neurological Surgery, Dallas, TX, USA. Electronic address:

Background: Non-functioning pituitary adenomas (NFPA) are often discovered incidentally. The natural history of NFPA is not well understood, obfuscating evidence-based management decisions. Meta-data of radiographically followed NFPA may help guide conservative versus operative treatment of these tumors.

Methods: We searched PubMed, Medline, Embase, and Ovid for studies with NFPA managed nonoperatively with radiographic follow-up. Studies on postoperative outcomes after NFPA resection and studies that did not delineate NFPA data from functional pituitary lesions were excluded. NFPA were divided into micro- and macroadenomas based on size at presentation. We performed a meta-analysis of aggregate data for length of follow-up, change in tumor size, rate of apoplexy, and need for resection during follow-up.

Results: Our database search yielded 1787 articles, of which 19 were included for final analysis. The studies included 1057 patients with NFPA followed radiographically. Macroadenomas were significantly more likely to undergo growth (34% vs. 12%; p < 0.01) or apoplexy (5% vs. < 1%; p = 0.01) compared to microadenomas. Resection was performed in 11% of all NFPA patients during follow-up regardless of size at presentation. Meta-regression showed that surgery during follow-up was associated with macroadenomas and negatively associated with microadenomas that decreased in size.

Conclusion: Low-quality evidence suggests that NFPA classified as macroadenomas have an increased rate of growth and apoplexy during follow-up compared to microadenomas. A significant minority of all NFPA patients ultimately underwent surgery. In select patients, nonoperative management may be the appropriate strategy for NFPA. Macroadenomas may require closer follow-up.
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http://dx.doi.org/10.1016/j.jocn.2021.12.003DOI Listing
January 2022

Translating Access to Outcomes: The Impact of Socioeconomic Status on Completion of Breast Reconstruction at a National Cancer Institute (NCI)-Designated Cancer Center: Impact of SES on Completion.

J Plast Reconstr Aesthet Surg 2021 Sep 20. Epub 2021 Sep 20.

Department of Plastic Surgery, UT Southwestern Medical Center, 1801 Inwood Road, Dallas, TX. Electronic address:

The purpose of this study was to determine the impact of socioeconomic status (SES) on the completion of breast reconstruction, as defined by the percent of patients undergoing NAC reconstruction. Patients (n=949) who underwent primary breast reconstruction following a mastectomy recorded from 2007 to 2017 were divided into groups based on the median household income of their residential zip code (>/< $67,640). A three-step protocol was designed to (1) broadly compare between patients of low and high SES who were stratified by race and reconstruction type, (2) compare a smaller subset of low SES and high SES patients via propensity matching for demographic, baseline health, and oncologic factors, and (3) elucidate the strongest predictors of non-completion and delayed completion among low SES patients. Patients of lower SES appear less likely to complete NAC reconstruction, especially following staged reconstruction. That this finding presents in staged, but not immediate reconstruction, and disappears with propensity matching for oncologic factors suggests that reduced completion in patients of low SES may be attributable to advanced cancer staging and aggressive adjuvant therapy. Furthermore, expander conversion to autologous reconstruction significantly increased the likelihood of NAC reconstruction in multivariable analysis, and adjuvant radiation therapy significantly increased the time to NAC reconstruction. Further investigation will solidify the relationship between SES, cancer staging, and completion of reconstruction in a multi-site patient population. Larger multivariable analyses may also uncover other factors that can be modified or addressed to increase completion and optimize reconstruction for patients at risk of discontinuation.
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http://dx.doi.org/10.1016/j.bjps.2021.08.034DOI Listing
September 2021

Wavelet-based neurovascular coupling can predict brain abnormalities in neonatal encephalopathy.

Neuroimage Clin 2021 20;32:102856. Epub 2021 Oct 20.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

Background: Hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in neonates, but quantitative methods to predict outcomes early in their course of illness remain elusive. Real-time physiologic biomarkers of neurologic injury are needed in order to predict which neonates will benefit from therapies. Neurovascular coupling (NVC) describes the correlation of neural activity with cerebral blood flow, and the degree of impairment could predict those at risk for poor outcomes.

Objective: To determine if neurovascular coupling (NVC) calculated in the first 24-hours of life based on wavelet transform coherence analysis (WTC) of near-infrared spectroscopy (NIRS) and amplitude-integrated electroencephalography (aEEG) can predict abnormal brain MRI in neonatal HIE.

Methods: WTC analysis was performed between dynamic oscillations of simultaneously recorded aEEG and cerebral tissue oxygen saturation (SctO2) signals for the first 24 h after birth. The squared cross-wavelet coherence, R, of the time-frequency domain described by the WTC, is a localized correlation coefficient (ranging between 0 and 1) between these two signals in the time-frequency domain. Statistical analysis was based on Monte Carlo simulation with a 95% confidence interval to identify the time-frequency areas from the WTC scalograms. Brain MRI was performed on all neonates and classified as normal or abnormal based on an accepted classification system for HIE. Wavelet metrics of % significant SctO2-aEEG coherence was compared between the normal and abnormal MRI groups.

Result: This prospective study recruited a total of 36 neonates with HIE. A total of 10 had an abnormal brain MRI while 26 had normal MRI. The analysis showed that the SctO2-aEEG coherence between the group with normal and abnormal MRI were significantly different (p = 0.0007) in a very low-frequency (VLF) range of 0.06-0.2 mHz. Using receiver operating characteristic (ROC) curves, the use of WTC-analysis of NVC had an area under the curve (AUC) of 0.808, and with a cutoff of 10% NVC. Sensitivity was 69%, specificity was 90%, positive predictive value (PPV) was 94%, and negative predictive value (NPV) was 52% for predicting brain injury on MRI. This was superior to the clinical Total Sarnat score (TSS) where AUC was 0.442 with sensitivity 61.5%, specificity 30%, PPV 75%, and NPV 31%.

Conclusion: NVC is a promising neurophysiological biomarker in neonates with HIE, and in our prospective cohort was superior to the clinical Total Sarnat score for prediction of abnormal brain MRI.
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http://dx.doi.org/10.1016/j.nicl.2021.102856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564674PMC
January 2022

Differences Between Patients With Intermittent Claudication and Critical Limb Ischemia Undergoing Endovascular Intervention: Insights From the Excellence in Peripheral Artery Disease Registry.

Circ Cardiovasc Interv 2021 11 27;14(11):e010635. Epub 2021 Oct 27.

University of Texas Southwestern Medical Center, Dallas (K.P., Y.L., M.A.A., N.M., I.T., S.B.).

Background: There are limited data on differences in angiographic distribution of peripheral artery disease and endovascular revascularization strategies in patients presenting with intermittent claudication (IC) and critical limb ischemia (CLI). We aimed to compare anatomic features, treatment strategies, and clinical outcomes between patients with IC and CLI undergoing endovascular revascularization.

Methods: We examined 3326 patients enrolled in the Excellence in Peripheral Artery Disease registry from 2006 to 2019 who were referred for endovascular intervention for IC (n=1983) or CLI (n=1343). The primary outcome was 1-year major adverse limb events, which included death, repeat target limb revascularization, or target limb amputation.

Results: Patients with CLI were older and more likely to have diabetes and chronic kidney disease and less likely to receive optimal medical therapy compared with IC. Patients with IC had higher femoropopliteal artery interventions (IC 87% versus CLI 65%; <0.001), while below the knee interventions were more frequent in CLI (CLI 47% versus IC 12%; <0.001). Patients with CLI were more likely to have multilevel peripheral artery disease (CLI 32% versus IC 15%, <0.001). Patients with IC were predominantly revascularized with stents (IC 48% versus CLI 37%; <0.001) while balloon angioplasty was more frequent in CLI (CLI 37% versus IC 25%; <0.001). All-cause mortality was higher in patients with CLI (CLI 4% versus IC 2%; =0.014). Major adverse limb event rates for patients with IC and CLI were 16% and 26%, respectively (<0.001) and remained higher in CLI after multivariable adjustment of baseline risk factors.

Conclusions: Patients with IC and CLI have significant anatomic, lesion, and treatment differences with significantly higher mortality and adverse limb outcomes in CLI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01904851. Graphic Abstract: A graphic abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.121.010635DOI Listing
November 2021

Defining Enhanced Recovery Pathway with or without Liposomal Bupivacaine in DIEP Flap Breast Reconstruction.

Plast Reconstr Surg 2021 Nov;148(5):948-957

From the Departments of Plastic Surgery and Anesthesia, University of Texas Southwestern Medical Center; University of Texas Southwestern Medical School; and Department of Clinical Science, Division of Biostatistics, Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center.

Background: Enhanced recovery after surgery (ERAS) includes multiple interventions that have yielded positive outcomes in a number of surgical fields. The authors evaluated whether an ERAS protocol and the subsequent addition of liposomal bupivacaine affect patient outcomes specifically in deep inferior epigastric perforator (DIEP) flap breast reconstruction.

Methods: All patients treated with DIEP flaps from January of 2016 to December of 2019 were reviewed retrospectively. The ERAS protocol was implemented midway through 2017; halfway through 2018, intraoperative transversus abdominis plane blocks with liposomal bupivacaine were added to the protocol. Such interventions allowed for comparison of three patient groups: before ERAS, during ERAS, and after ERAS plus liposomal bupivacaine. Primary outcomes observed were postoperative opioid consumption and length of stay. The p values were obtained using the Wilcoxon test for pairwise comparisons.

Results: After adjusting for ERAS group compliance, 216 patients were analyzed. The pre-ERAS group was composed of 67 patients, the ERAS group was composed of 69 patients, and the ERAS plus liposomal bupivacaine group was composed of 80 patients. Postoperative opioid consumption was reduced when comparing the pre-ERAS and ERAS groups (from 275.7 oral morphine equivalents to 146.7 oral morphine equivalents; p < 0.0001), and also reduced with the addition of liposomal bupivacaine (115.3 oral morphine equivalents; p = 0.016). Furthermore, hospital length of stay was decreased from 3.6 days in the pre-ERAS group to 3.2 days (p = 0.0029) in the ERAS group, and to 2.6 days (p < 0.0001) in the ERAS group plus liposomal bupivacaine groups.

Conclusions: Enhanced recovery after surgery protocols decrease postoperative opioid consumption and hospital length of stay in DIEP flap breast reconstruction. The addition of liposomal bupivacaine further strengthens the impact of the protocol.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0000000000008409DOI Listing
November 2021

No benefit of vorapaxar on walking performance in patients with intermittent claudication.

Vasc Med 2021 Oct 5:1358863X211042082. Epub 2021 Oct 5.

North Texas VA Health Care System, Dallas, TX, USA.

The effect of pharmacologic agents in improving walking and quality of life measures in patients with intermittent claudication (IC) is variable. The objective of this study was to investigate the effect of the novel antithrombotic vorapaxar on symptom status in patients with IC. The study was a multicenter, randomized, placebo-controlled trial wherein patients with IC were treated with either vorapaxar or placebo in addition to a home exercise program for 6 months. Walking performance and quality of life were assessed by graded treadmill test (GTT) and 12-Item Short-Form Survey (SF-12), respectively, at baseline and at 6 months. A total of 102 subjects were randomized across 12 centers. Of the subjects randomized, 66 completed all study assessments and comprised the dataset that was analyzed. After 6 months, there was no significant difference between the vorapaxar and placebo groups in walking performance, as reflected by the GTT, or in quality of life, as reflected by the SF-12. There were no severe bleeding events in either group. This study found no benefit of vorapaxar in patients with IC and reiterates the need for future drug therapy studies that expand the benefits of supervised exercise therapy in patients with IC. .
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http://dx.doi.org/10.1177/1358863X211042082DOI Listing
October 2021

Substance use and mental health burden in head and neck and other cancer survivors: A National Health Interview Survey analysis.

Cancer 2022 Jan 9;128(1):112-121. Epub 2021 Sep 9.

Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: Tobacco dependence, alcohol abuse, depression, distress, and other adverse patient-level influences are common in head and neck cancer (HNC) survivors. Their interrelatedness and precise burden in comparison with survivors of other cancers are poorly understood.

Methods: National Health Interview Survey data from 1997 to 2016 were pooled. The prevalence of adverse patient-level influences among HNC survivors and matched survivors of other cancers were compared using descriptive statistics. Multivariable logistic regressions evaluating covariate associations with the primary study outcomes were performed. These included 1) current cigarette smoking and/or heavy alcohol use (>14 drinks per week) and 2) high mental health burden (severe psychological distress [Kessler Index ≥ 13] and/or frequent depressive/anxiety symptoms).

Results: In all, 918 HNC survivors and 3672 matched survivors of other cancers were identified. Compared with other cancer survivors, more HNC survivors were current smokers and/or heavy drinkers (24.6% [95% CI, 21.5%-27.7%] vs 18.0% [95% CI, 16.6%-19.4%]) and exhibited a high mental health burden (18.6% [95% CI, 15.7%-21.5%] vs 13.0% [95% CI, 11.7%-14.3%]). In multivariable analyses, 1) a high mental health burden predicted for smoking and/or heavy drinking (odds ratio [OR], 1.4; 95% CI, 1.0-1.9), and 2) current cigarette smoking predicted for a high mental health burden (OR, 1.7; 95% CI, 1.2-2.3). Furthermore, nonpartnered marital status and uninsured/Medicaid insurance status were significantly associated with both cigarette smoking and/or heavy alcohol use (ORs, 1.9 [95% CI, 1.4-2.5] and 1.5 [95% CI, 1.0-2.1], respectively) and a high mental health burden (ORs, 1.4 [95% CI, 1.1 -1.8] and 3.0 [95% CI, 2.2-4.2], respectively).

Conclusions: Stakeholders should allocate greater supportive care resources to HNC survivors. The interdependence of substance abuse, adverse mental health symptoms, and other adverse patient-level influences requires development of novel, multimodal survivorship care interventions.
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http://dx.doi.org/10.1002/cncr.33881DOI Listing
January 2022

EEG Spectral Power: A Proposed Physiological Biomarker to Classify the Hypoxic-Ischemic Encephalopathy Severity in Real Time.

Pediatr Neurol 2021 09 12;122:7-14. Epub 2021 Jun 12.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Background: Mild hypoxic-ischemic encephalopathy (HIE) constitutes a large unstudied population with considerable debate on how to define and treat due to the dynamic evolution of the clinical signs of encephalopathy. We propose to address this gap with quantitative physiological biomarkers to aid in stratification of the disease severity. The objectives of this prospective cohort study were to measure the electroencephalographic (EEG) power as an objective biomarker of the evolution of the clinical encephalopathy in newborns with mild to severe HIE.

Methods: EEG was collected in infants with HIE using four bipolar electrodes analyzed for the first three hours of the recording. Delta power (DP, 0.5 to 4 Hz) and total power (TP, 0.5 to 20 Hz) were compared between groups with different HIE severity using a univariate ordinal logistic regression model and receiver operating characteristic curves.

Results: A total of 44 term-born infants with mild to severe HIE were identified within six hours of birth. The DP and TP values were significantly higher for the mild group than for the moderate group for all bipolar electrodes. A one-unit increase in DP was associated with significantly lower odds of encephalopathy. DP best distinguished mild from higher encephalopathy grades by area under the curve.

Conclusions: We conclude that DP and TP are sensitive real-time biomarkers for monitoring the dynamic evolution of the encephalopathy severity in the first day of life. The quantitative EEG power may lead to timely recognition of the worsening of the encephalopathy and guide future therapeutic interventions targeting mild HIE.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.06.001DOI Listing
September 2021

Prepectoral versus Subpectoral Tissue Expander Breast Reconstruction: A Historically Controlled, Propensity Score-Matched Comparison of Perioperative Outcomes.

Plast Reconstr Surg 2021 Jul;148(1):1-9

From the Departments of Plastic Surgery and Population and Data Sciences and the Medical School, University of Texas Southwestern Medical Center.

Background: The rising popularity of prepectoral tissue expander placement with acellular dermal matrices in immediate breast reconstruction has prompted many studies on the safety of this technique. However, a comprehensive propensity-matched, historically controlled trial comparing perioperative outcomes following prepectoral versus partial subpectoral (dual-plane) placement of tissue expanders is lacking.

Methods: Retrospective propensity-matched cohort analysis was performed on all patients of two senior reconstructive surgeons who underwent bilateral tissue expander placement following a mastectomy with one of three breast surgeons at a single academic institution from 2012 onward (n = 260). Two matched groups (prepectoral and partial subpectoral) each consisted of 102 patients. Univariate and multivariable analyses were also performed to contextualize the risks associated with prepectoral reconstruction relative to demographic characteristics and other clinical factors.

Results: Compared to dual-plane subpectoral placement, prepectoral placement resulted in similar rates of overall perioperative complications (32 percent versus 31 percent; p = 1.00) and perioperative complications that required operative treatment (21 percent versus 21 percent; p = 1.00). There were no significant differences between the groups in complication rates for hematomas, seromas, impaired wound healing, and infection. Although prepectoral placement was associated with prolonged time to drain removal, those patients completed the expansion process twice as fast, were expanded further in the operating room, and were more than twice as likely to forgo clinic-based expansion. Prepectoral reconstruction was not associated with increased risk for any complications in univariate or multivariable analysis.

Conclusions: Prepectoral tissue expander placement permitted greater intraoperative filling of expanders and a reduced likelihood of clinic-based expansion, with no increase in adverse outcomes compared to partial subpectoral placement. Adoption of this technique may reduce unnecessary clinic visits; shorten the delay before adjuvant therapy; and minimize patient apprehension, pain, and discomfort related to clinic-based expansion.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0000000000008013DOI Listing
July 2021

Outcomes of Pediatric Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis.

Crit Care Med 2021 04;49(4):682-692

University of Texas Southwestern Medical Center, Dallas, TX.

Objective: The goal of this work is to provide insight into survival and neurologic outcomes of pediatric patients supported with extracorporeal cardiopulmonary resuscitation.

Data Sources: A systematic search of Embase, PubMed, Cochrane, Scopus, Google Scholar, and Web of Science was performed from January 1990 to May 2020.

Study Selection: A comprehensive list of nonregistry studies with pediatric patients managed with extracorporeal cardiopulmonary resuscitation was included.

Data Extraction: Study characteristics and outcome estimates were extracted from each article.

Data Synthesis: Estimates were pooled using random-effects meta-analysis. Differences were estimated using subgroup meta-analysis and meta-regression. The Meta-analyses Of Observational Studies in Epidemiology guideline was followed and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation system. Twenty-eight studies (1,348 patients) were included. There was a steady increase in extracorporeal cardiopulmonary resuscitation occurrence rate from the 1990s until 2020. There were 32, 338, and 1,094 patients' articles published between 1990 and 2000, 2001 and 2010, and 2010 and 2020, respectively. More than 70% were cannulated for a primary cardiac arrest. Pediatric extracorporeal cardiopulmonary resuscitation patients had a 46% (CI 95% = 43-48%; p < 0.01) overall survival rate. The rate of survival with favorable neurologic outcome was 30% (CI 95% = 27-33%; p < 0.01).

Conclusions: The use of extracorporeal cardiopulmonary resuscitation is rapidly expanding, particularly for children with underlying cardiac disease. An overall survival of 46% and favorable neurologic outcomes add credence to this emerging therapy.
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http://dx.doi.org/10.1097/CCM.0000000000004882DOI Listing
April 2021

Clinical outcomes of patients with and without chronic kidney disease undergoing endovascular revascularization of infrainguinal peripheral artery disease: Insights from the XLPAD registry.

Catheter Cardiovasc Interv 2021 08 1;98(2):310-316. Epub 2021 Feb 1.

Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Objectives: The purpose of the present study was to define clinical outcomes of chronic kidney disease (CKD) patients undergoing endovascular revascularization of infrainguinal peripheral artery disease (PAD).

Background: CKD is an established predictor of advanced PAD. However, clinical outcomes for these patients following endovascular revascularization remain inadequately defined.

Methods: Using the ongoing multicenter Excellence in Peripheral Artery Disease (XLPAD) registry (NCT01904851), we analyzed all-cause death, target limb amputation, and need for repeat revascularization for patients with and without CKD undergoing infrainguinal endovascular revascularization between the years 2005 and 2018.

Results: Of 3,699 patients, 15.1% (n = 559) had baseline CKD. CKD patients had significantly higher incidence of heavily calcified lesions (48.4% vs. 38.1%, p < .001) and diffuse disease (66.9% vs. 61.5%, p = .007). Kaplan-Meier analysis showed significant differences between CKD and non-CKD patient outcomes at 12 months for freedom from target limb amputation (79.9% vs. 92.7%, p < .001) and all-cause death (90.1% vs. 97.6%, p < .001). However, freedom from target vessel revascularization was similar between the groups. After adjusting for baseline comorbidities in the CKD and non-CKD groups, the hazard ratios for target limb amputation and death at 12 months were 2.28 (95% confidence interval or CI 1.25-4.17, p < .001) and 4.38 (95% CI 2.58-7.45, p < .001), respectively.

Conclusions: Following endovascular revascularization for infrainguinal PAD, CKD was an independent predictor of all-cause death and target limb amputation at 12 months.
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http://dx.doi.org/10.1002/ccd.29491DOI Listing
August 2021

Intraoperative Microvascular Complications in Autologous Breast Reconstruction: The Effects of Resident Training on Microsurgical Outcomes.

J Reconstr Microsurg 2021 May 6;37(4):309-314. Epub 2020 Sep 6.

Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

Background:  Academic medical centers with large volumes of autologous breast reconstruction afford residents hand-on educational experience in microsurgical techniques. We present our experience with autologous reconstruction (deep inferior epigastric perforators, profunda artery perforator, lumbar artery perforator, bipedicled, and stacked) where a supervised trainee completed the microvascular anastomosis.

Methods:  Retrospective chart review was performed on 413 flaps (190 patients) with microvascular anastomoses performed by postgraduate year (PGY)-4, PGY-5, PGY-6, PGY-7 (microsurgery fellow), or attending physician (AP). Comorbidities, intra-operative complications, revisions, operative time, ischemia time, return to operating room (OR), and flap losses were compared between training levels.

Results:  Age and all comorbidities were equivalent between groups. Total operative time was highest for the AP group. Flap ischemia time, return to OR, and intraoperative complication were equivalent between groups. Percentage of flaps requiring at least one revision of the original anastomosis was significantly higher in PGY-4 and AP than in microsurgical fellows: PGY-4 (16%), PGY-5 (12%), PGY-6 (7%), PGY-7 (2.1%), and AP (16%), = 0.041. Rates of flap loss were equivalent between groups, with overall flap loss between all groups 2/413 (<1%).

Conclusion:  With regard to flap loss and microsurgical vessel compromise, lower PGYs did not significantly worsen surgical outcomes for patients. AP had the longest total operative time, likely due to flap selection bias. PGY-4 and AP groups had higher rates of revision of original anastomosis compared with PGY-7, though ultimately these differences did not impact overall operative time, complication rate, or flap losses. Hands-on supervised microsurgical education appears to be both safe for patients, and also an effective way of building technical proficiency in plastic surgery residents.
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http://dx.doi.org/10.1055/s-0040-1716404DOI Listing
May 2021

EEG is A Predictor of Neuroimaging Abnormalities in Pediatric Extracorporeal Membrane Oxygenation.

J Clin Med 2020 Aug 4;9(8). Epub 2020 Aug 4.

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

The goal of this project was to evaluate if severity of electroencephalogram (EEG) during or shortly after being placed on extracorporeal membrane oxygenation (ECMO) would correlate with neuroimaging abnormalities, and if that could be used as an early indicator of neurologic injury. This was a retrospective chart review spanning November 2009 to May 2018. Patients who had an EEG recording during ECMO or within 48 hours after being decannulated (early group) or within 3 months of being on ECMO (late group) were included if they also had ECMO-related neuroimaging. In the early EEG group, severity of the EEG findings of mild, moderate, and severe EEG correlated to mild, moderate, and severe neuroimaging scores. Patients on venoarterial (VA) ECMO were noted to have higher EEG and neuroimaging severity; this was statistically significant. There was no association in the late EEG group to neuroimaging abnormalities. Our study highlights that EEG severity can be an early predictor for neuroimaging abnormalities that can be identified by computed tomography (CT) and or magnetic resonance imaging (MRI). This can provide guidance for both the medical team and families, allowing for a better understanding of overall prognosis.
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http://dx.doi.org/10.3390/jcm9082512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463499PMC
August 2020

Regional heterogeneity of cerebral hemodynamics in mild neonatal encephalopathy measured with multichannel near-infrared spectroscopy.

Pediatr Res 2021 03 3;89(4):882-888. Epub 2020 Jun 3.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Neuromonitoring at the bedside is the key to understand the pathophysiological mechanisms of brain injury associated with neonatal encephalopathy. The current practice is to monitor the forehead using a noninvasive cerebral oximetry-it remains unknown to what extent cerebral hemodynamics in other brain regions is different to the frontal region.

Method: A multichannel near-infrared spectroscopy (NIRS) system was used to monitor neonates (n = 14) with fetal acidosis and mild neonatal encephalopathy at four brain regions (the frontal, posterior, left temporal, and right temporal lobes). The data were compared to delineate the regional difference in (1) cerebral hemodynamics and (2) pressure autoregulation. For both analyses, wavelet transform coherence was applied.

Results: We observed frontal-posterior heterogeneity as indicated by significantly lower coherence between these two regions (p = 0.02). Furthermore, areas with regional magnetic resonance imaging (MRI)-detected lesions showed greater hemodynamic variations compared to non-affected areas (p = 0.03), while cerebral autoregulation was not affected and showed no difference.

Conclusion: Cerebral hemodynamics in mild neonatal encephalopathy is heterogeneous across different brain regions, while cerebral autoregulation remains intact. These findings indicate the robustness of the wavelet measure of cerebral autoregulation in this population, but need to be further investigated in the presence of severe injury.

Impact: This proof-of-concept study is the first to investigate the regional difference of cerebral hemodynamics and autoregulation in mild neonatal encephalopathy. Study findings confirm that brain functions are complex in the developing neonatal brain and that cerebral hemodynamics are region specific in newborns with frontal-posterior heterogeneity among brain regions probed by multichannel NIRS. Regional MRI lesions were associated with differences across NIRS regional channels among the affected side. Cerebral autoregulation with multichannel NIRS is not affected by regional MRI abnormalities.
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http://dx.doi.org/10.1038/s41390-020-0992-5DOI Listing
March 2021

Embracing study heterogeneity for finding genetic interactions in large-scale research consortia.

Genet Epidemiol 2020 01 4;44(1):52-66. Epub 2019 Oct 4.

Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania.

Genetic interactions have been recognized as a potentially important contributor to the heritability of complex diseases. Nevertheless, due to small effect sizes and stringent multiple-testing correction, identifying genetic interactions in complex diseases is particularly challenging. To address the above challenges, many genomic research initiatives collaborate to form large-scale consortia and develop open access to enable sharing of genome-wide association study (GWAS) data. Despite the perceived benefits of data sharing from large consortia, a number of practical issues have arisen, such as privacy concerns on individual genomic information and heterogeneous data sources from distributed GWAS databases. In the context of large consortia, we demonstrate that the heterogeneously appearing marginal effects over distributed GWAS databases can offer new insights into genetic interactions for which conventional methods have had limited success. In this paper, we develop a novel two-stage testing procedure, named phylogenY-based effect-size tests for interactions using first 2 moments (YETI2), to detect genetic interactions through both pooled marginal effects, in terms of averaging site-specific marginal effects, and heterogeneity in marginal effects across sites, using a meta-analytic framework. YETI2 can not only be applied to large consortia without shared personal information but also can be used to leverage underlying heterogeneity in marginal effects to prioritize potential genetic interactions. We investigate the performance of YETI2 through simulation studies and apply YETI2 to bladder cancer data from dbGaP.
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http://dx.doi.org/10.1002/gepi.22262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980207PMC
January 2020

National Survey of Hospitalists' Experiences with Incidental Pulmonary Nodules.

J Hosp Med 2019 06 20;14(6):353-356. Epub 2019 Feb 20.

University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Incidental pulmonary nodules (IPNs) are common and often require follow-up. The Fleischner Society guidelines were created to support IPN management. We developed a 14-item survey to examine hospitalists' exposure to and management of IPNs. The survey targeted attendees of the 2016 Society of Hospital Medicine (SHM) annual conference. We recruited 174 attendees. In total, 82% were identified as hospitalist physicians and 7% as advanced practice providers; 63% practiced for >5 years and 62% supervised trainees. All reported seeing ≥1 IPN case in the past six months, with 39% seeing three to five cases and 39% seeing six or more cases. Notwithstanding, 42% were unfamiliar with the Fleischner Society guidelines. When determining the IPN follow-up, 83% used radiology report recommendations, 64% consulted national or international guidelines, and 34% contacted radiologists; 34% agreed that determining the follow-up was challenging; only 15% reported availability of automated tracking systems. In conclusion, despite frequent IPN exposure, hospitalists are frequently unaware of the Fleischner Society guidelines and rely on radiologists' recommendations.
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http://dx.doi.org/10.12788/jhm.3115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824805PMC
June 2019

DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway.

Clin Cancer Res 2019 01 23;25(2):641-651. Epub 2018 Oct 23.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease. Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with kinase activating mutations were tested for sensitivity to anti-ERBB2 agents and . Biochemical changes were measured by reverse-phase protein arrays.

Results: WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type model.

Conclusions: The and models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating mutations in patients with SBA that harbor these alterations.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335167PMC
January 2019

Copas-like selection model to correct publication bias in systematic review of diagnostic test studies.

Stat Methods Med Res 2019 Oct-Nov;28(10-11):2912-2923. Epub 2018 Jul 31.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The accuracy of a diagnostic test, which is often quantified by a pair of measures such as sensitivity and specificity, is critical for medical decision making. Separate studies of an investigational diagnostic test can be combined through meta-analysis; however, such an analysis can be threatened by publication bias. To the best of our knowledge, there is no existing method that accounts for publication bias in the meta-analysis of diagnostic tests involving bivariate outcomes. In this paper, we extend the Copas selection model from univariate outcomes to bivariate outcomes for the correction of publication bias when the probability of a study being published can depend on its sensitivity, specificity, and the associated standard errors. We develop an expectation-maximization algorithm for the maximum likelihood estimation under the proposed selection model. We investigate the finite sample performance of the proposed method through simulation studies and illustrate the method by assessing a meta-analysis of 17 published studies of a rapid diagnostic test for influenza.
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http://dx.doi.org/10.1177/0962280218791602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443505PMC
December 2020

The performance of rapid plasma reagin (RPR) titer in HIV-negative general paresis after neurosyphilis therapy.

BMC Infect Dis 2018 04 2;18(1):144. Epub 2018 Apr 2.

Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong, 510630, People's Republic of China.

Background: Repeated nontreponemal serologic test for syphilis titers is recommended to evaluate treatment response. However, it is unknown whether serum rapid plasma reagin (RPR) titer can serve as a surrogate for determining the efficacy of treatment in general paresis (GP) remains unknown.

Methods: We retrospectively reviewed data from 105 GP patients, who were divided into two groups (62 CSF RPR+ patients and 43 CSF RPR- patients) according to reactive RPR test status in CSF. Clinical assessment included the Mini-Mental State Examination (MMSE) scores, CSF examinations (WBC count, protein concentration and RPR titer), and serum tests (RPR titer and TPPA). Among the 105 GP patients, 13 CSF RPR+ patients and 6 CSF RPR- patients had a 12 months follow-up of CSF, serum measures and MMSE.

Results: The median serum RPR titer was significantly higher in CSF RPR+ patients than that in CSF RPR- GP patients, 1:8 [IQR 1:4-1:32] vs. 1:4 [IQR 1:4-1:8] (P < 0.001). The number of CSF RPR+ patients with serum RPR titer≥1:32 was significantly higher when compared with CSF RPR- patients (P = 0.001). For CSF RPR+ patients, the MMSE scores improved or remained constantly after penicillin treatment. For CSF RPR+ patients, the CSF RPR titer declined four-fold in 85% (11/13) of the patients, whereas the serum RPR titer declined four-fold in only 46% (6/13) of the patients, the odds ratio is 6.4 (95% confidence interval 1.0-41.2).

Conclusions: A four-fold decline in CSF RPR titer is a good predictor for treatment efficacy in CSF RPR+ GP patients within 12 months after the completion of therapy.
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http://dx.doi.org/10.1186/s12879-018-3062-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879544PMC
April 2018

Bayesian mixed treatment comparisons meta-analysis for correlated outcomes subject to reporting bias.

J R Stat Soc Ser C Appl Stat 2018 01 17;67(1):127-144. Epub 2017 Mar 17.

Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, U.S.A.

Many randomized controlled trials (RCTs) report more than one primary outcome. As a result, multivariate meta-analytic methods for the assimilation of treatment effects in systematic reviews of RCTs have received increasing attention in the literature. These methods show promise with respect to bias reduction and efficiency gain compared to univariate meta-analysis. However, most methods for multivariate meta-analysis have focused on pairwise treatment comparisons (i.e., when the number of treatments is two). Current methods for mixed treatment comparisons (MTC) meta-analysis (i.e., when the number of treatments is more than two) have focused on univariate or very recently, bivariate outcomes. To broaden their application, we propose a framework for MTC meta-analysis of multivariate (≥ 2) outcomes where the correlations among multivariate outcomes within- and between-studies are accounted for through copulas, and the joint modeling of multivariate random effects, respectively. We consider a Bayesian hierarchical model using Markov Chain Monte Carlo methods for estimation. An important feature of the proposed framework is that it allows for borrowing of information across correlated outcomes. We show via simulation that our approach reduces the impact of outcome reporting bias (ORB) in a variety of missing outcome scenarios. We apply the method to a systematic review of RCTs of pharmacological treatments for alcohol dependence, which tends to report multiple outcomes potentially subject to ORB.
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http://dx.doi.org/10.1111/rssc.12220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846497PMC
January 2018

On meta- and mega-analyses for gene-environment interactions.

Genet Epidemiol 2017 12 7;41(8):876-886. Epub 2017 Nov 7.

Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Gene-by-environment (G × E) interactions are important in explaining the missing heritability and understanding the causation of complex diseases, but a single, moderately sized study often has limited statistical power to detect such interactions. With the increasing need for integrating data and reporting results from multiple collaborative studies or sites, debate over choice between mega- versus meta-analysis continues. In principle, data from different sites can be integrated at the individual level into a "mega" data set, which can be fit by a joint "mega-analysis." Alternatively, analyses can be done at each site, and results across sites can be combined through a "meta-analysis" procedure without integrating individual level data across sites. Although mega-analysis has been advocated in several recent initiatives, meta-analysis has the advantages of simplicity and feasibility, and has recently led to several important findings in identifying main genetic effects. In this paper, we conducted empirical and simulation studies, using data from a G × E study of lung cancer, to compare the mega- and meta-analyses in four commonly used G × E analyses under the scenario that the number of studies is small and sample sizes of individual studies are relatively large. We compared the two data integration approaches in the context of fixed effect models and random effects models separately. Our investigations provide valuable insights in understanding the differences between mega- and meta-analyses in practice of combining small number of studies in identifying G × E interactions.
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http://dx.doi.org/10.1002/gepi.22085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775907PMC
December 2017

A meta-analytic framework for detection of genetic interactions.

Genet Epidemiol 2016 11 15;40(7):534-543. Epub 2016 Aug 15.

Division of Biostatistics, School of Public Health, The University of Texas, Houston, TX 77030, USA.

With varying, but substantial, proportions of heritability remaining unexplained by summaries of single-SNP genetic variation, there is a demand for methods that extract maximal information from genetic association studies. One source of variation that is difficult to assess is genetic interactions. A major challenge for naive detection methods is the large number of possible combinations, with a requisite need to correct for multiple testing. Assumptions of large marginal effects, to reduce the search space, may be restrictive and miss higher order interactions with modest marginal effects. In this paper, we propose a new procedure for detecting gene-by-gene interactions through heterogeneity in estimated low-order (e.g., marginal) effect sizes by leveraging population structure, or ancestral differences, among studies in which the same phenotypes were measured. We implement this approach in a meta-analytic framework, which offers numerous advantages, such as robustness and computational efficiency, and is necessary when data-sharing limitations restrict joint analysis. We effectively apply a dimension reduction procedure that scales to allow searches for higher order interactions. For comparison to our method, which we term phylogenY-aware Effect-size Tests for Interactions (YETI), we adapt an existing method that assumes interacting loci will exhibit strong marginal effects to our meta-analytic framework. As expected, YETI excels when multiple studies are from highly differentiated populations and maintains its superiority in these conditions even when marginal effects are small. When these conditions are less extreme, the advantage of our method wanes. We assess the Type-I error and power characteristics of complementary approaches to evaluate their strengths and limitations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081230PMC
http://dx.doi.org/10.1002/gepi.21996DOI Listing
November 2016

A simple and robust method for multivariate meta-analysis of diagnostic test accuracy.

Stat Med 2017 01 31;36(1):105-121. Epub 2016 Aug 31.

Department of Biostatistics, Brown University School of Public Health, Providence, RI 02903, U.S.A.

Meta-analysis of diagnostic test accuracy often involves mixture of case-control and cohort studies. The existing bivariate random-effects models, which jointly model bivariate accuracy indices (e.g., sensitivity and specificity), do not differentiate cohort studies from case-control studies and thus do not utilize the prevalence information contained in the cohort studies. The recently proposed trivariate generalized linear mixed-effects models are only applicable to cohort studies, and more importantly, they assume a common correlation structure across studies and trivariate normality on disease prevalence, test sensitivity, and specificity after transformation by some pre-specified link functions. In practice, very few studies provide justifications of these assumptions, and sometimes these assumptions are violated. In this paper, we evaluate the performance of the commonly used random-effects model under violations of these assumptions and propose a simple and robust method to fully utilize the information contained in case-control and cohort studies. The proposed method avoids making the aforementioned assumptions and can provide valid joint inferences for any functions of overall summary measures of diagnostic accuracy. Through simulation studies, we find that the proposed method is more robust to model misspecifications than the existing methods. We apply the proposed method to a meta-analysis of diagnostic test accuracy for the detection of recurrent ovarian carcinoma. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.7093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143393PMC
January 2017

A hybrid model for combining case-control and cohort studies in systematic reviews of diagnostic tests.

J R Stat Soc Ser C Appl Stat 2015 Apr;64(3):469-489

Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA.

Systematic reviews of diagnostic tests often involve a mixture of case-control and cohort studies. The standard methods for evaluating diagnostic accuracy only focus on sensitivity and specificity and ignore the information on disease prevalence contained in cohort studies. Consequently, such methods cannot provide estimates of measures related to disease prevalence, such as population averaged or overall positive and negative predictive values, which reflect the clinical utility of a diagnostic test. In this paper, we propose a hybrid approach that jointly models the disease prevalence along with the diagnostic test sensitivity and specificity in cohort studies, and the sensitivity and specificity in case-control studies. In order to overcome the potential computational difficulties in the standard full likelihood inference of the proposed hybrid model, we propose an alternative inference procedure based on the composite likelihood. Such composite likelihood based inference does not suffer computational problems and maintains high relative efficiency. In addition, it is more robust to model mis-specifications compared to the standard full likelihood inference. We apply our approach to a review of the performance of contemporary diagnostic imaging modalities for detecting metastases in patients with melanoma.
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http://dx.doi.org/10.1111/rssc.12087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401477PMC
April 2015

A composite likelihood method for bivariate meta-analysis in diagnostic systematic reviews.

Stat Methods Med Res 2017 04 14;26(2):914-930. Epub 2014 Dec 14.

4 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, USA.

Diagnostic systematic review is a vital step in the evaluation of diagnostic technologies. In many applications, it involves pooling pairs of sensitivity and specificity of a dichotomized diagnostic test from multiple studies. We propose a composite likelihood (CL) method for bivariate meta-analysis in diagnostic systematic reviews. This method provides an alternative way to make inference on diagnostic measures such as sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. Its main advantages over the standard likelihood method are the avoidance of the nonconvergence problem, which is nontrivial when the number of studies is relatively small, the computational simplicity, and some robustness to model misspecifications. Simulation studies show that the CL method maintains high relative efficiency compared to that of the standard likelihood method. We illustrate our method in a diagnostic review of the performance of contemporary diagnostic imaging technologies for detecting metastases in patients with melanoma.
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http://dx.doi.org/10.1177/0962280214562146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466215PMC
April 2017

A unification of models for meta-analysis of diagnostic accuracy studies without a gold standard.

Biometrics 2015 Jun 30;71(2):538-47. Epub 2014 Oct 30.

Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota 55455, U.S.A.

Several statistical methods for meta-analysis of diagnostic accuracy studies have been discussed in the presence of a gold standard. However, in practice, the selected reference test may be imperfect due to measurement error, non-existence, invasive nature, or expensive cost of a gold standard. It has been suggested that treating an imperfect reference test as a gold standard can lead to substantial bias in the estimation of diagnostic test accuracy. Recently, two models have been proposed to account for imperfect reference test, namely, a multivariate generalized linear mixed model (MGLMM) and a hierarchical summary receiver operating characteristic (HSROC) model. Both models are very flexible in accounting for heterogeneity in accuracies of tests across studies as well as the dependence between tests. In this article, we show that these two models, although with different formulations, are closely related and are equivalent in the absence of study-level covariates. Furthermore, we provide the exact relations between the parameters of these two models and assumptions under which two models can be reduced to equivalent submodels. On the other hand, we show that some submodels of the MGLMM do not have corresponding equivalent submodels of the HSROC model, and vice versa. With three real examples, we illustrate the cases when fitting the MGLMM and HSROC models leads to equivalent submodels and hence identical inference, and the cases when the inferences from two models are slightly different. Our results generalize the important relations between the bivariate generalized linear mixed model and HSROC model when the reference test is a gold standard.
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http://dx.doi.org/10.1111/biom.12264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416105PMC
June 2015

ZIP4 is a novel molecular marker for glioma.

Neuro Oncol 2013 Aug 17;15(8):1008-16. Epub 2013 Apr 17.

The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX, USA.

Background: Dysregulated zinc transport has been observed in many cancers. However, the status of zinc homeostasis and the expression profile of zinc transporters in brain and brain tumors have not been reported.

Methods: The gene profiles of 14 zinc importers (ZIPs) and 10 zinc exporters (ZnTs) in patients with glioma were studied by investigating the association between the zinc transporters and brain tumor characteristics (tumor grade and overall survival time). Three independent cohorts were analyzed to cross-validate the findings: the Chinese Glioma Genome Atlas (CGCA) cohort (n = 186), the US National Cancer Institute Repository for Molecular Brain Neoplasia Data (REMBRANDT) cohort (n = 335), and The University of Texas (UT) cohort (n = 34).

Results: The expression of ZIP3, 4, 8, 14, ZnT5, 6, and 7 were increased, and the expression of ZnT10 was decreased in grade IV gliomas, compared with grade II gliomas. Among all 24 zinc transporters, ZIP4 is most significantly associated with tumor grade and overall survival; this finding is consistent across 2 independent cohorts (CGCA and REMBRANDT) and is partially validated by the third cohort (UT). High ZIP4 expression was significantly associated with higher grade of gliomas and shorter overall survival (hazard ratio = 1.61, 95% confidence interval = 1.02-2.53, P = .040 in CGCA cohort; hazard ratio = 1.32, 95% confidence interval = 1.08-1.61, P = .007 in REMBRANDT cohort).

Conclusions: Dysregulated expression of zinc transporters is involved in the progression of gliomas. Our results suggest that ZIP4 may serve as a potential diagnostic and prognostic marker for gliomas.
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http://dx.doi.org/10.1093/neuonc/not042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714151PMC
August 2013
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