Publications by authors named "QinGxia Chen"

102 Publications

Before-Visit Questionnaire: A Tool to Augment Communication and Decrease Provider Documentation Burden in Pediatric Diabetes.

Appl Clin Inform 2021 Oct 20;12(5):969-978. Epub 2021 Oct 20.

Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States.

Objective:  To develop and evaluate an electronic tool that collects interval history and incorporates it into a provider summary note.

Methods:  A parent-facing online before-visit questionnaire (BVQ) collected information from parents and caregivers of pediatric diabetes patients prior to a clinic encounter. This information was related to interval history and perceived self-management barriers. The BVQ generated a summary note that providers could paste in their own documentation. Parents also completed postvisit experience questionnaires. We assessed the BVQs perceived usefulness to parents and providers and compared provider documentation content and length pre- and post-BVQ rollout. We interviewed providers regarding their experiences with the system-generated note.

Results:  Seventy-three parents of diabetic children were recruited and completed the BVQ. A total of 79% of parents stated that the BVQ helped with visit preparation and 80% said it improved perceived quality of visits. All 16 participating providers reviewed BVQs prior to patient encounters and 100% considered the summary beneficial. Most providers (81%) desired summaries less than 1 week old. A total of 69% of providers preferred the prose version of the summary; however, 75% also viewed the bulleted version as preferable for provider review. Analysis of provider notes revealed that BVQs increased provider documentation of patients' adherence and barriers. We observed a 50% reduction in typing by providers to document interval histories. Providers not using summaries typed an average of 137 words (standard deviation [SD]: 74) to document interval history compared with 68 words [SD 47] typed with BVQ use.

Discussion:  Providers and parents of children with diabetes appreciated the use of previsit, parent-completed BVQs that automatically produced provider documentation. Despite the BVQ redistributing work from providers to parents, its use was acceptable to both groups.

Conclusion:  Parent-completed questionnaires on the patient's behalf that generate provider documentation encourage communication between parents and providers regarding disease management and reduce provider workload.
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http://dx.doi.org/10.1055/s-0041-1736223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528566PMC
October 2021

Ensemble learning to predict opioid-related overdose using statewide prescription drug monitoring program and hospital discharge data in the state of Tennessee.

J Am Med Inform Assoc 2021 Oct 19. Epub 2021 Oct 19.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objective: To develop and validate algorithms for predicting 30-day fatal and nonfatal opioid-related overdose using statewide data sources including prescription drug monitoring program data, Hospital Discharge Data System data, and Tennessee (TN) vital records. Current overdose prevention efforts in TN rely on descriptive and retrospective analyses without prognostication.

Materials And Methods: Study data included 3 041 668 TN patients with 71 479 191 controlled substance prescriptions from 2012 to 2017. Statewide data and socioeconomic indicators were used to train, ensemble, and calibrate 10 nonparametric "weak learner" models. Validation was performed using area under the receiver operating curve (AUROC), area under the precision recall curve, risk concentration, and Spiegelhalter z-test statistic.

Results: Within 30 days, 2574 fatal overdoses occurred after 4912 prescriptions (0.0069%) and 8455 nonfatal overdoses occurred after 19 460 prescriptions (0.027%). Discrimination and calibration improved after ensembling (AUROC: 0.79-0.83; Spiegelhalter P value: 0-.12). Risk concentration captured 47-52% of cases in the top quantiles of predicted probabilities.

Discussion: Partitioning and ensembling enabled all study data to be used given computational limits and helped mediate case imbalance. Predicting risk at the prescription level can aggregate risk to the patient, provider, pharmacy, county, and regional levels. Implementing these models into Tennessee Department of Health systems might enable more granular risk quantification. Prospective validation with more recent data is needed.

Conclusion: Predicting opioid-related overdose risk at statewide scales remains difficult and models like these, which required a partnership between an academic institution and state health agency to develop, may complement traditional epidemiological methods of risk identification and inform public health decisions.
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http://dx.doi.org/10.1093/jamia/ocab218DOI Listing
October 2021

Potential impact of oral flora dispersal on patients wearing face masks when undergoing ophthalmologic procedures.

BMJ Open Ophthalmol 2021 5;6(1):e000804. Epub 2021 Oct 5.

Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Objective: The purpose of this study is to investigate the amount of oral flora dispersion towards the ocular surface in relation to various face mask scenarios.

Methods And Analysis: Thirty participants were recruited for this prospective cross-sectional study. Each participant was seated and instructed to hold a blood agar plate perpendicular to the bridge of their nose and facing downward. Participants then partook in three unique face mask scenarios: no face mask, surgical face mask and surgical face mask with tape securing the superior edge. During each scenario, participants were instructed to forcefully exhale for 5 s three times. The primary outcome measure was the number of colony-forming units (CFUs) grown on each face mask scenario-specific plate.

Results: Thirty participants were recruited for the study, and a total of 90 chocolate agar plates were successfully incubated. The proportion of detecting any CFU was 6.67% (95% CI: 0.818% to 22.1%) for no mask scenario, 0% (95% CI: 0% to 11.6%) for mask scenario and 3.33% (95% CI: 0.0844% to 17.2%) for mask-taped scenario. The mean differences in proportion of detecting any CFU were 3.33% (95% CI: 0% to 10%, p=0.309) for no mask versus mask taped, 3.35% (95% CI: 0% to 10%, p=0.307) for mask taped versus mask and 6.68% (95% CI: 0% to 16.7%, p=0.142) for no mask versus mask.

Conclusion: This study showed no difference in bacterial dispersion towards the ocular surface when comparing no face mask, a surgical face mask without tape or a surgical face mask with tape.
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http://dx.doi.org/10.1136/bmjophth-2021-000804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493904PMC
October 2021

Parent Activation in the Neonatal Intensive Care Unit.

Am J Perinatol 2021 Oct 12. Epub 2021 Oct 12.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.

Objective:  Patient activation is the knowledge, skills, and confidence to manage one's health; parent activation is a comparable concept related to a parent's ability to manage a child's health. Activation in adults is a modifiable risk factor and associated with clinical outcomes and health care utilization. We examined activation in parents of hospitalized newborns observing temporal trends and associations with sociodemographic characteristics, neonate characteristics, and outcomes.

Study Design:  Participants included adult parents of neonates admitted to a level-IV neonatal intensive care unit in an academic medical center. Activation was measured with the 10-item Parent version of the Patient Activation Measure (P-PAM) at admission, discharge, and 30 days after discharge. Associations with sociodemographic variables, health literacy, clinical variables, and health care utilization were evaluated.

Results:  A total of 96 adults of 64 neonates were enrolled. The overall mean P-PAM score on admission was 81.8 (standard deviation [SD] = 18), 88.8 (SD = 13) at discharge, and 86.8 (SD = 16) at 30-day follow-up. Using linear mixed regression model, P-PAM score was significantly associated with timing of measurement. Higher P-PAM scores were associated with higher health literacy ( = 0.002) and higher in mothers compared to fathers ( = 0.040). There were no significant associations of admission P-PAM scores with sociodemographic characteristics. Parents of neonates who had a surgical diagnosis had a statistically significant ( = 0.003) lower score than those who did not. There were no associations between discharge P-PAM scores and neonates' lengths of stay or other indicators of illness severity.

Conclusion:  Parental activation in the NICU setting was higher than reported in the adult and limited pediatric literature; scores increased from admission to discharge and 30-day postdischarge. Activation was higher in mothers and parents with higher health literacy. Additional larger scale studies are needed to determine whether parental activation is associated with long-term health care outcomes as seen in adults.

Key Points: · Little is known about activation in parents of neonates.. · Activation plays a role in health outcomes in adults.. · Larger studies are needed to explore parent activation..
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http://dx.doi.org/10.1055/s-0041-1736294DOI Listing
October 2021

Age does not influence the PPV of Vision Screening to detect ARF.

Ophthalmology 2021 Sep 7. Epub 2021 Sep 7.

Vanderbilt Eye Institute.

Among 3114 children seen at Vanderbilt Eye Institute from 11/1/2017-3/1/2020, the positive predictive value of vision screening to detect Amblyopia Risk Factors was similar for children <3 and for those aged 3-5 years.
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http://dx.doi.org/10.1016/j.ophtha.2021.08.026DOI Listing
September 2021

Imprecision and Preferences in Interpretation of Verbal Probabilities in Health: a Systematic Review.

J Gen Intern Med 2021 Aug 6. Epub 2021 Aug 6.

Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.

Introduction: Many health providers and communicators who are concerned that patients will not understand numbers instead use verbal probabilities (e.g., terms such as "rare" or "common") to convey the gist of a health message.

Objective: To assess patient interpretation of and preferences for verbal probability information in health contexts.

Methods: We conducted a systematic review of literature published through September 2020. Original studies conducted in English with samples representative of lay populations were included if they assessed health-related information and elicited either (a) numerical estimates of verbal probability terms or (b) preferences for verbal vs. quantitative risk information.

Results: We identified 33 original studies that referenced 145 verbal probability terms, 45 of which were included in at least two studies and 19 in three or more. Numerical interpretations of each verbal term were extremely variable. For example, average interpretations of the term "rare" ranged from 7 to 21%, and for "common," the range was 34 to 71%. In a subset of 9 studies, lay estimates of verbal probability terms were far higher than the standard interpretations established by the European Commission for drug labels. In 10 of 12 samples where preferences were elicited, most participants preferred numerical information, alone or in combination with verbal labels.

Conclusion: Numerical interpretation of verbal probabilities is extremely variable and does not correspond well to the numerical probabilities established by expert panels. Most patients appear to prefer quantitative risk information, alone or in combination with verbal labels. Health professionals should be aware that avoiding numeric information to describe risks may not match patient preferences, and that patients interpret verbal risk terms in a highly variable way.
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http://dx.doi.org/10.1007/s11606-021-07050-7DOI Listing
August 2021

Assessing Importance of Biomarkers: a Bayesian Joint Modeling Approach of Longitudinal and Survival Data with Semicompeting Risks.

Stat Modelling 2021 Feb 27;21(1-2):30-55. Epub 2020 Jul 27.

Department of Biostatistics, Vanderbilt University, Nashville, TN, USA.

Longitudinal biomarkers such as patient-reported outcomes (PROs) and quality of life (QOL) are routinely collected in cancer clinical trials or other studies. Joint modeling of PRO/QOL and survival data can provide a comparative assessment of patient-reported changes in specific symptoms or global measures that correspond to changes in survival. Motivated by a head and neck cancer clinical trial, we develop a class of trajectory-based models for longitudinal and survival data with disease progression. Specifically, we propose a class of mixed effects regression models for longitudinal measures, a cure rate model for the disease progression time ( ), and a Cox proportional hazards model with time-varying covariates for the overall survival time ( ) to account for and treatment switching. Under the semi-competing risks framework, the disease progression is the nonterminal event, the occurrence of which is subject to a terminal event of death. The properties of the proposed models are examined in detail. Within the Bayesian paradigm, we derive the decompositions of the deviance information criterion (DIC) and the logarithm of the pseudo marginal likelihood (LPML) to assess the fit of the longitudinal component of the model and the fit of each survival component, separately. We further develop ΔDIC as well as ΔLPML to determine the importance and contribution of the longitudinal data to the model fit of the and data.
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http://dx.doi.org/10.1177/1471082x20933363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315720PMC
February 2021

Association of Age-adjusted Charlson Comorbidity Index With Orbital Fungal Disease Outcomes.

Ophthalmic Plast Reconstr Surg 2021 Jun 4. Epub 2021 Jun 4.

Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, U.S.A. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, U.S.A. Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A. Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A. Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.

Purpose: To determine whether the age-adjusted Charlson comorbidity index (age-CCI) in sino-orbital fungal disease patients correlates with disease-specific mortality.

Methods: Hospital billing systems at 2 academic institutions were queried for patients with ICD-9, ICD-10, and CPT codes used in fungal disease who also had orbital disease and significant visual loss. Thirty-two patients at Institution A and 18 patients at Institution B met the inclusion criteria of microbiologic or pathologic confirmation of fungal infection and completion of inpatient ophthalmology evaluation. Patients without radiographic abnormality in the sinus or orbit were excluded. Demographic, diagnostic, treatment, and outcome variables were recorded. Our primary outcome was death due to fungal disease.

Results: Of the 50 medical records examined, 44 patients met the criteria for fungal-related death outcome on multivariate analysis. The regression coefficient for age-CCI and fungal-related mortality was 0.242 (95% CI, 0.012-0.779) with a p value of 0.038.

Conclusions: Age-CCI is significantly associated with fungal-related mortality. This relationship remains significant when controlling for 5 covariates of fungal organism phylum, presence or absence of CNS disease, exenteration, local treatment use, and presence or absence of an immunosuppressive diagnosis. Age-CCI shows promise as a clinical and research tool in the evaluation of invasive fungal disease involving the orbit.
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http://dx.doi.org/10.1097/IOP.0000000000001987DOI Listing
June 2021

Correlation Between Ophthalmology Market Saturation and Medicare Utilization Rates.

Am J Ophthalmol 2021 Apr 25;229:137-144. Epub 2021 Apr 25.

Department of Ophthalmology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.. Electronic address:

Purpose: To characterize usage of ophthalmologic services by Medicare Fee-For-Service (FFS) beneficiaries relative to geography-specific market saturation, demographics, and contextual factors DESIGN: Cross-sectional study METHODS: Data sets from Centers for Medicare & Medicaid Services, US Census Bureau, US Department of Agriculture, and Housing and Urban Development, were used to calculate county- and state-level ophthalmologic service usage, market saturation, and demographic characteristics. Negative binomial regression models were used to evaluate the association between results and demographic or population-specific variables.

Results: Ophthalmologic service usage ranged from 58.2% to 15.2%, whereas saturation ranged from 21,763 to 91.4 FFS beneficiaries per registered ophthalmologist. Usage was significantly associated with demographic characteristics in each geography: lower proportion of African American (P = .009), Hispanic (P < .001), and other race beneficiaries (P < .001), relative to white beneficiaries; a higher proportion of female (P < .001) relative to male; a higher proportion of adults having completed an associate degree or some college (P = .001), or holding a bachelor's degree or higher (P < .001), relative to a high school diploma; a lower proportion of adults in each geography experiencing poverty (P = .009), geographies with lower Multidimensional Deprivation Index (P < .001); a higher urban-influence code (P < .001). There was no significant correlation between the usage of ophthalmologic services and the geographic market saturation of ophthalmologists (Spearman rho, -0.030, P = .227).

Conclusions And Relevance: Ophthalmologic service usage is significantly influenced by population demographics; however, increased provider density alone appears insufficient to promote the usage of eye care services.
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http://dx.doi.org/10.1016/j.ajo.2021.04.011DOI Listing
April 2021

DDIWAS: High-throughput electronic health record-based screening of drug-drug interactions.

J Am Med Inform Assoc 2021 07;28(7):1421-1430

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objective: We developed and evaluated Drug-Drug Interaction Wide Association Study (DDIWAS). This novel method detects potential drug-drug interactions (DDIs) by leveraging data from the electronic health record (EHR) allergy list.

Materials And Methods: To identify potential DDIs, DDIWAS scans for drug pairs that are frequently documented together on the allergy list. Using deidentified medical records, we tested 616 drugs for potential DDIs with simvastatin (a common lipid-lowering drug) and amlodipine (a common blood-pressure lowering drug). We evaluated the performance to rediscover known DDIs using existing knowledge bases and domain expert review. To validate potential novel DDIs, we manually reviewed patient charts and searched the literature.

Results: DDIWAS replicated 34 known DDIs. The positive predictive value to detect known DDIs was 0.85 and 0.86 for simvastatin and amlodipine, respectively. DDIWAS also discovered potential novel interactions between simvastatin-hydrochlorothiazide, amlodipine-omeprazole, and amlodipine-valacyclovir. A software package to conduct DDIWAS is publicly available.

Conclusions: In this proof-of-concept study, we demonstrate the value of incorporating information mined from existing allergy lists to detect DDIs in a real-world clinical setting. Since allergy lists are routinely collected in EHRs, DDIWAS has the potential to detect and validate DDI signals across institutions.
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http://dx.doi.org/10.1093/jamia/ocab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279788PMC
July 2021

Fibrogranular materials function as organizers to ensure the fidelity of multiciliary assembly.

Nat Commun 2021 02 24;12(1):1273. Epub 2021 Feb 24.

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.

Multicilia are delicate motile machineries, and how they are accurately assembled is poorly understood. Here, we show that fibrogranular materials (FGMs), large arrays of electron-dense granules specific to multiciliated cells, are essential for their ultrastructural fidelity. Pcm1 forms the granular units that further network into widespread FGMs, which are abundant in spherical FGM cores. FGM cores selectively concentrate multiple important centriole-related proteins as clients, including Cep131 that specifically decorates a foot region of ciliary central pair (CP) microtubules. FGMs also tightly contact deuterosome-procentriole complexes. Disruption of FGMs in mouse cells undergoing multiciliogenesis by Pcm1 RNAi markedly deregulates centriolar targeting of FGM clients, elongates CP-foot, and alters deuterosome size, number, and distribution. Although the multicilia are produced in correct numbers, they display abnormal ultrastructure and motility. Our results suggest that FGMs organize deuterosomes and centriole-related proteins to facilitate the faithful assembly of basal bodies and multiciliary axonemes.
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http://dx.doi.org/10.1038/s41467-021-21506-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904937PMC
February 2021

Comparison of family health history in surveys vs electronic health record data mapped to the observational medical outcomes partnership data model in the All of Us Research Program.

J Am Med Inform Assoc 2021 03;28(4):695-703

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objective: Family health history is important to clinical care and precision medicine. Prior studies show gaps in data collected from patient surveys and electronic health records (EHRs). The All of Us Research Program collects family history from participants via surveys and EHRs. This Demonstration Project aims to evaluate availability of family health history information within the publicly available data from All of Us and to characterize the data from both sources.

Materials And Methods: Surveys were completed by participants on an electronic portal. EHR data was mapped to the Observational Medical Outcomes Partnership data model. We used descriptive statistics to perform exploratory analysis of the data, including evaluating a list of medically actionable genetic disorders. We performed a subanalysis on participants who had both survey and EHR data.

Results: There were 54 872 participants with family history data. Of those, 26% had EHR data only, 63% had survey only, and 10.5% had data from both sources. There were 35 217 participants with reported family history of a medically actionable genetic disorder (9% from EHR only, 89% from surveys, and 2% from both). In the subanalysis, we found inconsistencies between the surveys and EHRs. More details came from surveys. When both mentioned a similar disease, the source of truth was unclear.

Conclusions: Compiling data from both surveys and EHR can provide a more comprehensive source for family health history, but informatics challenges and opportunities exist. Access to more complete understanding of a person's family health history may provide opportunities for precision medicine.
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http://dx.doi.org/10.1093/jamia/ocaa315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973437PMC
March 2021

Variability Within Optic Nerve Optical Coherence Tomography Measurements Distinguishes Papilledema From Pseudopapilledema.

J Neuroophthalmol 2020 Oct 28. Epub 2020 Oct 28.

Department of Ophthalmology and Visual Sciences (AMF, RAL, QC, SPD), Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Biostatistics (YL, QC), Vanderbilt University Medical Center, Nashville, Tennessee.

Background: To report a linear risk score obtained using clock-hour optical coherence tomography (OCT) data from papilledema and pseudopapilledema nerves that differentiates between the 2 diagnoses with high sensitivity and specificity.

Methods: Patients presenting to a single neuro-ophthalmologist with papilledema or pseudopapilledema were included for a retrospective review. The absolute consecutive difference in OCT retinal nerve fiber layer (RNFL) thickness between adjacent clock hours and the mean magnitude of thickness for clock hours 1-12 were compared between the 2 groups using mixed-effect models adjusting for age and clock hour with a random intercept for subjects and eyes (nested within subject). The area under the curve (AUC) for the receiver operating characteristics curve and a separate calibration curve was used to evaluate potential clinical usage.

Results: Forty-four eyes with papilledema and 72 eyes with pseudopapilledema, 36 of whom had optic nerve drusen met criteria. The papilledema group had a higher mean RNFL thickness (papilledema = 163 ± 68 µm, pseudopapilledema = 82 ± 22 µm, P < 0.001). The papilledema groups also had more variability between consecutive clock hours (papilledema = 57 ± 20 µm, pseudopapilledema = 26 ± 11 µm, P < 0.001). A linear combination of each patient's averaged values separated the 2 groups with an AUC of 98.4% (95% CI 95.5%-100%) with an optimized sensitivity of 88.9% and specificity of 95.5% as well as good calibration (mean absolute error = 0.015).

Conclusions: Patients with papilledema have higher intrinsic variability and magnitude within their OCT, and this finding reliably distinguishes them from those with pseudopapilledema.
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http://dx.doi.org/10.1097/WNO.0000000000001137DOI Listing
October 2020

Seven decades of chemotherapy clinical trials: a pan-cancer social network analysis.

Sci Rep 2020 10 16;10(1):17536. Epub 2020 Oct 16.

Sequoia Regional Cancer Center, Visalia, CA, USA.

Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.
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http://dx.doi.org/10.1038/s41598-020-73466-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568560PMC
October 2020

Medial Rectus Advancement for Secondary Exotropia.

Am J Ophthalmol 2021 01 20;221:65-74. Epub 2020 Aug 20.

Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Purpose: To determine the preoperative characteristics and surgical results after medial rectus advancement in patients with secondary exotropia.

Design: Retrospective, interventional case series.

Methods: Setting: Tertiary Care University Medical Center. PatientPopulation: 221 patients with a diagnosis of secondary exotropia who underwent medial rectus advancement surgery by a single surgeon.

Observation: Preoperative demographics, exodeviation and motility, intraoperative findings, and postoperative results were recorded. MainOutcomeMeasure: Success of surgery, defined as Esotropia <15 prism diopters (pd) at postoperative week 1, or any deviation of <8 pd at postoperative month 2 (POM2).

Results: A total of 98 patients underwent unilateral medial rectus advancement (UMRadv), 89 underwent UMRadv with lateral rectus recession (LRc), and 34 underwent bilateral medial rectus advancement (BMRadv). POM2 success rates were 66.7% in UMRadv patients, 62.1% in UMRadv + LRc, and 56% in BMRadv. A total of 117 patients had preoperative adduction deficits, which were significantly associated with the finding of an intraoperative stretched scar (P < .001). Larger preoperative duction deficits were associated with larger stretched scars (P < .001). At POM2, the mean effect of surgery (pd of correction/mm) was 2.3 ± 1.4 pd/mm for UMRadv, 2.5 ± 0.8 pd/mm for UMRadv + LRc, and 2.8 ± 1.1 pd/mm for BMRadv. Patients with a stretched scar had significantly less correction per millimeter (2.2 ± 1.2 pd/mm) compared with those without (2.6 ± 1.2 pd/mm, P < .001). A total of 38.6% of patients experienced exodrift greater than 10 pd. Exodrift was significantly larger in the BMRadv group (P < .005).

Discussion: These results provide guidance for surgical correction based on preoperative deviation and ductions. Adduction deficits indicate a stretched scar, which must be treated with resection and advancement of the medial rectus. A larger amount of surgery is needed in patients with a stretched scar. Exodrift is common, and therefore aiming for approximately 10 pd of overcorrection at postoperative week 1 can improve final outcomes.

Conclusion: Medial rectus advancement results in successful surgical results at POM2 for secondary exotropia.
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http://dx.doi.org/10.1016/j.ajo.2020.08.029DOI Listing
January 2021

LncRNA LINC00641 Sponges miR-497-5p to Ameliorate Neural Injury Induced by Anesthesia via Up-Regulating BDNF.

Front Mol Neurosci 2020 30;13:95. Epub 2020 Jun 30.

Department of Urology, The First Hospital of Quanzhou, Quanzhou, China.

Introduction: Ketamine, which is widely used in anesthesia, can induce cortical neurotoxicity in patients. This study aims to investigate the effects of long non-coding RNA LINC00641 on the ketamine-induced neural injury.

Materials And Methods: In this study, rat pheochromocytoma cells (PC12 cells) were used as a cell model and Sprague-Dawley postnatal day 7 rats were used for experiments . Ketamine-induced aberrant expression levels of LINC00641, miR-497-5p and brain-derived neurotrophic factor (BDNF) were examined by qRT-PCR. The effects of LINC00641 and miR-497-5p on ketamine-induced neural injury were then examined by MTT assays and TUNEL analysis. In addition, the activity of ROS and caspase-3 was measured. The regulatory relationships between LINC00641 and miR-497-5p, miR-497-5p and BDNF were detected by dual-luciferase reporter assay, respectively.

Results: Ketamine induced the apoptosis of PC12 cells, accompanied by down-regulation of LINC00641 and BDNF, and up-regulation of miR-497-5p. LINC00641 overexpression enhanced the resistance to the apoptosis of PC12 cells, while transfection of miR-497-5p had opposite effects. Furthermore, LINC00641 could bind to miR-497-5p and reduce its expression, but indirectly increase the BDNF expression, which was considered as a protective factor in neural injury and activated TrkB/PI3K/Akt pathway.

Conclusion: Collectively, LINC00641/miR-497-5p/BDNF axis was validated to be an important signaling pathway in modulating ketamine-induced neural injury.
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http://dx.doi.org/10.3389/fnmol.2020.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344214PMC
June 2020

Porcine Urinary Bladder Extracellular Matrix for Treatment of Periocular Skin Defects.

Ophthalmic Plast Reconstr Surg 2021 May-Jun 01;37(3S):S6-S10

Department of Ophthalmology and Visual Sciences.

Purpose: To describe the experience of 4 oculoplastic surgeons with porcine bladder matrix for periocular anterior lamella and donor site skin defects either as stand-alone treatment or in conjunction with other reconstructive procedures. The authors hypothesized that defect size and location influence the requirement for additional matrix treatments or ancillary procedures.

Methods: Following the Institutional Review Board approval, the authors conducted a retrospective review of 17 patients treated with porcine bladder matrix at 2 oculoplastic practices between 2016 and 2018. Powdered matrix was applied to the skin defect and overlaid with a matrix sheet. Subsequent rounds of matrix treatment or other reconstructive procedures were performed as necessary. Defect size and location were correlated to the number of ancillary matrix treatments or surgical procedures via univariate analysis.

Results: Twenty-five sites (21 primary and 4 donor) in 17 individuals (8-95 years, M = 58.8 years, 10 males) were treated with porcine bladder matrix. All wounds healed successfully. Additional matrix treatments were administered at 5 sites. Ancillary procedures were performed for 7 sites. Upper lid involvement and larger defect size tended to require additional ancillary procedures (p = 0.006), while lower eyelid and other periocular defects required fewer procedures (p < 0.001).

Conclusion: Porcine bladder matrices are useful adjuncts to healing periocular anterior lamella defects in various settings. Such repairs are useful in nonsurgical candidates, but must take into account varying levels of complexity based on lesion location. Smaller defects are more conducive to application of matrices as stand-alone treatment, while larger or upper eyelid defects often require additional procedures.
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http://dx.doi.org/10.1097/IOP.0000000000001738DOI Listing
May 2021

O-GlcNAc transferase regulates centriole behavior and intraflagellar transport to promote ciliogenesis.

Protein Cell 2020 11;11(11):852-857

Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, Key Laboratory of Bioactive Materials of the Ministry of Education, Nankai University, Tianjin, 300071, China.

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http://dx.doi.org/10.1007/s13238-020-00746-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647980PMC
November 2020

Cep57 and Cep57l1 function redundantly to recruit the Cep63-Cep152 complex for centriole biogenesis.

J Cell Sci 2020 07 3;133(13). Epub 2020 Jul 3.

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China

The Cep63-Cep152 complex located at the mother centriole recruits Plk4 to initiate centriole biogenesis. How the complex is targeted to mother centrioles, however, is unclear. In this study, we show that Cep57 and its paralog, Cep57l1, colocalize with Cep63 and Cep152 at the proximal end of mother centrioles in both cycling cells and multiciliated cells undergoing centriole amplification. Both Cep57 and Cep57l1 bind to the centrosomal targeting region of Cep63. The depletion of both proteins, but not either one, blocks loading of the Cep63-Cep152 complex to mother centrioles and consequently prevents centriole duplication. We propose that Cep57 and Cep57l1 function redundantly to ensure recruitment of the Cep63-Cep152 complex to the mother centrioles for procentriole formation.
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http://dx.doi.org/10.1242/jcs.241836DOI Listing
July 2020

Patient Messaging Content Associated with Initiating Hormonal Therapy after a Breast Cancer Diagnosis.

AMIA Annu Symp Proc 2019 4;2019:962-971. Epub 2020 Mar 4.

Vanderbilt University, Nashville, TN.

Hormonal therapy is an effective, but challenging, long-term treatment for patients with hormone-receptor-positive breast cancer. Raising the rate of patients who initiate therapy may be possible by characterizing the factors that influence a patient's decision. We hypothesized that online patient portal messages convey such factors. To investigate this hypothesis, we focused on breast cancer patients who were prescribed hormonal therapy at Vanderbilt University Medical Center and sent messages through the portal between diagnosis and therapy initiation. We first conducted a topic modeling analysis to generate the main themes of portal messages. We subsequently applied survival analysis to learn the association between the factors conveyed in messages, in term of semantic word groups, and the time elapsed from diagnosis to therapy initiation. We found that consulting with healthcare providers increased the probability of therapy initiation, while mentions of symptoms or negative emotions exhibited a reduced probability.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153093PMC
August 2020

Estimation of treatment effects and model diagnostics with two-way time-varying treatment switching: an application to a head and neck study.

Lifetime Data Anal 2020 10 3;26(4):685-707. Epub 2020 Mar 3.

Everest Medicines, Shanghai, China.

Treatment switching frequently occurs in clinical trials due to ethical reasons. Intent-to-treat analysis without adjusting for switching yields biased and inefficient estimates of the treatment effects. In this paper, we propose a class of semiparametric semi-competing risks transition survival models to accommodate two-way time-varying switching. Theoretical properties of the proposed method are examined. An efficient expectation-maximization algorithm is derived to obtain maximum likelihood estimates and model diagnostic tools. Existing software is used to implement the algorithm. Simulation studies are conducted to demonstrate the validity of the model. The proposed method is further applied to data from a clinical trial with patients having recurrent or metastatic squamous-cell carcinoma of head and neck.
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http://dx.doi.org/10.1007/s10985-020-09495-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483904PMC
October 2020

Electronic Health Records for Drug Repurposing: Current Status, Challenges, and Future Directions.

Clin Pharmacol Ther 2020 04 3;107(4):712-714. Epub 2020 Feb 3.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1002/cpt.1769DOI Listing
April 2020

Photocatalytic Conversion of Waste Plastics into C Fuels under Simulated Natural Environment Conditions.

Angew Chem Int Ed Engl 2020 09 28;59(36):15497-15501. Epub 2020 Feb 28.

Hefei National Laboratory for Physical Sciences at Microscale, National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, 230026, P. R. China.

Reported here is the first highly selective conversion of various waste plastics into C fuels under simulated natural environment conditions by a sequential photoinduced C-C cleavage and coupling pathway, where single-use bags, disposable food containers, food wrap films, and their main components of polyethylene, polypropylene, and polyvinyl chloride can be photocatalytically transformed into CH COOH without using sacrificial agents. As an example, polyethylene is photodegraded 100 % into CO within 40 h by single-unit-cell thick Nb O layers, while the produced CO is further photoreduced to CH COOH. Various methods and experiments disclose that O and OH radicals trigger the oxidative C-C cleavage of polyethylene to form CO , while other investigations show that the yielded CH COOH stems from CO photoreduction by C-C coupling of COOH intermediates. This two-step plastic-to-fuel conversion may help to simultaneously address the white pollution crisis and harvest highly valuable multicarbon fuels in natural environments.
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http://dx.doi.org/10.1002/anie.201915766DOI Listing
September 2020

Pediatric diabetic retinopathy telescreening.

J AAPOS 2020 02 12;24(1):10.e1-10.e5. Epub 2020 Jan 12.

Vanderbilt Eye Institute, Vanderbilt University, Nashville, Tennessee.

Purpose: To describe the role of telemedicine screening for pediatric diabetic retinopathy (DR) and to identify risk factors for pediatric DR.

Methods: The medical records of a telemedicine program at a tertiary, academic medical center over 17 months were reviewed retrospectively. Patients visiting an academic pediatric endocrinology clinic who met guidelines underwent telescreening. Presence of pediatric DR and risk factors for retinopathy were evaluated.

Results: The fundus photographs of 852 patients 10-23 years of age were reviewed. Diabetic retinopathy was noted in 51 (6%). Patients with an abnormal screening photograph were compared to patients with diabetes who had normal screening photographs (n = 64). Older age, longer diabetes duration, type 1 diabetes, and higher average glycated hemoglobin (HbA1c) from the year prior to the photograph were associated with increased risk of retinopathy. Of these, longer duration (P = 0.003) and higher average A1c (P = 0.02) were significant after adjusting for sex, race, and age.

Conclusions: Our telemedicine program found a higher percentage of diabetic retinopathy screening non-mydriatic photographs than prior studies found through standard ophthalmic examinations. In this relatively small sample size, longer duration of disease and higher average A1c were associated with increased risk of having diabetic retinopathy in our study.
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http://dx.doi.org/10.1016/j.jaapos.2019.10.010DOI Listing
February 2020

Indication of Measures of Uncertainty for Statistical Significance in Abstracts of Published Oncology Trials: A Systematic Review and Meta-analysis.

JAMA Netw Open 2019 Dec 2;2(12):e1917530. Epub 2019 Dec 2.

Division of Hematology and Oncology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.

Importance: There is growing consensus that reliance on P values, particularly a cutoff level of .05 for statistical significance, is a factor in the challenges in scientific reproducibility. Despite this consensus, publications describing clinical trial results with P values near .05 anecdotally use declarative statements that do not express uncertainty.

Objectives: To quantify uncertainty expression in abstracts describing the results of cancer randomized clinical trials (RCTs) with P values between .01 and .10 and examine whether trial features are associated with uncertainty expression.

Data Sources: A total of 5777 prospective trials indexed on HemOnc.org, as of September 15, 2019.

Study Selection: Two-arm RCTs with a superiority end point with P values between .01 and .10.

Data Extraction And Synthesis: Abstracts were evaluated based on an uncertainty expression algorithm. Ordinal logistic regression modeling with multiple imputation was performed to identify whether characteristics of study design, results, trial authors, and context P values were normalized by dividing by prespecified α value.

Main Outcomes And Measures: Uncertainty expression in abstracts as determined by the algorithm and its association with trial and publication characteristics.

Results: Of 5777 trials screened, 556 met analysis criteria. Of these, 222 trials (39.9%) did not express uncertainty, 161 trials (29.0%) expressed some uncertainty, and 173 trials (31.1%) expressed full uncertainty. In ordinal logistic regression with multiple imputation, trial features with statistically significant associations with uncertainty expression included later year of publication (odds ratio [OR], 1.70; 95% CI, 1.24-2.32; P < .001), normalized P value (OR, 1.36; 95% CI, 1.11-1.67; P = .003), noncooperative group studies (OR, 1.72; 95% CI, 1.12-2.63; P = .01), and reporting an end point other than overall survival (OR, 1.41; 95% CI, 1.01-1.96; P = .047). Funding source, number of authors, journal impact tier, author nationality, study of unapproved drugs, abstract word count, whether the marginal end point was a primary or coprimary end point, and effect size (in subgroup analysis) did not have statistically significant associations with uncertainty expression.

Conclusions And Relevance: Published oncology articles with marginally significant results may often incompletely convey uncertainty. Although it appears that more uncertainty is expressed in recent abstracts, full uncertainty expression remains uncommon, and seemingly is less common when reporting overall survival, results with P values lower than α levels, and cooperative group studies.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.17530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991218PMC
December 2019

Cox regression increases power to detect genotype-phenotype associations in genomic studies using the electronic health record.

BMC Genomics 2019 Nov 4;20(1):805. Epub 2019 Nov 4.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: The growth of DNA biobanks linked to data from electronic health records (EHRs) has enabled the discovery of numerous associations between genomic variants and clinical phenotypes. Nonetheless, although clinical data are generally longitudinal, standard approaches for detecting genotype-phenotype associations in such linked data, notably logistic regression, do not naturally account for variation in the period of follow-up or the time at which an event occurs. Here we explored the advantages of quantifying associations using Cox proportional hazards regression, which can account for the age at which a patient first visited the healthcare system (left truncation) and the age at which a patient either last visited the healthcare system or acquired a particular phenotype (right censoring).

Results: In comprehensive simulations, we found that, compared to logistic regression, Cox regression had greater power at equivalent Type I error. We then scanned for genotype-phenotype associations using logistic regression and Cox regression on 50 phenotypes derived from the EHRs of 49,792 genotyped individuals. Consistent with the findings from our simulations, Cox regression had approximately 10% greater relative sensitivity for detecting known associations from the NHGRI-EBI GWAS Catalog. In terms of effect sizes, the hazard ratios estimated by Cox regression were strongly correlated with the odds ratios estimated by logistic regression.

Conclusions: As longitudinal health-related data continue to grow, Cox regression may improve our ability to identify the genetic basis for a wide range of human phenotypes.
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http://dx.doi.org/10.1186/s12864-019-6192-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829851PMC
November 2019

Association of Genetic Risk of Obesity with Postoperative Complications Using Mendelian Randomization.

World J Surg 2020 01;44(1):84-94

The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: The extent to which obesity and genetics determine postoperative complications is incompletely understood.

Methods: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components.

Results: Individuals with overweight or obese BMI (≥25 kg/m) had increased risk of incisional hernia (odds ratio [OR] 1.7-5.5, p < 3.1 × 10), and people with obesity (BMI ≥ 30 kg/m) had increased risk of postoperative infection (OR 1.2-2.3, p < 2.5 × 10). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8-2.5], p = 1.4 × 10) and postoperative infection (OR 1.6 [95% CI 1.4-1.9], p = 3.1 × 10). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures.

Conclusions: Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.
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http://dx.doi.org/10.1007/s00268-019-05202-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925615PMC
January 2020

Developing Customizable Cancer Information Extraction Modules for Pathology Reports Using CLAMP.

Stud Health Technol Inform 2019 Aug;264:1041-1045

School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas.

Natural language processing (NLP) technologies have been successfully applied to cancer research by enabling automated phenotypic information extraction from narratives in electronic health records (EHRs) such as pathology reports; however, developing customized NLP solutions requires substantial effort. To facilitate the adoption of NLP in cancer research, we have developed a set of customizable modules for extracting comprehensive types of cancer-related information in pathology reports (e.g., tumor size, tumor stage, and biomarkers), by leveraging the existing CLAMP system, which provides user-friendly interfaces for building customized NLP solutions for individual needs. Evaluation using annotated data at Vanderbilt University Medical Center showed that CLAMP-Cancer could extract diverse types of cancer information with good F-measures (0.80-0.98). We then applied CLAMP-Cancer to an information extraction task at Mayo Clinic and showed that we can quickly build a customized NLP system with comparable performance with an existing system at Mayo Clinic. CLAMP-Cancer is freely available for academic use.
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http://dx.doi.org/10.3233/SHTI190383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359882PMC
August 2019

Cost-aware active learning for named entity recognition in clinical text.

J Am Med Inform Assoc 2019 11;26(11):1314-1322

School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Objective: Active Learning (AL) attempts to reduce annotation cost (ie, time) by selecting the most informative examples for annotation. Most approaches tacitly (and unrealistically) assume that the cost for annotating each sample is identical. This study introduces a cost-aware AL method, which simultaneously models both the annotation cost and the informativeness of the samples and evaluates both via simulation and user studies.

Materials And Methods: We designed a novel, cost-aware AL algorithm (Cost-CAUSE) for annotating clinical named entities; we first utilized lexical and syntactic features to estimate annotation cost, then we incorporated this cost measure into an existing AL algorithm. Using the 2010 i2b2/VA data set, we then conducted a simulation study comparing Cost-CAUSE with noncost-aware AL methods, and a user study comparing Cost-CAUSE with passive learning.

Results: Our cost model fit empirical annotation data well, and Cost-CAUSE increased the simulation area under the learning curve (ALC) scores by up to 5.6% and 4.9%, compared with random sampling and alternate AL methods. Moreover, in a user annotation task, Cost-CAUSE outperformed passive learning on the ALC score and reduced annotation time by 20.5%-30.2%.

Discussion: Although AL has proven effective in simulations, our user study shows that a real-world environment is far more complex. Other factors have a noticeable effect on the AL method, such as the annotation accuracy of users, the tiredness of users, and even the physical and mental condition of users.

Conclusion: Cost-CAUSE saves significant annotation cost compared to random sampling.
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http://dx.doi.org/10.1093/jamia/ocz102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798575PMC
November 2019

Analysis of Anti-Vascular Endothelial Growth Factor Injection Claims Data in US Medicare Part B Beneficiaries From 2012 to 2015.

JAMA Ophthalmol 2019 Aug;137(8):921-928

Department of Ophthalmology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Importance: The frequency of anti-vascular endothelial growth factor (VEGF) injections has grown exponentially with the introduction of bevacizumab, ranibizumab, and most recently aflibercept. The cost associated with these medications has garnered significant national attention, warranting a granular analysis of their use.

Objective: To analyze trends in anti-VEGF injections for US Medicare Part B beneficiaries from 2012 to 2015.

Design, Setting, And Participants: This observational cohort study used 2012-2015 data from the Centers for Medicare & Medicaid Services Medicare Part B Provider Utilization Files to analyze trends in intravitreal injections of anti-VEGF medications among Medicare Part B beneficiaries and their health care professionals.

Main Outcomes And Measures: The primary outcome measure was distribution of and change over time in the number of anti-VEGF injections performed for ranibizumab, aflibercept, and bevacizumab.

Results: A total of 2 574 124 intravitreal injections were performed by 3348 ophthalmologists in the outpatient setting for Medicare Part B beneficiaries during the 2015 calendar year; 100 ophthalmologists (3.0%) performed the highest volume of intravitreal injections. The total number of intravitreal injections administered in 2015 was 870 843 for aflibercept, 697 412 for ranibizumab, and 1 147 432 for bevacizumab. Ranibizumab injections decreased by 7.1% from 2012 to 2015 and bevacizumab injections decreased by 17.1%. From 2013 to 2015, aflibercept injections increased by 69.4%. The 100 ophthalmologists performing the highest volume of ranibizumab injections, as gauged by number of injections administered, accounted for 31.0% (95% CI, 30.994%-30.997%) of all ranibizumab injections nationally. The 100 ophthalmologists performing the highest volume of aflibercept injections accounted for 17.6% (95% CI, 17.638%-17.641%) of all aflibercept injections and the 100 ophthalmologists performing the highest volume of bevacizumab injections accounted for 19.6% (95% CI, 19.649%-19.653%) of all bevacizumab injections administered nationally to Medicare Part B beneficiaries. The highest number of injections per 1000 Medicare Part B beneficiaries occurred in Nebraska (aflibercept), Tennessee (ranibizumab), and South Dakota (bevacizumab).

Conclusions And Relevance: A total of 3.0% of ophthalmologists account for 17.6% to 31.0% of the total number of anti-VEGF injections administered nationally in the Medicare Part B population. Overall, bevacizumab and ranibizumab injections have decreased, coinciding with a 69.4% increase in aflibercept injections.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.1971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587152PMC
August 2019
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