Generate Analysis-Ready Data for Real-world Evidence: Tutorial for Harnessing Electronic Health Records With Advanced Informatic Technologies.

Although randomized controlled trials (RCTs) are the gold standard for establishing the efficacy and safety of a medical treatment, real-world evidence (RWE) generated from real-world data has been vital in postapproval monitoring and is being promoted for the regulatory process of experimental therapies. An emerging source of real-world data is electronic health records (EHRs), which contain detailed information on patient care in both structured (eg, diagnosis codes) and unstructured (eg, clinical notes and images) forms. Despite the granularity of the data available in EHRs, the critical variables required to reliably assess the relationship between a treatment and clinical outcome are challenging to extract. To address this fundamental challenge and accelerate the reliable use of EHRs for RWE, we introduce an integrated data curation and modeling pipeline consisting of 4 modules that leverage recent advances in natural language processing, computational phenotyping, and causal modeling techniques with noisy data. Module 1 consists of techniques for data harmonization. We use natural language processing to recognize clinical variables from RCT design documents and map the extracted variables to EHR features with description matching and knowledge networks. Module 2 then develops techniques for cohort construction using advanced phenotyping algorithms to both identify patients with diseases of interest and define the treatment arms. Module 3 introduces methods for variable curation, including a list of existing tools to extract baseline variables from different sources (eg, codified, free text, and medical imaging) and end points of various types (eg, death, binary, temporal, and numerical). Finally, module 4 presents validation and robust modeling methods, and we propose a strategy to create gold-standard labels for EHR variables of interest to validate data curation quality and perform subsequent causal modeling for RWE. In addition to the workflow proposed in our pipeline, we also develop a reporting guideline for RWE that covers the necessary information to facilitate transparent reporting and reproducibility of results. Moreover, our pipeline is highly data driven, enhancing study data with a rich variety of publicly available information and knowledge sources. We also showcase our pipeline and provide guidance on the deployment of relevant tools by revisiting the emulation of the Clinical Outcomes of Surgical Therapy Study Group Trial on laparoscopy-assisted colectomy versus open colectomy in patients with early-stage colon cancer. We also draw on existing literature on EHR emulation of RCTs together with our own studies with the Mass General Brigham EHR.

Tissue-based Immunohistochemical Biomarker Expression in Malignant Glandular Lesions of the Uterine Cervix: A Systematic Review.

Literature published between 1975 and 2015 was systematically reviewed to conduct a case-comparator study of tissue based, immunohistochemical biomarker expression among malignant glandular histotypes of the uterine cervix so as to identify differences that could have diagnostic utility. Of the 902 abstracts, 154 articles had a full review, and 52 were included. Biomarker positivity in cases of adenocarcinoma in situ (AIS) were compared with atypical lobular endocervical glandular hyperplasia and invasive histotypes grouped as mucinous, endometrioid, adenosquamous, serous clear cell, minimal deviation-gastric type, and mesonephric carcinomas (7 AIS case-comparators). The invasive histotypes were compared with each other (30 adenocarcinoma case-comparators). Biomarker positivity in all 37 case-comparators was calculated as weighted averages of histotype-specific estimates. Unsupervised hierarchical clustering examined differences in expression and were visualized via heatmaps and dendrograms. Of the 56 biomarkers tested, 1 or more of 15 showed a 50% or more difference in positive expression in 6 (86%) of the AIS and 21 (70%) of the adenocarcinoma case-comparators. There was no data on the comparison of serous clear cell to mesonephric carcinoma. AIS case-comparator biomarkers were HIK1083, alpha SMA, PAX8, VIL1, CEA, p53, p16, and CD10, and only alpha SMA had a difference of 100%. The adenocarcinoma case-comparator biomarkers were CEA, p53, Claudin18, HIK1083, p16, Calretinin, CD10, PR, Chromogranin, MUC6, Vimentin and p63, and none had a difference of 100%. Biomarker expression in the discrimination of AIS from invasive adenocarcinoma, and the invasive histotypes from each other is understudied. One or more of 15 biomarkers could have diagnostic utility.

Tissue-based Immunohistochemical Biomarker Accuracy in the Diagnosis of Malignant Glandular Lesions of the Uterine Cervix: A Systematic Review of the Literature and Meta-Analysis.

Immunohistochemistry is widely used to support a pathology diagnosis of cervical adenocarcinoma despite the absence of a systematic review and meta-analysis of the published data. This systematic review and meta-analysis was performed to investigate the sensitivity and specificity of immunohistochemistry biomarkers in the tissue-based diagnosis of cervical adenocarcinoma histotypes compared with normal endocervix and benign glandular lesions. The systematic review and meta-analysis used a PICOT framework and QUADAS-2 to evaluate the quality of included studies. The literature search spanned 40 years and ended June 30, 2015. Abstracts of identified records were independently screened by 2 of the authors who then conducted a full-text review of selected articles. Sensitivity and specificity of immunohistochemistry expression in malignant glandular lesions of the cervix classified per WHO 2003 compared with 5 benign comparators (normal/benign endocervix, and benign endocervical, endometrioid, gastric, and mesonephric lesions) were calculated. Of 902 abstracts screened, 154 articles were selected for full review. Twenty-five articles with results for 36 biomarkers were included. The only biomarker with enough studies for a meta-analysis was p16 and the definition of positive p16 staining among them was variable. Nevertheless, any positive p16 expression was sensitive, ranging from 0.94 to 0.98 with narrow confidence intervals (CIs), for adenocarcinoma in situ (AIS) and mucinous adenocarcinomas in comparison with normal/benign endocervix and benign endocervical and endometrioid lesions. Specificity for AIS and mucinous adenocarcinomas was also high with narrow CIs compared with benign endocervical lesions. The specificity was high for AIS, 0.99 (0.24, 1.0), and mucinous adenocarcinoma, 0.95 (0.52, 1.0), compared with normal/benign endocervix but with wider CIs, and low with very wide CIs compared with benign endometrioid lesions: 0.31 (0.00, 0.99) and 0.34 (0.00, 0.99), respectively. Results from single studies showed that p16, p16/Ki67 dual stain, ProExC, CEA, ESA, HIK1083, Claudin 18, and ER loss in perilesional stromal cells were useful with high (≥0.75) sensitivity and specificity estimates in ≥1 malignant versus benign comparisons. None of the biomarkers had highly useful sensitivity and specificity estimates for AIS, mucinous adenocarcinomas, or minimal deviation adenocarcinoma/gastric adenocarcinoma compared with benign gastric or mesonephric lesions or for mesonephric carcinoma compared with normal/benign endocervix, benign endocervical, endometrial, or mesonephric lesions. Any expression of p16 supports a diagnosis of AIS and mucinous adenocarcinomas in comparison with normal/benign endocervix and benign endocervical lesions. The majority of studies did not separate mosaic/focal p16 staining from diffuse staining as a distinct pattern of p16 overexpression and this may have contributed to the poor performance of p16 in distinguishing AIS and mucinous adenocarcinomas from benign endometrioid lesions. Single studies support further investigation of 8 additional biomarkers that have highly useful sensitivity and specificity estimates for ≥1 malignant glandular lesions compared with ≥1 of the 5 benign comparators.

Development of a Soft Tissue Knee Clinical Decision-Making Tool for Patients Presenting to Primary Point-of-Care Providers in Alberta, Canada.

Several barriers exist in Alberta, Canada to providing accurate and accessible diagnoses for patients presenting with acute knee injuries and chronic knee problems. In efforts to improve quality of care for these patients, an evidence-informed clinical decision-making tool was developed. Forty-five expert panelists were purposively chosen to represent stakeholder groups, various expertise, and each of Alberta Health Services' 5 geographical health regions. A systematic rapid review and modified Delphi approach were executed with the intention of developing standardized clinical decision-making processes for acute knee injuries, atraumatic/overuse conditions, knee arthritis, and degenerative meniscus. Standardized criteria for screening, history-taking, physical examination, diagnostic imaging, timelines, and treatment were developed. This tool standardizes and optimizes assessment and diagnosis of acute knee injuries and chronic knee problems in Alberta. This project was a highly collaborative, province-wide effort led by Alberta Health Services' Bone and Joint Health Strategic Clinical Network (BJH SCN) and the Alberta Bone and Joint Health Institute (ABJHI).

Identification of Presurgical Risk Factors for the Development of Chronic Postsurgical Pain in Adults: A Comprehensive Umbrella Review.

Purpose: Risk factors for the development of chronic postsurgical pain (CPSP) have been reported in primary studies and an increasing number of reviews. The objective of this umbrella review was to compile and understand the published presurgical risk factors associated with the development of CPSP for various surgery types. Methods: Six databases were searched from January 2000 to June 2023 to identify meta-analyses, scoping studies, and systematic reviews investigating presurgical CPSP predictors in adult patients. Articles were screened by title/abstract and subsequently by full text by two independent reviewers. The selected papers were appraised for their scientific quality and validity. Data were extracted and descriptively analyzed. Results: Of the 2344 retrieved articles, 36 reviews were selected for in-depth scrutiny. The number of primary studies in these reviews ranged from 4 to 317. The surgery types assessed were arthroplasty (n = 13), spine surgery (n = 8), breast surgery (n = 4), shoulder surgery (n = 2), thoracic surgery (n = 2), and carpal tunnel syndrome (n = 1). One review included a range of orthopedic surgeries; six reviews included a variety of surgeries. A total of 39 presurgical risk factors were identified, some of which shared the same defining tool. Risk factors were themed into six broad categories: psychological, pain-related, health-related, social/lifestyle-related, demographic, and genetic. The strength of evidence for risk factors was inconsistent across different reviews and, in some cases, conflicting. A consistently high level of evidence was found for preoperative pain, depression, anxiety, and pain catastrophizing. Conclusion: This umbrella review identified a large number of presurgical risk factors which have been suggested to be associated with the development of CPSP after various surgeries. The identification of presurgical risk factors is crucial for the development of screening tools to predict CPSP. Our findings will aid in designing screening tools to better identify patients at risk of developing CPSP and inform strategies for prevention and treatment.

Chronic postsurgical pain (CPSP) is pain experienced predominantly at the surgical site for longer than 3 months after a surgical procedure. Depending on surgery type, it can affect between 10 and 80% of people undergoing major surgeries, which may have negative effects such as a lower quality of life, disability, and persistent opioid use. Targeted identification and management of at risk patients in the presurgical phase may decrease the risk of CPSP. This umbrella review generated a list of potential risk factors for CPSP from evidence-based reviews of the current literature. Thirty-nine presurgical risk factors were identified in this review. Risk factors are divided into six broad categories: psychological, pain-related, health-related, demographic, genetic, and social/lifestyle-related. Although the strength of evidence for individual risk factors varied across reviews, risk factors in the psychological category consistently showed a strong impact on the development of CPSP. It is vital to understand which individuals are vulnerable and at risk for CPSP. The findings of this umbrella review will aid in designing screening tools to identify surgical candidates at risk. Some risk factors, such as genetics, cannot be altered. However, many identified risk factors are modifiable and may inform strategies for the prevention and treatment of CPSP using screening tools. Our findings may guide future research to consider an in-depth analysis of risk factor characterization to group modifiable presurgical risk factors. At risk patients will be offered psychological, physical, and pharmacological treatments accordingly to mitigate their risk of developing CPSP and ultimately improve patient outcomes in surgery.

Temporal dynamics of nucleus accumbens neurons in male mice during reward seeking.

The nucleus accumbens (NAc) regulates reward-motivated behavior, but the temporal dynamics of NAc neurons that enable "free-willed" animals to obtain rewards remain elusive. Here, we recorded Ca2+ activity from individual NAc neurons when mice performed self-paced lever-presses for sucrose. NAc neurons exhibited three temporally-sequenced clusters, defined by times at which they exhibited increased Ca2+ activity: approximately 0, -2.5 or -5 sec relative to the lever-pressing. Dopamine D1 receptor (D1)-expressing neurons and D2-neurons formed the majority of the -5-sec versus -2.5-sec clusters, respectively, while both neuronal subtypes were represented in the 0-sec cluster. We found that pre-press activity patterns of D1- or D2-neurons could predict subsequent lever-presses. Inhibiting D1-neurons at -5 sec or D2-neurons at -2.5 sec, but not at other timepoints, reduced sucrose-motivated lever-pressing. We propose that the time-specific activity of D1- and D2-neurons mediate key temporal features of the NAc through which reward motivation initiates reward-seeking behavior.

Machine learning based survival prediction in Glioma using large-scale registry data.

Gliomas are the most common central nervous system tumors exhibiting poor clinical outcomes. The ability to estimate prognosis is crucial for both patients and providers in order to select the most appropriate treatment. Machine learning (ML) allows for sophisticated approaches to survival prediction using real world clinical parameters needed to achieve superior predictive accuracy. We employed Cox Proportional hazards (CPH) model, Support Vector Machine (SVM) model, Random Forest (RF) model in a large glioma dataset (3462 patients, diagnosed 2000-2018) to explore the most optimal approach to survival prediction. Features employed were age, sex, surgical resection status, tumor histology and tumor site, administration of radiation therapy (RT) and chemotherapy status. Concordance index (c-index) was employed to assess the accuracy of survival time prediction. All three models performed well with prediction accuracy (CI 0.767, 0.771, 0.57 for CPH, SVM, RF models respectively) with the best performance achieved when incorporating RT and chemotherapy administration status which emerged as key predictive features. Within the subset of glioblastoma patients, similar prediction accuracy was achieved. These findings should prompt stricter clinician oversight over registry data accuracy through quality assurance as we move towards meaningful predictive ability using ML approaches in glioma.

Optimizing management of the elderly patient with glioblastoma: Survival prediction online tool based on BC Cancer Registry real-world data.

Background: Glioblastoma (GBM) is associated with fatal outcomes and devastating neurological presentations especially impacting the elderly. Management remains controversial and representation in clinical trials poor. We generated 2 nomograms and a clinical decision making web tool using real-world data. Methods: Patients ≥60 years of age with histologically confirmed GBM (ICD-O-3 histology codes 9440/3, 9441/3, and 9442/3) diagnosed 2005-2015 were identified from the BC Cancer Registry (n = 822). Seven hundred and twenty-nine patients for which performance status was captured were included in the analysis. Age, performance and resection status, administration of radiation therapy (RT), and chemotherapy were reviewed. Nomograms predicting 6- and 12-month overall survival (OS) probability were developed using Cox proportional hazards regression internally validated by c-index. A web tool powered by JavaScript was developed to calculate the survival probability. Results: Median OS was 6.6 months (95% confidence interval [CI] 6-7.2 months). Management involved concurrent chemoradiation (34%), RT alone (42%), and chemo alone (2.3%). Twenty-one percent of patients did not receive treatment beyond surgical intervention. Age, performance status, extent of resection, chemotherapy, and RT administration were all significant independent predictors of OS. Patients <80 years old who received RT had a significant survival advantage, regardless of extent of resection (hazard ratio range from 0.22 to 0.60, CI 0.15-0.95). A nomogram was constructed from all 729 patients (Harrell's Concordance Index = 0.78 [CI 0.71-0.84]) with a second nomogram based on subgroup analysis of the 452 patients who underwent RT (Harrell's Concordance Index = 0.81 [CI 0.70-0.90]). An online calculator based on both nomograms was generated for clinical use. Conclusions: Two nomograms and accompanying web tool incorporating commonly captured clinical features were generated based on real-world data to optimize decision making in the clinic.

Temporal Trends in Clinical Evidence of 5-Year Survival Within Electronic Health Records Among Patients With Early-Stage Colon Cancer Managed With Laparoscopy-Assisted Colectomy vs Open Colectomy.

Importance: Temporal shifts in clinical knowledge and practice need to be adjusted for in treatment outcome assessment in clinical evidence. Objective: To use electronic health record (EHR) data to (1) assess the temporal trends in treatment decisions and patient outcomes and (2) emulate a randomized clinical trial (RCT) using EHR data with proper adjustment for temporal trends. Design, Setting, and Participants: The Clinical Outcomes of Surgical Therapy (COST) Study Group Trial assessing overall survival of patients with stages I to III early-stage colon cancer was chosen as the target trial. The RCT was emulated using EHR data of patients from a single health care system cohort who underwent colectomy for early-stage colon cancer from January 1, 2006, to December 31, 2017, and were followed up to January 1, 2020, from Mass General Brigham. Analyses were conducted from December 2, 2019, to January 24, 2022. Exposures: Laparoscopy-assisted colectomy (LAC) vs open colectomy (OC). Main Outcomes and Measures: The primary outcome was 5-year overall survival. To address confounding in the emulation, pretreatment variables were selected and adjusted. The temporal trends were adjusted by stratification of the calendar year when the colectomies were performed with cotraining across strata. Results: A total of 943 patients met key RCT eligibility criteria in the EHR emulation cohort, including 518 undergoing LAC (median age, 63 [range, 20-95] years; 268 [52%] women; 121 [23%] with stage I, 165 [32%] with stage II, and 232 [45%] with stage III cancer; 32 [6%] with colon adhesion; 278 [54%] with right-sided colon cancer; 18 [3%] with left-sided colon cancer; and 222 [43%] with sigmoid colon cancer) and 425 undergoing OC (median age, 65 [range, 28-99] years; 223 [52%] women; 61 [14%] with stage I, 153 [36%] with stage II, and 211 [50%] with stage III cancer; 39 [9%] with colon adhesion; 202 [47%] with right-sided colon cancer; 39 [9%] with left-sided colon cancer; and 201 [47%] with sigmoid colon cancer). Tests for temporal trends in treatment assignment (χ2 = 60.3; P < .001) and overall survival (χ2 = 137.2; P < .001) were significant. The adjusted EHR emulation reached the same conclusion as the RCT: LAC is not inferior to OC in overall survival rate with risk difference at 5 years of -0.007 (95% CI, -0.070 to 0.057). The results were consistent for stratified analysis within each temporal period. Conclusions and Relevance: These findings suggest that confounding bias from temporal trends should be considered when conducting clinical evidence studies with long time spans. Stratification of calendar time and cotraining of models is one solution. With proper adjustment, clinical evidence may supplement RCTs in the assessment of treatment outcome over time.

An End-to-end System for Automatic Characterization of Iba1 Immunopositive Microglia in Whole Slide Imaging.

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Detailed studies of the microglial response after TBI require high throughput quantification of changes in microglial count and morphology in histological sections throughout the brain. In this paper, we present a fully automated end-to-end system that is capable of assessing microglial activation in white matter regions on whole slide images of Iba1 stained sections. Our approach involves the division of the full brain slides into smaller image patches that are subsequently automatically classified into white and grey matter sections. On the patches classified as white matter, we jointly apply functional minimization methods and deep learning classification to identify Iba1-immunopositive microglia. Detected cells are then automatically traced to preserve their complex branching structure after which fractal analysis is applied to determine the activation states of the cells. The resulting system detects white matter regions with 84% accuracy, detects microglia with a performance level of 0.70 (F1 score, the harmonic mean of precision and sensitivity) and performs binary microglia morphology classification with a 70% accuracy. This automated pipeline performs these analyses at a 20-fold increase in speed when compared to a human pathologist. Moreover, we have demonstrated robustness to variations in stain intensity common for Iba1 immunostaining. A preliminary analysis was conducted that indicated that this pipeline can identify differences in microglia response due to TBI. An automated solution to microglia cell analysis can greatly increase standardized analysis of brain slides, allowing pathologists and neuroscientists to focus on characterizing the associated underlying diseases and injuries.