Publications by authors named "Theresa L Walunas"

30 Publications

  • Page 1 of 1

Considerations Before Selecting a Stepped-Wedge Cluster Randomized Trial Design for a Practice Improvement Study.

Ann Fam Med 2022 May-Jun;20(3):255-261

Northwestern University, Feinberg School of Medicine, Chicago, Illinois.

Purpose: Despite the growing popularity of stepped-wedge cluster randomized trials (SW-CRTs) for practice-based research, the design's advantages and challenges are not well documented. The objective of this study was to identify the advantages and challenges of the SW-CRT design for large-scale intervention implementations in primary care settings.

Methods: The EvidenceNOW: Advancing Heart Health initiative, funded by the Agency for Healthcare Research and Quality, included a large collection of SW-CRTs. We conducted qualitative interviews with 17 key informants from EvidenceNOW grantees to identify the advantages and challenges of using SW-CRT design.

Results: All interviewees reported that SW-CRT can be an effective study design for large-scale intervention implementations. Advantages included (1) incentivized recruitment, (2) staggered resource allocation, and (3) statistical power. Challenges included (1) time-sensitive recruitment, (2) retention, (3) randomization requirements and practice preferences, (4) achieving treatment schedule fidelity, (5) intensive data collection, (6) the Hawthorne effect, and (7) temporal trends.

Conclusions: The challenges experienced by EvidenceNOW grantees suggest that certain favorable real-world conditions constitute a context that increases the odds of a successful SW-CRT. An existing infrastructure can support the recruitment of many practices. Strong retention plans are needed to continue to engage sites waiting to start the intervention. Finally, study outcomes should be ones already captured in routine practice; otherwise, funders and investigators should assess the feasibility and cost of data collection..
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http://dx.doi.org/10.1370/afm.2810DOI Listing
September 2020

Multiancestral polygenic risk score for pediatric asthma.

J Allergy Clin Immunol 2022 May 18. Epub 2022 May 18.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.

Background: Asthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.

Objectives: This study aimed to train and validate a PRS relying on genetic determinants for asthma to provide predictions for disease occurrence in pediatric cohorts of diverse ancestries.

Methods: This study applied a Bayesian regression framework method using the Trans-National Asthma Genetic Consortium genome-wide association study summary statistics to derive a multiancestral PRS score, used one Electronic Medical Records and Genomics (eMERGE) cohort as a training set, used a second independent eMERGE cohort to validate the score, and used the UK Biobank data to replicate the findings. A phenome-wide association study was performed using the PRS to identify shared genetic etiology with other phenotypes.

Results: The multiancestral asthma PRS was associated with asthma in the 2 pediatric validation datasets. Overall, the multiancestral asthma PRS has an area under the curve (AUC) of 0.70 (95% CI, 0.69-0.72) in the pediatric validation 1 and AUC of 0.66 (0.65-0.66) in the pediatric validation 2 datasets. We found significant discrimination across pediatric subcohorts of European (AUC, 95% CI, 0.60 and 0.66), African (AUC, 95% CI, 0.61 and 0.66), admixed American (AUC, 0.64 and 0.70), Southeast Asian (AUC, 0.65), and East Asian (AUC, 0.73) ancestry. Pediatric participants with the top 5% PRS had 2.80 to 5.82 increased odds of asthma compared to the bottom 5% across the training, validation 1, and validation 2 cohorts when adjusted for ancestry. Phenome-wide association study analysis confirmed the strong association of the identified PRS with asthma (odds ratio, 2.71, P = 3.71 × 10) and related phenotypes.

Conclusions: A multiancestral PRS for asthma based on Bayesian posterior genomic effect sizes identifies increased odds of pediatric asthma.
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http://dx.doi.org/10.1016/j.jaci.2022.03.035DOI Listing
May 2022

Many Medicare Beneficiaries Do Not Fill High-Price Specialty Drug Prescriptions.

Health Aff (Millwood) 2022 04;41(4):487-496

Nancy L. Keating, Harvard University and Brigham and Women's Hospital, Boston, Massachusetts.

For high-price drugs, Medicare Part D beneficiaries who do not receive a low-income subsidy must pay a percentage of the drug's price for each medication fill. Without that subsidy, which lowers out-of-pocket spending, beneficiaries typically pay hundreds or thousands of dollars for a single fill. We estimated the proportion of Part D beneficiaries in fee-for-service Medicare, with and without a subsidy, who do not initiate treatment (that is, do not fill a new prescription) with high-price Part D drugs newly prescribed for four conditions. Examining 17,076 new prescriptions issued between 2012 and 2018 for Part D beneficiaries from eleven geographically diverse health systems, we found that beneficiaries receiving subsidies were nearly twice as likely to obtain the prescribed drug within ninety days as those without subsidies. Among beneficiaries without subsidies, we observed noninitiation for 30 percent of prescriptions written for anticancer drugs, 22 percent for hepatitis C treatments, and more than 50 percent for disease-modifying therapies for either immune system disorders or hypercholesterolemia. Our findings support current legislative efforts to increase the accessibility of high-price medications by reducing out-of-pocket expenses under Medicare Part D, particularly for beneficiaries without low-income subsidies.
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http://dx.doi.org/10.1377/hlthaff.2021.01742DOI Listing
April 2022

A systematic review of pharmacologic treatment efficacy for depression in older patients with cancer.

Brain Behav Immun Health 2022 May 23;21:100449. Epub 2022 Mar 23.

Department of Neurological Surgery at Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Older adults ≥65 years of age represent the majority of new cancer diagnoses and are vulnerable to developing depression-like symptoms. Evaluation and management of depression in older cancer patients is underappreciated despite its high prevalence and impact on health-related quality of life. Although antidepressants are the primary pharmacologics used to treat depressive-like symptoms, the efficacy and overall benefit(s) are not well-characterized in older adult patients with cancer. The objective of this investigation was to review what is known about the efficacy of pharmacologic treatment for older adults with depression and cancer.

Methods: PubMed (Medline) and EMBASE (Elsevier) databases were analyzed for relevant literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results: 1,919 unique studies were identified for title and abstract screening. Forty-eight publications were retrieved for full review. None of the identified studies evaluated the potential for benefit after pharmacological treatment among older adults with cancer and depression. Twenty-seven publications met all study criteria except for an analysis focused on older patients.

Conclusion: We discovered a universal absence of literature with a relevance to pharmacologic antidepressant treatment effects in older adult patients with cancer. This included a lack of evaluation in patients with brain tumors who have an unusually high predilection for developing depression. Our findings suggest that new research is critically needed for understanding optimal clinical management strategies in older adults with cancer and depression who are treated with antidepressants.
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http://dx.doi.org/10.1016/j.bbih.2022.100449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968450PMC
May 2022

Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR.

J Immunother Cancer 2021 09;9(9)

Department of Medicine and Center for Health Information Partnerships, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.
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http://dx.doi.org/10.1136/jitc-2021-002627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420733PMC
September 2021

Remdesivir Versus Standard-of-Care for Severe Coronavirus Disease 2019 Infection: An Analysis of 28-Day Mortality.

Open Forum Infect Dis 2021 Jul 26;8(7):ofab278. Epub 2021 May 26.

Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom.

Background: Remdesivir is approved by the US Food and Drug Administration for the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19) and has been shown to shorten time to recovery and improve clinical outcomes in randomized trials.

Methods: This was the final day 28 comparative analysis of data from a phase 3, randomized, open-label study comparing 2 remdesivir regimens (5 vs 10 days, combined for this analysis [remdesivir cohort]) and a real-world retrospective longitudinal cohort study of patients receiving standard-of-care treatment (nonremdesivir cohort). Eligible patients, aged ≥18 years, had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), oxygen saturation ≤94% on room air or required supplemental oxygen, with pulmonary infiltrates. Propensity score matching (up to 1:10 ratio) was used to ensure comparable populations. We assessed day 14 clinical recovery (determined using a 7-point ordinal scale) and day 28 all-cause mortality (coprimary endpoints).

Results: A total of 368 (remdesivir) and 1399 (nonremdesivir) patients were included in the matched analysis. The day 14 clinical recovery rate was significantly higher among the remdesivir versus the nonremdesivir cohort (65.2% vs 57.1%; odds ratio [OR], 1.49; 95% confidence interval [CI], 1.16-1.90; = 0.002). The day 28 mortality rate was significantly lower in the remdesivir cohort versus the nonremdesivir cohort (12.0% vs 16.2%; OR, 0.67; 95% CI, 0.47-.95;  = .03).

Conclusions: Remdesivir was associated with significantly higher rates of day 14 clinical recovery, and lower day 28 mortality, compared with standard-of-care treatment in hospitalized patients with COVID-19. These data, taken together, support the use of remdesivir to improve clinical recovery and decrease mortality from SARS-CoV-2 infection.
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http://dx.doi.org/10.1093/ofid/ofab278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244650PMC
July 2021

Pleiotropy of systemic lupus erythematosus risk alleles and cardiometabolic disorders: A phenome-wide association study and inverse-variance weighted meta-analysis.

Lupus 2021 Jul 12;30(8):1264-1272. Epub 2021 May 12.

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, USA.

Objectives: To test the hypothesis that genetic predisposition to systemic lupus erythematosus (SLE) increases the risk of cardiometabolic disorders.

Methods: Using 41 single nucleotide polymorphisms (SNPs) associated with SLE, we calculated a weighted genetic risk score (wGRS) for SLE. In a large biobank we tested the association between this wGRS and 9 cardiometabolic phenotypes previously associated with SLE: atrial fibrillation, ischemic stroke, coronary artery disease, type 1 and type 2 diabetes, obesity, chronic kidney disease, hypertension, and hypercholesterolemia. Additionally, we performed a phenome-wide association analysis (pheWAS) to discover novel clinical associations with a genetic predisposition to SLE. Findings were replicated in the Electronic Medical Records and Genomics (eMERGE) Network. To further define the association between SLE-related risk alleles and the selected cardiometabolic phenotypes, we performed an inverse variance weighted regression (IVWR) meta-analysis.

Results: The wGRS for SLE was calculated in 74,759 individuals of European ancestry. Among the pre-selected phenotypes, the wGRS was significantly associated with type 1 diabetes (OR [95%CI] =1.11 [1.06, 1.17], P-value = 1.05x10). In the PheWAS, the wGRS was associated with several autoimmune phenotypes, kidney disorders, and skin neoplasm; but only the associations with autoimmune phenotypes were replicated. In the IVWR meta-analysis, SLE-related risk alleles were nominally associated with type 1 diabetes (P = 0.048) but the associations were heterogeneous and did not meet the adjusted significance threshold.

Conclusion: A weighted GRS for SLE was associated with an increased risk of several autoimmune-related phenotypes including type I diabetes but not with cardiometabolic disorders.
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http://dx.doi.org/10.1177/09612033211014952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205989PMC
July 2021

Evaluation of structured data from electronic health records to identify clinical classification criteria attributes for systemic lupus erythematosus.

Lupus Sci Med 2021 04;8(1)

Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Objective: Our objective was to develop algorithms to identify lupus clinical classification criteria attributes using structured data found in the electronic health record (EHR) and determine whether they could be used to describe a cohort of people with lupus and discriminate them from a defined healthy control cohort.

Methods: We created gold standard lupus and healthy patient cohorts that were fully adjudicated for the American College of Rheumatology (ACR), Systemic Lupus International Collaborating Clinics (SLICC) and European League Against Rheumatism/ACR (EULAR/ACR) classification criteria and had matched EHR data. We implemented rule-based algorithms using structured data within the EHR system for each attribute of the three classification criteria. Individual criteria attribute and classification criteria algorithms as a whole were assessed over our combined cohorts and the overall performance of the algorithms was measured through sensitivity and specificity.

Results: Individual classification criteria attributes had a wide range of sensitivities, 7% (oral ulcers) to 97% (haematological disorders) and specificities, 56% (haematological disorders) to 98% (photosensitivity), but all could be identified in EHR data. In general, algorithms based on laboratory results performed better than those primarily based on diagnosis codes. All three classification criteria systems effectively distinguished members of our case and control cohorts, but the SLICC criteria-based algorithm had the highest overall performance (76% sensitivity, 99% specificity).

Conclusions: It is possible to characterise disease manifestations in people with lupus using classification criteria-based algorithms that assess structured EHR data. These algorithms may reduce chart review burden and are a foundation for identifying subpopulations of patients with lupus based on disease presentation to support precision medicine applications.
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http://dx.doi.org/10.1136/lupus-2021-000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076919PMC
April 2021

Does coaching matter? Examining the impact of specific practice facilitation strategies on implementation of quality improvement interventions in the Healthy Hearts in the Heartland study.

Implement Sci 2021 03 31;16(1):33. Epub 2021 Mar 31.

Department of Preventive Medicine, Division of Healthcare and Biomedical Informatics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Practice facilitation is a multicomponent implementation strategy used to improve the capacity for practices to address care quality and implementation gaps. We sought to assess whether practice facilitators use of coaching strategies aimed at improving self-sufficiency were associated with improved implementation of quality improvement (QI) interventions in the Healthy Hearts in the Heartland Study.

Methods: We mapped 27 practice facilitation activities to a framework that classifies practice facilitation strategies by the degree to which the practice develops its own process expertise (Doing Tasks, Project Management, Consulting, Teaching, and Coaching) and then used regression tree analysis to group practices by facilitation strategies experienced. Kruskal-Wallis tests were used to assess whether practice groups identified by regression tree analysis were associated with successful implementation of QI interventions and practice and study context variables.

Results: There was no association between number of strategies performed by practice facilitators and number of QI interventions implemented. Regression tree analysis identified 4 distinct practice groups based on the number of Project Management and Coaching strategies performed. The median number of interventions increased across the groups. Practices receiving > 4 project management and > 6 coaching activities implemented a median of 17 of 35 interventions. Groups did not differ significantly by practice size, association with a healthcare network, or practice type. Statistically significant differences in practice location, number and duration of facilitator visits, and early study termination emerged among the groups, compared to the overall practice population.

Conclusions: Practices that engage in more coaching-based strategies with practice facilitators are more likely to implement more QI interventions, and practice receptivity to these strategies was not dependent on basic practice demographics.
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http://dx.doi.org/10.1186/s13012-021-01100-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011080PMC
March 2021

A Taxonomy for External Support for Practice Transformation.

J Am Board Fam Med 2021 Jan-Feb;34(1):32-39

From Health Partners Institute, Minneapolis, MN (LIS); Virginia Commonwealth University, Richmond, VA (AKu, AKr); Kaiser Permanente Washington Health Research Institute, Seattle, WA (MLP); School of Global Public Health, New York University (NYU), New York, NY (DRS); University of Colorado, Aurora, CO (WPD, DF); Feinberg School of Medicine, Northwestern University, Chicago, IL (TLW, AKh); NYU Langone Health, New York NY, (AMN, CB); Oregon Health Sciences University, Portland, OR (LRF, DJC, LG); University of North Carolina at Chapel Hill, Chapel Hill, NC (SC); School of Public Health, UTHealth, Dallas, TX (BAB); Lehigh Valley Health Center, Easton, PA (WM); University of Oklahoma, Oklahoma City, OK (DD, ZN).

Background: There is no commonly accepted comprehensive framework for describing the practical specifics of external support for practice change. Our goal was to develop such a taxonomy that could be used by both external groups or researchers and health care leaders.

Methods: The leaders of 8 grants from Agency for Research and Quality for the EvidenceNOW study of improving cardiovascular preventive services in over 1500 primary care practices nationwide worked collaboratively over 18 months to develop descriptions of key domains that might comprehensively characterize any external support intervention. Combining literature reviews with our practical experiences in this initiative and past work, we aimed to define these domains and recommend measures for them.

Results: The taxonomy includes 1 domain to specify the conceptual model(s) on which an intervention is built and another to specify the types of support strategies used. Another 5 domains provide specifics about the dose/mode of that support, the types of change process and care process changes that are encouraged, and the degree to which the strategies are prescriptive and standardized. A model was created to illustrate how the domains fit together and how they would respond to practice needs and reactions.

Conclusions: This taxonomy and its use in more consistently documenting and characterizing external support interventions should facilitate communication and synergies between 3 areas (quality improvement, practice change research, and implementation science) that have historically tended to work independently. The taxonomy was designed to be as useful for practices or health systems managing change as it is for research.
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http://dx.doi.org/10.3122/jabfm.2021.01.200225DOI Listing
August 2021

Identifying Practice Facilitation Delays and Barriers in Primary Care Quality Improvement

J Am Board Fam Med 2020 Sep-Oct;33(5):655-664

From the Feinberg School of Medicine, Northwestern University, Chicago, IL (JY, AAW); Center for Health Information Partnerships (CHiP), Institute of Public Health & Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL (JY, JEB, TLW, ANK); Department of Communication Studies, Northwestern University, Evanston, IL (RZ); Division of Health and Biomedical Informatics, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL (ANK, NDS); Division of General Internal Medicine and Geriatrics, Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL (TLW, ANK).

Objective: Practice facilitation is an effective approach to implementing quality improvement (QI) interventions in practice-based research networks (PBRNs). Regular facilitator-practice interactions are necessary for successful facilitation, and missed engagements may hinder the process of practice improvement. This study employs a mixed-methods approach to characterize the dynamics of practice facilitation and examine facilitation delays and barriers, as well as their association with the achievement of QI program goals in a PBRN initiative.

Methods: This study presents a secondary analysis of data from 226 primary care practices that participated in the Healthy Hearts in the Heartland (H3) initiative. We performed a time series analysis to identify delays in facilitation activities, and then qualitatively analyzed practice facilitators' notes (n = 4358) to uncover facilitation barriers. Finally, we assessed the relationship between delays, barriers, and QI intervention completion.

Results: While most facilitation activities occurred at regular, practice-specific tempos, nearly all practices experienced at least 1 delay. Practices with more delays had lower QI intervention completion rates. Practices with more delays were more likely to have encountered barriers such as lack of time and staff, lack of staff engagement, technical issues, and staff turnover.

Discussion And Conclusion: This study is the first to quantify irregular intervals between facilitation activities and demonstrate their negative association with project completion. The analytic method can be applied to identify at-risk practices and to accelerate timely interventions in future studies. Our delay detection algorithm could inform the design of a decision support system that notifies facilitators which practices may benefit from timely attention and resources.
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http://dx.doi.org/10.3122/jabfm.2020.05.200058DOI Listing
July 2021

Remdesivir for Severe Coronavirus Disease 2019 (COVID-19) Versus a Cohort Receiving Standard of Care.

Clin Infect Dis 2021 12;73(11):e4166-e4174

Gilead Sciences, Foster City, California, USA.

Background: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care.

Methods: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality.

Results: After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001).

Conclusions: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19.

Clinical Trials Registration: NCT04292899 and EUPAS34303.
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http://dx.doi.org/10.1093/cid/ciaa1041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454434PMC
December 2021

Challenges to electronic clinical quality measurement using third-party platforms in primary care practices: the healthy hearts in the heartland experience.

JAMIA Open 2019 Dec 20;2(4):423-428. Epub 2019 Sep 20.

The Center for Health Information Partnerships (CHiP), Institute of Public Health & Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Third-party platforms have emerged to support small primary care practices for calculating and reporting electronic clinical quality measures (eCQM) for federal programs like The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) and Merit-based Incentive Payment System (MIPS). Yet little is known about the capabilities and limitations of electronic health record systems (EHRs) to enable data access for these programs. We connected 116 small- to medium-sized practices with seven different EHRs to popHealth, an open-source eCQM platform. We identified the prevalence of following problems with eCQM data for data extraction in seven different EHRs: (1) Lack of coded data in five of seven; (2) Incorrectly categorized data in four of seven; (3) Isosemantic data (data within the incorrect context) in four of seven; (4) Coding that could not be directly evaluated in six of seven; (5) Errors in date assignment and labeled as historical values in five of seven; and (6) Inadequate data to assign the correct code in two of seven. We recommend specific enhancements to EHR systems that can promote effective eCQM implementation and reporting to MACRA and MIPS.
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http://dx.doi.org/10.1093/jamiaopen/ooz038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994020PMC
December 2019

A Polygenic and Phenotypic Risk Prediction for Polycystic Ovary Syndrome Evaluated by Phenome-Wide Association Studies.

J Clin Endocrinol Metab 2020 06;105(6)

Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Context: As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice.

Objective: Utilizing polygenic risk prediction, we aim to identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment.

Design, Patients, And Methods: Leveraging the electronic health records (EHRs) of 124 852 individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores (PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). We evaluated its predictive capability across different ancestries and perform a PRS-based phenome-wide association study (PheWAS) to assess the phenomic expression of the heightened risk of PCOS.

Results: The integrated polygenic prediction improved the average performance (pseudo-R2) for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null model across European, African, and multi-ancestry participants respectively. The subsequent PRS-powered PheWAS identified a high level of shared biology between PCOS and a range of metabolic and endocrine outcomes, especially with obesity and diabetes: "morbid obesity", "type 2 diabetes", "hypercholesterolemia", "disorders of lipid metabolism", "hypertension", and "sleep apnea" reaching phenome-wide significance.

Conclusions: Our study has expanded the methodological utility of PRS in patient stratification and risk prediction, especially in a multifactorial condition like PCOS, across different genetic origins. By utilizing the individual genome-phenome data available from the EHR, our approach also demonstrates that polygenic prediction by PRS can provide valuable opportunities to discover the pleiotropic phenomic network associated with PCOS pathogenesis.
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http://dx.doi.org/10.1210/clinem/dgz326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453038PMC
June 2020

Effects of 2 Forms of Practice Facilitation on Cardiovascular Prevention in Primary Care: A Practice-randomized, Comparative Effectiveness Trial.

Med Care 2020 04;58(4):344-351

Department of Medicine, Division of General Internal Medicine and Geriatrics.

Background: Effective quality improvement (QI) strategies are needed for small practices.

Objective: The objective of this study was to compare practice facilitation implementing point-of-care (POC) QI strategies alone versus facilitation implementing point-of-care plus population management (POC+PM) strategies on preventive cardiovascular care.

Design: Two arm, practice-randomized, comparative effectiveness study.

Participants: Small and mid-sized primary care practices.

Interventions: Practices worked with facilitators on QI for 12 months to implement POC or POC+PM strategies.

Measures: Proportion of eligible patients in a practice meeting "ABCS" measures: (Aspirin) Aspirin/antiplatelet therapy for ischemic vascular disease, (Blood pressure) Controlling High Blood Pressure, (Cholesterol) Statin Therapy for the Prevention and Treatment of Cardiovascular Disease, and (Smoking) Tobacco Use: Screening and Cessation Intervention, and the Change Process Capability Questionnaire. Measurements were performed at baseline, 12, and 18 months.

Results: A total of 226 practices were randomized, 179 contributed follow-up data. The mean proportion of patients meeting each performance measure was greater at 12 months compared with baseline: Aspirin 0.04 (95% confidence interval: 0.02-0.06), Blood pressure 0.04 (0.02-0.06), Cholesterol 0.05 (0.03-0.07), Smoking 0.05 (0.02-0.07); P<0.001 for each. Improvements were sustained at 18 months. At 12 months, baseline-adjusted difference-in-differences in proportions for the POC+PM arm versus POC was: Aspirin 0.02 (-0.02 to 0.05), Blood pressure -0.01 (-0.04 to 0.03), Cholesterol 0.03 (0.00-0.07), and Smoking 0.02 (-0.02 to 0.06); P>0.05 for all. Change Process Capability Questionnaire improved slightly, mean change 0.30 (0.09-0.51) but did not significantly differ across arms.

Conclusion: Facilitator-led QI promoting population management approaches plus POC improvement strategies was not clearly superior to POC strategies alone.
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http://dx.doi.org/10.1097/MLR.0000000000001260DOI Listing
April 2020

Qualitative evaluation of a cardiovascular quality improvement programmereveals sizable data inaccuracies in small primary care practices.

BMJ Open Qual 2019 27;8(4):e000702. Epub 2019 Nov 27.

Center for Health Information Partnerships, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

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http://dx.doi.org/10.1136/bmjoq-2019-000702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887491PMC
July 2020

Using Electronic Health Records to Measure Quality Improvement Efforts: Findings from a Large Practice Facilitation Initiative.

Jt Comm J Qual Patient Saf 2020 01 5;46(1):11-17. Epub 2019 Nov 5.

Background: Federal incentives for electronic health record (EHR) use typically require quality measure reporting over calendar year or 90-day periods. However, required reporting periods may not align with time frames of real-world quality improvement (QI) efforts. This study described primary care practices' ability to obtain measures with reporting periods aligning with a large QI initiative.

Methods: Researchers conducted a substudy of a randomized trial testing practice facilitation strategies for preventive cardiovascular care. Three quality measures (aspirin for ischemic vascular disease; blood pressure control for hypertension; smoking screening/cessation) were collected quarterly over one year. The primary outcome was a binary indicator of whether a practice facilitator obtained all three measures with "rolling 12-month" reporting periods (that is, the year preceding each study quarter).

Results: The study included 107 practices, 63 (58.9%) of which met the primary outcome of obtaining all measures with rolling 12-month reporting periods. Smaller practices were less likely to meet the primary outcome (p < 0.001). Practices used 11 different EHRs, 3 of which were unable to consistently produce rolling 12-month measures; at 33 practices (30.8%) using these 3 EHRs, facilitators met a secondary outcome of obtaining prior calendar year and rolling 3-month measures. Facilitators reported barriers to data collection such as practices lacking optional EHR features, and EHRs' inability to produce reporting periods across two calendar years.

Conclusion: EHR vendors' compliance with federal reporting requirements is not necessarily sufficient to support real-world QI work. Improvements are needed in the flexibility and usability of EHRs' quality measurement functions, particularly for smaller practices.
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http://dx.doi.org/10.1016/j.jcjq.2019.09.006DOI Listing
January 2020

Contrasting Perspectives of Practice Leaders and Practice Facilitators May Be Common in Quality Improvement Initiatives.

J Healthc Qual 2020 May-Jun;42(3):e32-e38

Practice facilitation is an approach for advancing quality improvement (QI), but its success depends on effective relationships and communication among participants. Our goal was to identify patterns of contrasting perspectives on implementation issues between practice leaders and their practice facilitators, and factors that may contribute to them. We conducted individual interviews with practice leaders and the practice facilitators assigned to them as part of a program focused on preventive cardiology within primary care practices. We used summative content analysis to quantify the incidence of contrasting perspectives, and bivariate and qualitative analyses to explore relationships between contrasting perspectives and contextual factors. Among the 16 dyads, contrasting perspectives commonly related to the easiest or hardest QI interventions to implement (8 of 16 dyads) and the practice's success implementing interventions (5 of 16 dyads). There was a nonsignificant, inverse correlation (r = -0.19, p = .47) between the number of in-person QI visits from the facilitator and the total number of contrasting perspectives. Turnover of staff was frequently reported in dyads with contrasting perspectives. Although the impact of contrasting perspectives warrants additional study, planners of QI initiatives using practice facilitation should consider taking steps to minimize contrasting perspectives, or the potential adverse consequences of them, by addressing turnover challenges and encouraging opportunities to share perspectives.
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http://dx.doi.org/10.1097/JHQ.0000000000000223DOI Listing
January 2021

Making work visible for electronic phenotype implementation: Lessons learned from the eMERGE network.

J Biomed Inform 2019 11 19;99:103293. Epub 2019 Sep 19.

Department of Biomedical Informatics, Columbia University, New York, NY, United States. Electronic address:

Background: Implementation of phenotype algorithms requires phenotype engineers to interpret human-readable algorithms and translate the description (text and flowcharts) into computable phenotypes - a process that can be labor intensive and error prone. To address the critical need for reducing the implementation efforts, it is important to develop portable algorithms.

Methods: We conducted a retrospective analysis of phenotype algorithms developed in the Electronic Medical Records and Genomics (eMERGE) network and identified common customization tasks required for implementation. A novel scoring system was developed to quantify portability from three aspects: Knowledge conversion, clause Interpretation, and Programming (KIP). Tasks were grouped into twenty representative categories. Experienced phenotype engineers were asked to estimate the average time spent on each category and evaluate time saving enabled by a common data model (CDM), specifically the Observational Medical Outcomes Partnership (OMOP) model, for each category.

Results: A total of 485 distinct clauses (phenotype criteria) were identified from 55 phenotype algorithms, corresponding to 1153 customization tasks. In addition to 25 non-phenotype-specific tasks, 46 tasks are related to interpretation, 613 tasks are related to knowledge conversion, and 469 tasks are related to programming. A score between 0 and 2 (0 for easy, 1 for moderate, and 2 for difficult portability) is assigned for each aspect, yielding a total KIP score range of 0 to 6. The average clause-wise KIP score to reflect portability is 1.37 ± 1.38. Specifically, the average knowledge (K) score is 0.64 ± 0.66, interpretation (I) score is 0.33 ± 0.55, and programming (P) score is 0.40 ± 0.64. 5% of the categories can be completed within one hour (median). 70% of the categories take from days to months to complete. The OMOP model can assist with vocabulary mapping tasks.

Conclusion: This study presents firsthand knowledge of the substantial implementation efforts in phenotyping and introduces a novel metric (KIP) to measure portability of phenotype algorithms for quantifying such efforts across the eMERGE Network. Phenotype developers are encouraged to analyze and optimize the portability in regards to knowledge, interpretation and programming. CDMs can be used to improve the portability for some 'knowledge-oriented' tasks.
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http://dx.doi.org/10.1016/j.jbi.2019.103293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894517PMC
November 2019

Assessing the Concordance of Clinical Classification Criteria for Lupus Between Electronic Health Records and a Physician Curated Registry.

Stud Health Technol Inform 2019 Aug;264:1466-1467

Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America.

We developed a computable phenotype for systemic lupus erythematosus (SLE) based on the Systemic Lupus International Collaborative Clinics clinical classification criteria set for SLE. We evaluated the phenotype over registry and EHR data for the same patient population to determine concordance of criteria detected in both datasets and to assess which types of structured data detected individual classification criteria. We identified a concordance of 68% between registry and EHR data relying solely on structured data.
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http://dx.doi.org/10.3233/SHTI190487DOI Listing
August 2019

Design of healthy hearts in the heartland (H3): A practice-randomized, comparative effectiveness study.

Contemp Clin Trials 2018 08 2;71:47-54. Epub 2018 Jun 2.

Center for Health Information Partnerships (CHiP), Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Medicine, Division of General Internal Medicine and Geriatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Background: The Healthy Hearts in the Heartland (H3) study is part of a nationwide effort, EvidenceNOW, seeking to better understand the ability of small primary care practices to improve "ABCS" clinical quality measures: appropriate Aspirin therapy, Blood pressure control, Cholesterol management, and Smoking cessation. H3 aimed to assess feasibility of implementing Point-of-Care (POC) or POC plus Population Management (POC + PM) quality improvement (QI) strategies to improve ABCS at practices in Illinois, Indiana, and Wisconsin. We describe the design and randomization of the H3 study.

Methods: We conducted a two-arm (1:1, POC:POC + PM), practice-randomized, comparative effectiveness study in 226 primary care practices across four "waves" of randomization with a 12-month intervention period, followed by a six-month sustainability period. Randomization controlled imbalance in nine baseline variables through a modified constrained algorithm. Among others, we used initial, unverified estimates of baseline ABCS values.

Results: We randomized 112 and 114 practices to POC and POC + PM arms, respectively. Randomization ensured baseline comparability for all nine key variables, including the ABCS measures indicating proportion of patients at the practice level meeting each quality measure. Median(Inner Quartile Range) values were A: 0.78(0.66-0.86) in POC arm vs. 0.77(0.63-0.86) in POC + PM arm, B: 0.64(0.53-0.73) vs. 0.64(0.53-0.75), C: 0.78(0.63-0.86) vs. 0.75(0.64-0.81), S: 0.80(0.65-0.81) vs. 0.79(0.61-0.91).

Discussion: Surrogate estimates for the true ABCS at baseline coupled with the unique randomization logic achieved adequate baseline balance on these outcomes. Similar practice- or cluster-randomized trials may consider adaptations of this design. Final analyses on 12- and 18-month ABCS outcomes for the H3 study are forthcoming.

Trial Registration: This trial is registered on ClinicalTrials.gov (Initial post: 11/05/2015; identifier: NCT02598284; https://clinicaltrials.gov/ct2/show/NCT02598284?term=NCT02598284&rank=1).
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http://dx.doi.org/10.1016/j.cct.2018.06.004DOI Listing
August 2018

Engaging Primary Care Practices in Studies of Improvement: Did You Budget Enough for Practice Recruitment?

Ann Fam Med 2018 04;16(Suppl 1):S72-S79

HealthPartners Institute, Bloomington, Minnesota.

Purpose: The methods and costs to enroll small primary care practices in large, regional quality improvement initiatives are unknown. We describe the recruitment approach, cost, and resources required to recruit and enroll 500 practices in the Northwest and Midwest regional cooperatives participating in the Agency for Healthcare Research and Quality (AHRQ)-funded initiative, EvidenceNOW: Advancing Heart Health in Primary Care.

Methods: The project management team of each cooperative tracked data on recruitment methods used for identifying and connecting with practices. We developed a cost-of-recruitment template and used it to record personnel time and associated costs of travel and communication materials.

Results: A total of 3,669 practices were contacted during the 14- to 18-month recruitment period, resulting in 484 enrolled practices across the 6 states served by the 2 cooperatives. The average number of interactions per enrolled practice was 7, with a total of 29,100 hours and a total cost of $2.675 million, or $5,529 per enrolled practice. Prior partnerships predicted recruiting almost 1 in 3 of these practices as contrasted to 1 in 20 practices without a previous relationship or warm hand-off.

Conclusions: Recruitment of practices for large-scale practice quality improvement transformation initiatives is difficult and costly. The cost of recruiting practices without existing partnerships is expensive, costing 7 times more than reaching out to familiar practices. Investigators initiating and studying practice quality improvement initiatives should budget adequate funds to support high-touch recruitment strategies, including building trusted relationships over a long time frame, for a year or more.
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http://dx.doi.org/10.1370/afm.2199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891317PMC
April 2018

Practice Facilitators' and Leaders' Perspectives on a Facilitated Quality Improvement Program.

Ann Fam Med 2018 04;16(Suppl 1):S65-S71

Northwestern University, Feinberg School of Medicine, Division of General Internal Medicine and Geriatrics, Chicago, Illinois.

Purpose: Practice facilitation is a promising approach to helping practices implement quality improvements. Our purpose was to describe practice facilitators' and practice leaders' perspectives on implementation of a practice facilitator-supported quality improvement program and describe where their perspectives aligned and diverged.

Methods: We conducted interviews with practice leaders and practice facilitators who participated in a program that included 35 improvement strategies aimed at the ABCS of heart health (aspirin use in high-risk individuals, blood pressure control, cholesterol management, and smoking cessation). Rapid qualitative analysis was used to collect, organize, and analyze the data.

Results: We interviewed 17 of the 33 eligible practice leaders, and the 10 practice facilitators assigned to those practices. Practice leaders and practice facilitators both reported value in the program's ability to bring needed, high-quality resources to practices. Practice leaders appreciated being able to set the schedule for facilitation and select among the 35 interventions. According to practice facilitators, however, relying on practice leaders to set the pace of the intervention resulted in a lower level of program intensity than intended. Practice leaders preferred targeted assistance, particularly electronic health record documentation guidance and linkages to state smoking cessation programs. Practice facilitators reported that the easiest interventions were those that did not alter care practices.

Conclusions: The dual perspectives of practice leaders and practice facilitators provide a more holistic picture of enablers and barriers to program implementation. There may be greater opportunities to assist small practices through simple, targeted practice facilitator-supported efforts rather than larger, comprehensive quality improvement projects.
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http://dx.doi.org/10.1370/afm.2197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891316PMC
April 2018

Disease Outcomes and Care Fragmentation Among Patients With Systemic Lupus Erythematosus.

Arthritis Care Res (Hoboken) 2017 09 8;69(9):1369-1376. Epub 2017 Aug 8.

Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Objective: To examine the impact of care fragmentation across multiple health care institutions on disease outcomes in patients with systemic lupus erythematosus (SLE).

Methods: Using the Chicago HealthLNK Data Repository, an assembly of electronic health records from 6 institutions, we identified patients with SLE, using International Classification of Diseases, Ninth Revision (ICD-9) codes, whose care was delivered at more than 1 organization. We examined whether patients had severe infections or comorbidities (ICD-9 code defined) that indicated SLE-induced damage. T-tests and chi-square tests were used to examine differences between fragmentation groups. Logistic regression was used to assess factors contributing to the occurrence of disease outcomes.

Results: We identified 4,276 patients with SLE. A total of 856 (20%) received care from more than 1 health care institution. African American patients and patients with public insurance were more likely to experience care fragmentation compared to white and private insurance patients (odds ratio [OR] 1.66, 95% confidence interval [95% CI] 1.44-1.97 and OR 1.63, 95% CI 1.42-1.95). We identified increased risk of infections (OR 1.57, 95% CI 1.30-1.88), cardiovascular disease (OR 1.51, 95% CI 1.23-1.86), end-stage renal disease (OR 1.34, 95% CI 1.05-1.70), nephritis (OR 1.28, 95% CI 1.07-1.54), and stroke (OR 1.28, 95% CI 1.01-1.62) among patients with fragmented care, adjusted for age, sex, race, insurance status, length of followup time, and total visit count.

Conclusion: In this cross-site cohort of SLE patients, care fragmentation is associated with increased risk of severe infection and comorbidities. These results suggest that improved health information exchange could positively impact outcomes for SLE patients.
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http://dx.doi.org/10.1002/acr.23161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447502PMC
September 2017

Payment Reform Needed to Address Health Disparities of Undiagnosed Diabetic Retinopathy in the City of Chicago.

Ophthalmol Ther 2017 Jun 24;6(1):123-131. Epub 2016 Nov 24.

Department of Ophthalmology, Center for Healthcare Studies, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Introduction: The Affordable Care Act (ACA) has expanded health coverage for thousands of Illinois residents. Expanded coverage, however, does not guarantee appropriate health care. Diabetes and its ocular complications serve as an example of how providers in underserved urban areas may not be able to keep up with new demand for labor- and technology-intensive health care unless changes in reimbursement policies are instituted.

Methods: A retrospective cohort study was conducted using medical encounter information from the Chicago HealthLNK Data Repository (HDR), an assembly of non-duplicated and de-identified patient medical records. We used a method of estimating the geographic distribution of undiagnosed diabetic retinopathy in the city of Chicago to illustrate the magnitude of potentially preventable eye disease. All rates were calculated for all ZIP Codes within Chicago (Cook County), and statistical differences between observed and geographically adjusted expected rates (p < 0.10, p < 0.05, p < 0.01) were highlighted as underserved areas.

Results: This analysis included 150,661 patients with diabetes identified from a total of nearly two million patients in Chicago. High rates of undetected diabetic retinopathy were found in low-income and minority areas. Within these areas, 37% of the identified diabetics were uninsured, with rates ranging widely from 20% to 68.6%. Among those with insurance, 32.8% were covered by Medicare and only 10% by Medicaid. Most patients with untreated diabetic retinopathy were found to reside in areas where primary health care is provided through Federally Qualified Health Centers.

Conclusions: With 150,661 diabetics identified in the city of Chicago, and this number continuing to rise each year, a manpower approach with ophthalmologist screening for diabetic retinopathy is not realistic. The ability to identify the growing number of diabetic patients with retinopathy in low-income areas will likely require the adoption of cost-effective screening technologies that are currently not funded by Medicare and Medicaid.
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http://dx.doi.org/10.1007/s40123-016-0072-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449291PMC
June 2017

Design and implementation of a privacy preserving electronic health record linkage tool in Chicago.

J Am Med Inform Assoc 2015 Sep 23;22(5):1072-80. Epub 2015 Jun 23.

University of Illinois Hospital and Health Sciences System, Chicago, IL, USA.

Objective: To design and implement a tool that creates a secure, privacy preserving linkage of electronic health record (EHR) data across multiple sites in a large metropolitan area in the United States (Chicago, IL), for use in clinical research.

Methods: The authors developed and distributed a software application that performs standardized data cleaning, preprocessing, and hashing of patient identifiers to remove all protected health information. The application creates seeded hash code combinations of patient identifiers using a Health Insurance Portability and Accountability Act compliant SHA-512 algorithm that minimizes re-identification risk. The authors subsequently linked individual records using a central honest broker with an algorithm that assigns weights to hash combinations in order to generate high specificity matches.

Results: The software application successfully linked and de-duplicated 7 million records across 6 institutions, resulting in a cohort of 5 million unique records. Using a manually reconciled set of 11 292 patients as a gold standard, the software achieved a sensitivity of 96% and a specificity of 100%, with a majority of the missed matches accounted for by patients with both a missing social security number and last name change. Using 3 disease examples, it is demonstrated that the software can reduce duplication of patient records across sites by as much as 28%.

Conclusions: Software that standardizes the assignment of a unique seeded hash identifier merged through an agreed upon third-party honest broker can enable large-scale secure linkage of EHR data for epidemiologic and public health research. The software algorithm can improve future epidemiologic research by providing more comprehensive data given that patients may make use of multiple healthcare systems.
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http://dx.doi.org/10.1093/jamia/ocv038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009931PMC
September 2015

The genetic basis of laboratory adaptation in Caulobacter crescentus.

J Bacteriol 2010 Jul 14;192(14):3678-88. Epub 2010 May 14.

Department of Biochemistry and Molecular Biology, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.

The dimorphic bacterium Caulobacter crescentus has evolved marked phenotypic changes during its 50-year history of culture in the laboratory environment, providing an excellent system for the study of natural selection and phenotypic microevolution in prokaryotes. Combining whole-genome sequencing with classical molecular genetic tools, we have comprehensively mapped a set of polymorphisms underlying multiple derived phenotypes, several of which arose independently in separate strain lineages. The genetic basis of phenotypic differences in growth rate, mucoidy, adhesion, sedimentation, phage susceptibility, and stationary-phase survival between C. crescentus strain CB15 and its derivative NA1000 is determined by coding, regulatory, and insertion/deletion polymorphisms at five chromosomal loci. This study evidences multiple genetic mechanisms of bacterial evolution as driven by selection for growth and survival in a new selective environment and identifies a common polymorphic locus, zwf, between lab-adapted C. crescentus and clinical isolates of Pseudomonas aeruginosa that have adapted to a human host during chronic infection.
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http://dx.doi.org/10.1128/JB.00255-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897358PMC
July 2010

Draft sequencing and comparative genomics of Xylella fastidiosa strains reveal novel biological insights.

Genome Res 2002 Oct;12(10):1556-63

Integrated Genomics, Inc., Chicago, Illinois 60612, USA.

Draft sequencing is a rapid and efficient method for determining the near-complete sequence of microbial genomes. Here we report a comparative analysis of one complete and two draft genome sequences of the phytopathogenic bacterium, Xylella fastidiosa, which causes serious disease in plants, including citrus, almond, and oleander. We present highlights of an in silico analysis based on a comparison of reconstructions of core biological subsystems. Cellular pathway reconstructions have been used to identify a small number of genes, which are likely to reside within the draft genomes but are not captured in the draft assembly. These represented only a small fraction of all genes and were predominantly large and small ribosomal subunit protein components. By using this approach, some of the inherent limitations of draft sequence can be significantly reduced. Despite the incomplete nature of the draft genomes, it is possible to identify several phage-related genes, which appear to be absent from the draft genomes and not the result of insufficient sequence sampling. This region may therefore identify potential host-specific functions. Based on this first functional reconstruction of a phytopathogenic microbe, we spotlight an unusual respiration machinery as a potential target for biological control. We also predicted and developed a new defined growth medium for Xylella.
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http://dx.doi.org/10.1101/gr.370702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC187531PMC
October 2002

Whole-genome comparative analysis of three phytopathogenic Xylella fastidiosa strains.

Proc Natl Acad Sci U S A 2002 Sep 30;99(19):12403-8. Epub 2002 Aug 30.

Integrated Genomics, Inc., 2201 West Campbell Park Drive, Chicago, IL 60612, USA.

Xylella fastidiosa (Xf) causes wilt disease in plants and is responsible for major economic and crop losses globally. Owing to the public importance of this phytopathogen we embarked on a comparative analysis of the complete genome of Xf pv citrus and the partial genomes of two recently sequenced strains of this species: Xf pv almond and Xf pv oleander, which cause leaf scorch in almond and oleander plants, respectively. We report a reanalysis of the previously sequenced Xf 9a5c (CVC, citrus) strain and the two "gapped" Xf genomes revealing ORFs encoding critical functions in pathogenicity and conjugative transfer. Second, a detailed whole-genome functional comparison was based on the three sequenced Xf strains, identifying the unique genes present in each strain, in addition to those shared between strains. Third, an "in silico" cellular reconstruction of these organisms was made, based on a comparison of their core functional subsystems that led to a characterization of their conjugative transfer machinery, identification of potential differences in their adhesion mechanisms, and highlighting of the absence of a classical quorum-sensing mechanism. This study demonstrates the effectiveness of comparative analysis strategies in the interpretation of genomes that are closely related.
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http://dx.doi.org/10.1073/pnas.132393999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC129457PMC
September 2002
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