Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia: CARE-FH Protocol.

The Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia (CARE-FH) study aims to improve diagnostic evaluation rates for FH at Geisinger, an integrated health delivery system. This clinical trial relies upon implementation science to transition the initial evaluation for FH into primary care, attempting to identify individuals prior to the onset of atherosclerotic cardiovascular disease events. The protocol for the CARE-FH study of this paper is available online. The first phase of the project focuses on trial design, including the development of implementation strategies to deploy evidence-based guidelines. The second phase will study the intervention, rolled out regionally to internal medicine, community medicine, and pediatric care clinicians using a stepped-wedge design, and analyzing data on diagnostic evaluation rates, and implementation, service, and health outcomes.

Genetic and Psychosocial Risk Factors Associated with Suicide Among Community Veterans: Implications for Screening, Treatment and Precision Medicine.

INTRODUCTION: Since veteran suicide is a concern and our knowledge of predictive factors is still limited, our objective was to assess risk factors for suicide, including genetic factors, among deployed veterans. METHODS: For this study, we surveyed 1730 veterans who were outpatients in a multi-hospital system in Pennsylvania. Altogether, 1041 veterans (60%) provided a DNA sample. The genetic risk variants investigated were within loci previously associated with PTSD and substance misuse, including CRHR1, CHRNA5, RORA, and FKBP5 genetic variations, which were used to calculate a polygenic risk score (range=0-8, mean=3.6, SD=1.4). RESULTS: Most veterans (56.2%) were deployed to Vietnam while significant numbers were deployed to Iraq, Afghanistan, and other post-Vietnam conflicts. Overall, 95.1% of the veterans were male, their mean age was 56.2 (SD=12), and 95.6% were Caucasian. Among the veterans, 24% had high combat exposure. The prevalence of lifetime suicidal thoughts was 11.3%. Additionally, 5.7% ever developed a suicide plan or attempted suicide in their lifetimes. Among those with a history of a lifetime suicide attempt or suicide plan, the PTSD genetic risk score was significantly higher (OR=3.96 vs 3.55, p=0.033), but for suicidal thoughts, this association was not significant (p=0.717). In multivariable analysis (MVA) logistic regression, significant predictors of attempting suicide or having a suicide plan were history of depression (OR=5.04, p<0.001), PTSD genetic risk score (OR=1.25, p=0.036), history of childhood abuse/neglect (OR=2.24, p=0.009), and lifetime marijuana use (OR= 1.56, p=0.020). Conversely, rural residence was protective for suicide risk (OR=0.49; p=0.031). For suicidal thoughts, in the MVA genetic risk score was not significant (p=0.697), but history of child abuse/neglect (p<0.001), history of depression (p>0.001), low psychological resilience (p=0.004), and lifetime marijuana use (p=0.022) were significant. DISCUSSION: In this study, we identified genetic risk variants and other predictors for suicide among veterans that may have implications for future screening and clinical care. Further research is advised.

Electronic health record analysis identifies kidney disease as the leading risk factor for hospitalization in confirmed COVID-19 patients.

BACKGROUND: Empirical data on conditions that increase risk of coronavirus disease 2019 (COVID-19) progression are needed to identify high risk individuals. We performed a comprehensive quantitative assessment of pre-existing clinical phenotypes associated with COVID-19-related hospitalization. METHODS: Phenome-wide association study (PheWAS) of SARS-CoV-2-positive patients from an integrated health system (Geisinger) with system-level outpatient/inpatient COVID-19 testing capacity and retrospective electronic health record (EHR) data to assess pre-COVID-19 pandemic clinical phenotypes associated with hospital admission (hospitalization). RESULTS: Of 12,971 individuals tested for SARS-CoV-2 with sufficient pre-COVID-19 pandemic EHR data at Geisinger, 1604 were SARS-CoV-2 positive and 354 required hospitalization. We identified 21 clinical phenotypes in 5 disease categories meeting phenome-wide significance (P<1.60x10-4), including: six kidney phenotypes, e.g. end stage renal disease or stage 5 CKD (OR = 11.07, p = 1.96x10-8), six cardiovascular phenotypes, e.g. congestive heart failure (OR = 3.8, p = 3.24x10-5), five respiratory phenotypes, e.g. chronic airway obstruction (OR = 2.54, p = 3.71x10-5), and three metabolic phenotypes, e.g. type 2 diabetes (OR = 1.80, p = 7.51x10-5). Additional analyses defining CKD based on estimated glomerular filtration rate, confirmed high risk of hospitalization associated with pre-existing stage 4 CKD (OR 2.90, 95% CI: 1.47, 5.74), stage 5 CKD/dialysis (OR 8.83, 95% CI: 2.76, 28.27), and kidney transplant (OR 14.98, 95% CI: 2.77, 80.8) but not stage 3 CKD (OR 1.03, 95% CI: 0.71, 1.48). CONCLUSIONS: This study provides quantitative estimates of the contribution of pre-existing clinical phenotypes to COVID-19 hospitalization and highlights kidney disorders as the strongest factors associated with hospitalization in an integrated US healthcare system.

The relationship between integrated pediatric psychology and primary care visit length, revenue, content over 24 months.

Introduction: Integrating behavioral health providers into pediatric primary care to provide behavioral health (BH) services is both effective and efficient; however, the impact of pediatric integrated services on the operational and financial outcomes of primary care provider (PCP) visits has not been thoroughly investigated. The present study examined whether length of practice integration predicts the relationship between BH content addressed in a PCP visit, visit length, and revenue generation. Method: A total of 1,209 pediatric encounters with 25 PCPs across 7 primary care offices in a predominantly rural health system were abstracted for the presence or absence of BH content, visit length, duration of integration, and revenue. χ2 analyses and the generalized linear model framework were used to address the study objectives. Results: Integration was associated with more PCP visits with a BH topic discussed at 6-11 months of integration but not at 14-24 months. Visits with a BH topic were longer than medical-only visits and shorter when a practice was integrated for 6-11 months but not at 14-24 months of integration. Public insurance and integration were associated with lower revenue generation per minute. Visit content was not associated with PCP revenue. Discussion: Results suggest a relationship between integration and the operational and financial outcomes of PCP visits. This study shows that initial efficiencies or improvements (e.g., time, cost, content) associated with integrating BH may be lost over time. Future studies should evaluate sustainability in relation to program impact. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Patient-reported quality of life recovery curves after robotic prostatectomy are similar across body mass index categories.

PURPOSE: To assess the impact of body mass index (BMI) on postoperative recovery curve of urinary and sexual function after robotic-assisted laparoscopic prostatectomy (RALP). We hypothesized that overweight and obese men have different recovery curves than normal weight men. MATERIALS AND METHODS: We reviewed preoperative and postoperative surveys from 691 men who underwent RALP from 2004-2014 in an integrated healthcare delivery system. Survey instruments included: sexual health inventory for men (SHIM), urinary behavior, leakage, and incontinence impact questionnaire (IIQ). A repeated measures analysis with autoregressive covariance structure was employed with linear splines with 2 knots for the time factor. We fit unadjusted and adjusted models and stratified by BMI (under/normal weight, overweight, and obese). Adjusted models included age, race/ethnicity, smoking status, diabetes, operation length, prostate-specific antigen, pathologic stage, nerve-sparing status, and surgery year. RESULTS: Mean age was 59 years. Most men were overweight (43%) and obese (42%). There were no significant differences in mean baseline SHIM, urinary behavior, leakage, and IIQ scores by BMI category. All groups had initial steep declines in urinary and sexual function in the first 3 months after RALP. There were no significant differences in postoperative urinary and sexual function score curves by BMI category. CONCLUSIONS: The pattern of urinary and sexual function recovery was similar across all BMI categories. Overweight and obese men may be counseled that urinary and sexual function recovery curves after surgery is similar to that of normal weight men.

Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study.

The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.

Factors associated with opioid overdose: a 10-year retrospective study of patients in a large integrated health care system.

OBJECTIVE: Opioid overdoses (ODs) have been increasing, and harm reduction efforts are a priority. The success of these efforts will be dependent on the identification of at-risk patients and improved access to the antidote naloxone. Therefore, to identify access to naloxone and factors associated with negative health outcomes, we conducted a retrospective study of patients with OD to identify those at highest risk of adverse outcomes and to assess the use of naloxone. METHODS: We conducted a study of electronic health records for patients admitted to the largest multihospital system in the region - the Geisinger Health System (GHS) for ODs - from April 2005 through March 2015. ODs were defined by International Classification of Diseases-9 codes (age range: 10-95 years). Bivariate analyses and multiple logistic regressions were conducted to identify pre-OD factors associated with adverse health outcomes post-OD. RESULTS: We identified 2,039 patients with one or more ODs, of whom 9.4% were deceased within 12 months. Patient demographics suggest that patients with OD had a mean age of 52 years, were not married (64%), and were unemployed (78%). Common comorbidities among patients with OD include cardiovascular disease (22%), diabetes (14%), cancer (13%), and the presence of one or more mental health disorders (35%). Few patients had a prescription order for naloxone (9%) after their OD. The majority of patients with OD were in proximity to GHS health care facilities, with 87% having a GHS primary care provider. In multiple logistic regressions, common predictors of adverse outcomes, including death, repeated ODs, frequent service use, and high service cost, were higher prescription opioid use, comorbid medical conditions, comorbid mental disorders, and concurrent use of other psychotropic medications. CONCLUSION: This study suggests opportunities for improving OD outcomes. Those who receive higher quantities of prescription opioids concurrent with other psychotropic medicines may need closer monitoring to avoid death, repeated OD events, higher service use, and higher service costs. Other opportunities for improving OD outcomes include the use of electronic health records to notify physicians of high-risk patients and updating of guidelines/operation manuals focused on the distribution of naloxone to those in highest need.

The Geisinger MyCode community health initiative: an electronic health record-linked biobank for precision medicine research.

PURPOSE: Geisinger Health System (GHS) provides an ideal platform for Precision Medicine. Key elements are the integrated health system, stable patient population, and electronic health record (EHR) infrastructure. In 2007, Geisinger launched MyCode, a system-wide biobanking program to link samples and EHR data for broad research use. METHODS: Patient-centered input into MyCode was obtained using participant focus groups. Participation in MyCode is based on opt-in informed consent and allows recontact, which facilitates collection of data not in the EHR and, since 2013, the return of clinically actionable results to participants. MyCode leverages Geisinger's technology and clinical infrastructure for participant tracking and sample collection. RESULTS: MyCode has a consent rate of >85%, with more than 90,000 participants currently and with ongoing enrollment of ~4,000 per month. MyCode samples have been used to generate molecular data, including high-density genotype and exome sequence data. Genotype and EHR-derived phenotype data replicate previously reported genetic associations. CONCLUSION: The MyCode project has created resources that enable a new model for translational research that is faster, more flexible, and more cost-effective than traditional clinical research approaches. The new model is scalable and will increase in value as these resources grow and are adopted across multiple research platforms.Genet Med 18 9, 906-913.

Assessing the Quality of Death and Dying in an Integrated Health Care System in Rural Pennsylvania.

CONTEXT: With growing emphasis on improving the value of health care, there is increased scrutiny of quality outcomes and high health expenditures during the final months of life. OBJECTIVES: The purpose of this project is to answer 1) how do next of kin (NOK) perceive the quality of their loved ones' dying and death; 2) are there patient and NOK characteristics that predict lower quality; and 3) are there structural aspects of care associated with lower quality? METHODS: A mailed survey was administered to a stratified random sample of NOK of Geisinger Health System patients who had died in the past year. The Quality of Death and Dying, the General Anxiety Disorder seven-item scale, the Patient Health Questionnaire eight-item depression scale, and selected questions from the Toolkit of Instruments to Measure End of Life Care were used. RESULTS: There were 672 respondents. Significant predictors of Quality of Death and Dying score were number of doctors involved in care (P = 0.0415), location of death (P < 0.0001), frequency of receiving confusing or contradictory information (P < 0.0001), illness progression (P = 0.0343), Patient Health Questionnaire-2 score (P = 0.0148), and General Anxiety Disorder seven-item scale score (P < 0.0070). CONCLUSION: Several findings suggest that factors such as NOK depression and anxiety, prolonged illness, dying in the hospital, receipt of conflicting information, and confusion around the doctor in charge are associated with lower quality of the dying and death experience for NOK. Further investigation is warranted to facilitate high-quality measurement and the use of measurement results to improve care.

Preventable major cardiovascular events associated with uncontrolled glucose, blood pressure, and lipids and active smoking in adults with diabetes with and without cardiovascular disease: a contemporary analysis.

OBJECTIVE: The objective of this study was to assess the incidence of major cardiovascular (CV) hospitalization events and all-cause deaths among adults with diabetes with or without CV disease (CVD) associated with inadequately controlled glycated hemoglobin (A1C), high LDL cholesterol (LDL-C), high blood pressure (BP), and current smoking. RESEARCH DESIGN AND METHODS: Study subjects included 859,617 adults with diabetes enrolled for more than 6 months during 2005-2011 in a network of 11 U.S. integrated health care organizations. Inadequate risk factor control was classified as LDL-C ≥100 mg/dL, A1C ≥7% (53 mmol/mol), BP ≥140/90 mm Hg, or smoking. Major CV events were based on primary hospital discharge diagnoses for myocardial infarction (MI) and acute coronary syndrome (ACS), stroke, or heart failure (HF). Five-year incidence rates, rate ratios, and average attributable fractions were estimated using multivariable Poisson regression models. RESULTS: Mean (SD) age at baseline was 59 (14) years; 48% of subjects were female, 45% were white, and 31% had CVD. Mean follow-up was 59 months. Event rates per 100 person-years for adults with diabetes and CVD versus those without CVD were 6.0 vs. 1.7 for MI/ACS, 5.3 vs. 1.5 for stroke, 8.4 vs. 1.2 for HF, 18.1 vs. 40 for all CV events, and 23.5 vs. 5.0 for all-cause mortality. The percentages of CV events and deaths associated with inadequate risk factor control were 11% and 3%, respectively, for those with CVD and 34% and 7%, respectively, for those without CVD. CONCLUSIONS: Additional attention to traditional CV risk factors could yield further substantive reductions in CV events and mortality in adults with diabetes.

Trends in diabetes incidence among 7 million insured adults, 2006-2011: the SUPREME-DM project.

An observational cohort analysis was conducted within the Surveillance, Prevention, and Management of Diabetes Mellitus (SUPREME-DM) DataLink, a consortium of 11 integrated health-care delivery systems with electronic health records in 10 US states. Among nearly 7 million adults aged 20 years or older, we estimated annual diabetes incidence per 1,000 persons overall and by age, sex, race/ethnicity, and body mass index. We identified 289,050 incident cases of diabetes. Age- and sex-adjusted population incidence was stable between 2006 and 2010, ranging from 10.3 per 1,000 adults (95% confidence interval (CI): 9.8, 10.7) to 11.3 per 1,000 adults (95% CI: 11.0, 11.7). Adjusted incidence was significantly higher in 2011 (11.5, 95% CI: 10.9, 12.0) than in the 2 years with the lowest incidence. A similar pattern was observed in most prespecified subgroups, but only the differences for persons who were not white were significant. In 2006, 56% of incident cases had a glycated hemoglobin (hemoglobin A1c) test as one of the pair of events identifying diabetes. By 2011, that number was 74%. In conclusion, overall diabetes incidence in this population did not significantly increase between 2006 and 2010, but increases in hemoglobin A1c testing may have contributed to rising diabetes incidence among nonwhites in 2011.

Prescription medication burden in patients with newly diagnosed diabetes: a SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) study.

OBJECTIVE: To understand the burden of medication use for patients with newly diagnosed diabetes both before and after diabetes diagnosis and to identify subpopulations of patients with newly diagnosed diabetes who face a relatively high drug burden. DESIGN: Retrospective cohort study. SETTING: 11 integrated health systems in the United States. PARTICIPANTS: 196,654 insured adults 20 years of age or older newly diagnosed with type 1 or type 2 diabetes from January 2005 through December 2009. MAIN OUTCOME MEASURES: Number of unique therapeutic classes of drugs dispensed in the 12 months before and 12 months after diagnosis of diabetes in five categories: overall, antihypertensive agents, antihyperlipidemic agents, mental health agents, and antihyperglycemic agents (in the postdiagnosis period only). RESULTS: The mean number of drug classes used by newly diagnosed patients with diabetes is high before diagnosis (5.0) and increases significantly afterward (6.6). Of this increase, 81% is due to antihyperglycemic initiation and increased use of medications to control hypertension and lipid levels. Multivariate analyses showed that overall drug burden after diabetes diagnosis was higher in women, older, white, and obese patients, as well as among those with higher glycosylated hemoglobin concentrations and comorbidity levels (significant for all comparisons). The overall number of drug classes used by newly diagnosed patients with diabetes after diagnosis decreased slightly but significantly between 2005 and 2009. CONCLUSION: Patients newly diagnosed with diabetes face a substantially increased burden of medications used to control diabetes and other comorbidities. This study shows an increased focus on cardiovascular disease risk factor control after diagnosis of diabetes. However, total drug burden may be slightly decreasing over time.

Bisphosphonates and mortality in women with CKD and the presence or absence of cardiovascular disease.

BACKGROUND AND OBJECTIVES: A modest protective association between bisphosphonate prescription and mortality among women with CKD but without clinically manifest cardiovascular disease has been shown. Whether a prior cardiovascular event (myocardial infarction, stroke, or heart failure) modifies this association is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort of adult women with stages 3 and 4 CKD receiving primary care in a rural integrated health care system during the period 2004-2011 without history of advanced malignancy or organ transplantation (n=6756, median age=74 years, median follow-up=4.3 years) was retrospectively assembled. The primary analysis compared those patients prescribed bisphosphonates (both prevalent and incident use during follow-up) with those patients not prescribed. Additional approaches were taken to account for survival and indication biases. The primary outcome was time to death by Cox multivariable regression. RESULTS: In the primary analysis, compared with women not prescribed a bisphosphonate, the hazard ratio (95% confidence interval) for death among women prescribed a bisphosphonate was 0.90 (0.78 to 1.04) if there was no history of cardiovascular event but 1.22 (1.04 to 1.42) if there was history of cardiovascular event (P for interaction=0.004). In the additional approaches, associations between bisphosphonate prescription and mortality among those patients with a prior cardiovascular history varied: hazard ratios (95% confidence intervals) were 1.25 (1.01 to 1.57), 1.48 (1.16 to 1.88), and 0.94 (0.66 to 1.34). Interaction by prior cardiovascular event history varied across these three approaches (P=0.07, P=0.22, and P=0.05). CONCLUSION: In this study of women with CKD, the association between bisphosphonate treatment and mortality risk was inconclusive across a series of analyses designed to account for various types of selection and indication bias.

Death and cardiovascular events after bacteriuria among adult women with chronic kidney disease.

BACKGROUND: The impact of bacteriuria on mortality and cardiovascular risk has not been previously reported for patients with chronic kidney disease (CKD). OBJECTIVE: To assess the relationship between outpatient episodes of bacteriuria and mortality and cardiovascular risk among women with CKD. DESIGN: Retrospective cohort study using an electronic health database from an integrated healthcare system in central Pennsylvania. SUBJECTS: Adult women with CKD receiving primary care at Geisinger Health System between January 1, 2004 and December 31, 2009 were eligible, and were followed through December 31, 2010 for study outcomes. MAIN MEASURES: The study exposure was bacteriuria, defined as an outpatient urine culture with bacterial growth of 10(4) cfu/mL. Treatment history (antibiotic prescription within 90 days) was identified. Study outcomes were death and the composite of hospitalization for myocardial infarction, congestive heart failure, or stroke. Multivariate-adjusted Cox models incorporated all bacteriuria episodes and antibiotic prescriptions in time-dependent fashion (in addition to other covariates) to account for the cumulative impact of infections, treatment, and hospitalization during follow-up. KEY RESULTS: 6807 women were followed for a median (interquartile range) of 5.2 (3.4, 5.9) years. In adjusted models, each untreated bacteriuria episode was associated with an increased risk of death (hazard ratio [HR] 1.56, 95% CI 1.35-1.81) and the composite cardiovascular outcome (HR 1.32, 95% CI 1.05-1.65); treated episodes were not associated with an increased risk of death or cardiovascular events. CONCLUSION: Among female patients with CKD, untreated bacteriuria occurring in the outpatient setting is associated with an increased risk of death and cardiovascular morbidity.

Bisphosphonate therapy, death, and cardiovascular events among female patients with CKD: a retrospective cohort study.

BACKGROUND: Accelerated vascular calcification contributes to cardiovascular disease burden in patients with chronic kidney disease (CKD). We hypothesized that bisphosphonate therapy would reduce the risk of mortality and cardiovascular events in this population. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult women with stage 3 or 4 CKD receiving primary care in a large rural integrated health care system in 2004-2010. EXPOSURE: Time-dependent exposure status based on outpatient prescription for any medication within the bisphosphonate class, obtained from electronic health records. OUTCOMES: Time to death and first cardiovascular event (composite of myocardial infarction, heart failure, or stroke). RESULTS: Data from 9,604 eligible female patients with CKD were analyzed; 3,234 were treated with bisphosphonate therapy. During a median follow-up of 3.9 (25th-75th percentile, 2.3-5.4) years, there were 286 versus 881 deaths and 206 versus 571 cardiovascular events (treated vs not-treated groups, respectively). In a multivariate Cox proportional hazard model, the adjusted HR for death (treated vs not treated) was 0.78 (95% CI, 0.67-0.91; P = 0.003). In Cox modeling adjusted for similar baseline covariates, treatment with bisphosphonates was not associated with a lower risk of the composite cardiovascular outcome (adjusted HR, 1.14; 95% CI, 0.94-1.39; P = 0.2). LIMITATIONS: Residual confounding by unidentified factors, exclusion of male patients, and lack of information about longitudinal drug adherence. CONCLUSIONS: For female patients with CKD, treatment with bisphosphonates is associated with a lower risk of death, but not cardiovascular events. Confirmatory studies and investigations of potential causal mechanisms are warranted.

GFR decline and mortality risk among patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Estimates of the effect of estimated GFR (eGFR) decline on mortality have focused on populations with normal kidney function, or have included limited information on factors previously shown to influence the risk of death among patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively assessed the effect of rate of eGFR decline on survival of patients with CKD receiving primary care through a large integrated health care system in central Pennsylvania between January 1, 2004, and December 31, 2009. RESULTS: A total of 15,465 patients were followed for a median of 3.4 years. Median rates of eGFR change by those in the lower, middle, and upper tertiles of eGFR slope were -4.8, -0.6, and 3.5 ml/min per 1.73 m(2)/yr, respectively. In Cox proportional hazard modeling for time to death, adjusted for baseline proteinuria, changes in nutritional parameters, and episodes of acute kidney injury during follow-up (among other covariates), the hazard ratio for those in the lower (declining) and upper (increasing) eGFR tertiles (relative to the middle, or stable, tertile) was 1.84 and 1.42, respectively. Longitudinal changes in nutritional status as well as episodes of acute kidney injury attenuated the risk only modestly. These findings were consistent across subgroups. CONCLUSIONS: eGFR change over time adds prognostic information to traditional mortality risk predictors among patients with CKD. The utility of incorporating eGFR trends into patient-risk assessment should be further investigated.