Effectiveness of BNT162b2 COVID-19 primary series vaccination in children aged 5-17 years in the United States: a cohort study.

BACKGROUND: COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study's objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. METHODS: This cohort study identified children aged 5-17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. RESULTS: There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36-40%]) and hospital/ED-diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56-65%]). VE estimates were lowest among children 5-11 years and during the Omicron-variant era. CONCLUSIONS: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED-diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. REGISTRATION: The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).

Effectiveness of monovalent COVID-19 booster/additional vaccine doses in the United States.

Background: Monovalent booster/additional doses of COVID-19 vaccines were first authorized in August 2021 in the United States. We evaluated the real-world effectiveness of receipt of a monovalent booster/additional dose of COVID-19 vaccine compared with receiving a primary vaccine series without a booster/additional dose. Methods: Cohorts of individuals receiving a COVID-19 booster/additional dose after receipt of a complete primary vaccine series were identified in 2 administrative insurance claims databases (Optum, CVS Health) supplemented with state immunization information system data between August 2021 and March 2022. Individuals with a complete primary series but without a booster/additional dose were one-to-one matched to boosted individuals on calendar date, geography, and clinical factors. COVID-19 diagnoses were identified in any medical setting, or specifically in hospitals/emergency departments (EDs). Propensity score-weighted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated with Cox proportional hazards models; vaccine effectiveness (VE) was estimated as 1 minus the HR by vaccine brand overall and within subgroups of variant-specific eras, immunocompromised status, and homologous/heterologous booster status. Results: Across both data sources, we identified 752,165 matched pairs for BNT162b2, 410,501 for mRNA-1273, and 11,398 for JNJ-7836735. For any medically diagnosed COVID-19, meta-analyzed VE estimates for BNT162b2, mRNA-1273, and JNJ-7836735, respectively, were: BNT162b2, 54% (95% CI, 53%-56%); mRNA-1273, 58% (95% CI, 56%-59%); JNJ-7836735, 34% (95% CI, 23%-44%). For hospital/ED-diagnosed COVID-19, VE estimates ranged from 70% to 76%. VE was generally lower during the Omicron era than the Delta era and for immunocompromised individuals. There was little difference observed by homologous or heterologous booster status. Conclusion: The original, monovalent booster/additional doses were reasonably effective in real-world use among the populations for which they were indicated during the study period. Additional studies may be informative in the future as new variants emerge and new vaccines become available.Registration: The study protocol was publicly posted on the BEST Initiative website (https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf).

Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND OBJECTIVES: Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use. RESULTS: A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use. DISCUSSION: Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia.

Use of Immunization Information Systems in Ascertainment of COVID-19 Vaccinations for Claims-Based Vaccine Safety and Effectiveness Studies.

Importance: Safety and effectiveness studies of COVID-19 vaccines are being conducted using clinical data, including administrative claims. However, claims data only partially capture administered COVID-19 vaccine doses for numerous reasons, such as vaccination at sites that do not generate claims for reimbursement. Objective: To evaluate the extent to which Immunization Information Systems (IIS) data linked to claims data enhances claims-based COVID-19 vaccine capture for a commercially insured population and to estimate the magnitude of misclassification of vaccinated individuals as having unvaccinated status in the linked IIS and claims data. Design, Setting, and Participants: This cohort study used claims data from a commercial health insurance database and obtained vaccination data from IIS repositories in 11 US states. Participants were individuals younger than 65 years who resided in 1 of 11 states of interest and who were insured in health plans from December 1, 2020, through December 31, 2021. Main Outcomes and Measures: Estimated proportion of individuals with at least 1 dose of any COVID-19 vaccine and proportion of individuals with a completed vaccine series based on general population guidelines. Vaccination status estimates were calculated and compared using claims data alone and linked IIS and claims data. Remaining misclassification of vaccination status was assessed by comparing linked IIS and claims data estimates with estimates from external surveillance data sources (Centers for Disease Control and Prevention [CDC] and state Department of Health [DOH]) and capture-recapture analysis. Results: This cohort study included 5 112 722 individuals (mean [SD] age, 33.5 [17.6] years; 2 618 098 females [51.2%]) from 11 states. Characteristics of those who received at least 1 vaccine dose and those who completed a vaccine series were similar to the overall study population. The proportion with at least 1 vaccine dose increased from 32.8% using claims data alone to 48.1% when the data were supplemented with IIS vaccination records. Vaccination estimates using linked IIS and claims data varied widely by state. The percentage of individuals who completed a vaccine series increased from 24.4% to 41.9% after the addition of IIS vaccine records and varied across states. The percentages of underrecording using linked IIS and claims data were 12.1% to 47.1% lower than those using CDC data, 9.1% to 46.9% lower than the state DOH, and 9.2% to 50.9% lower than capture-recapture analysis. Conclusion and Relevance: Results of this study suggested that supplementing COVID-19 claims records with IIS vaccination records substantially increased the number of individuals who were identified as vaccinated, yet potential underrecording remained. Improvements in reporting vaccination data to IIS infrastructures could allow frequent updates of vaccination status for all individuals and all vaccines.

Real-world characteristics, treatment experiences and corticosteroid utilisation of patients treated with tofacitinib for moderate to severe ulcerative colitis.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database. METHODS: Patients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation). RESULTS: Among patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3-6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib. CONCLUSIONS: Among patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.

Healthcare Resource Utilization and Costs of Steroid-Associated Complications in Patients With Graft-Versus-Host Disease.

Acute and chronic graft-versus-host disease (aGVHD/cGVHD) are serious conditions occurring after allogeneic hematopoietic cell transplantation (HCT). Steroids are the most common first-line therapy; however, they are frequently associated with numerous morbid complications. To describe the healthcare resource utilization (HCRU) and costs of steroid-related complications in patients receiving systemic steroids for GVHD. This retrospective study used medical and pharmacy claims from the Optum Research database. Eligible patients were diagnosed with GVHD (aGVHD, cGVHD, or both) after HCT and were treated with systemic steroids between July 1, 2010, and August 31, 2019. The index date was the date of the first claim for systemic steroids after GVHD diagnosis. The baseline period was the 6 months before the index date, and the follow-up period was 2 years after the index date. Outcome variables included HCRU and costs associated with steroid complications, grouped into 4 categories: bone/muscle, gastrointestinal, infection, and metabolic/endocrine. A multivariate analysis was used to assess the cost ratio associated with the presence of each steroid complication; the linear model was adjusted for baseline patient characteristics and types of steroid conditions identified during follow-up. Another multivariate analysis assessed the hazard ratio for hospitalization associated with each steroid complication using a Cox proportional hazards regression model adjusted for the time-varying presence of each complication category. A total of 689 patients were studied (median age, 55 years; male, 60%); 22% had aGVHD only, 21% had cGVHD only, and 39% had both types of GVHD. After 2 years of follow-up, 97% had at least 1 steroid-associated complication. The most common complication category was infection (79.5%), followed by metabolic/endocrine (32.4%), gastrointestinal (29.2%), and bone/muscle conditions (19.7%). About two thirds (66%) of patients with any steroid complication had ≥1 hospitalization requiring a median (interquartile range [IQR]) of 20 (8-43) hospital days. Patients with an infection experienced the highest hospitalization rate (72%) and thus the highest associated costs. The total mean (median [IQR]) healthcare cost potentially related to steroid complications was $164,787 ($50,834 [$8865-$182,693]), and the largest expense was hospitalization (mean [median {IQR}], $140,637 [$26,782 {$0-$141,398}]). Of the different steroid complications, infections were associated with the highest cost (mean [median {IQR}], $167,473 [$57,680 {$16,261-$178,698}]). In addition, a significantly higher total adjusted cost was associated with the presence of an infection, gastrointestinal complication, or bone/muscle complication in patients with GVHD versus the absence of each complication (all P < .001). Complications occurring after steroid treatment for GVHD may add substantially to the HCRU and costs associated with GVHD management. Infections in particular required inpatient care and were associated with the highest economic burden.

Association of Proton Pump Inhibitors With Higher Risk of Cardiovascular Disease and Heart Failure.

OBJECTIVE: To examine associations of cumulative exposure to proton pump inhibitors (PPIs) with total cardiovascular disease (CVD; composed of stroke, coronary heart disease, and heart failure [HF]) and HF alone in a cohort study of White and African American participants of the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Use of PPIs was assessed by pill bottle inspection at visit 1 (January 1, 1987 to 1989) and up to 10 additional times before baseline (visit 5; 2011 to 2013). We calculated cumulative exposure to PPIs as days of use from visit 1 to baseline. Participants (n=4346 free of total CVD at visit 5; mean age, 75 years) were observed for incident total CVD and HF events through December 31, 2016. We used Cox regression to measure associations of PPIs with total CVD and HF. RESULTS: After adjustment for potential confounding variables, participants with a cumulative exposure to PPIs of more than 5.1 years had a 2.02-fold higher risk of total CVD (95% CI, 1.50 to 2.72) and a 2.21-fold higher risk of HF (95% CI, 1.51 to 3.23) than nonusers. CONCLUSION: Long-term PPI use was associated with twice the risk of total CVD and HF compared with nonusers. Our findings are in concordance with other research and suggest another reason to be cautious of PPI overuse.

Adhesion pathway proteins and risk of atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The cellular adhesion pathway has been suggested as playing an important role in the pathogenesis of atrial fibrillation (AF). However, prior studies that have investigated the role of adhesion pathway proteins in risk of AF have been limited in the number of proteins that were studied and in the ethnic and racial diversity of the study population. Therefore we aimed to study the associations of fifteen adhesion pathway proteins with incident AF in a large, diverse population. METHODS: Multi-Ethnic Study of Atherosclerosis participants from four races/ethnicities (n = 2504) with protein levels measured were followed for incident AF (n = 253). HGF protein was measured on Exam 1 samples (N = 6669; AF n = 851). Cox proportional hazards regression was used to assess the association of AF with 15 adhesion pathway proteins. Bonferroni correction was applied to account for multiple comparisons. RESULTS: After adjusting for potential confounding variables (age, sex, race/ethnicity, height, body mass index, systolic blood pressure, antihypertension therapy, diabetes status, current smoker, current alcohol use, and total and HDL cholesterol), and accounting for multiple testing (P < 0.05/15 = 0.0033), circulating levels of the following proteins were positively associated with a higher risk of AF: MMP-2 (HR per standard deviation increment, 1.27; 95% CI 1.11‒1.45), TIMP-2 (HR 1.28; 95% CI 1.12‒1.46), VCAM-1 (HR 1.32; 95% CI 1.16‒1.50), and SLPI (HR 1.22; 95% CI 1.07‒1.38). The association between proteins and AF did not differ by race/ethnicity. CONCLUSIONS: Circulating levels of MMP-2, TIMP-2, VCAM-1, and SLPI were positively associated with an increased risk of incident AF in a diverse population. Our findings suggest that adhesion pathway proteins may be important risk predictors of AF.

The Impact of Adverse Events on Health Care Resource Utilization, Costs, and Mortality Among Patients Treated with Immune Checkpoint Inhibitors.

BACKGROUND: We investigated the association between adverse events (AEs) suspected to be immune-related and health care resource utilization, costs, and mortality among patients receiving programmed cell death 1/programmed cell death ligand 1 immune checkpoint inhibitor (ICI) monotherapy for urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, or Merkel cell carcinoma. PATIENTS AND METHODS: We conducted a retrospective cohort study using medical and pharmacy claims and enrollment information from U.S. commercial and Medicare Advantage with Part D enrollees in the Optum Research Database from March 1, 2014, through April 30, 2019. Claims were linked with mortality data from the Social Security Death Index and the National Death Index. Eligible patients had at least one ICI claim between September 1, 2014, and April 30, 2019. RESULTS: After adjusting for potential confounding variables, we found patients with AEs had more than double the risk of an inpatient stay (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.9-2.5) and an 80% higher risk of an emergency visit (HR, 1.8; 95% CI, 1.6-2.1) than patients without AEs. Adjusted 6-month total costs were $24,301 higher among patients with an AE versus those without ($99,037 vs. $74,736; 95% CI, $18,828-29,774; p < .001). Mean ± SD AE-related medical costs averaged $2,359 ± $7,496 per patient per month, driven by inpatient visits, which accounted for 89.9% of AE-related costs. Adjusted risk of mortality was similar in patients with and without AEs. CONCLUSION: Patients with AEs had higher risks of hospitalizations, emergency room visits, and higher health care costs, driven by inpatient stays, than patients without AEs. The adjusted risk of mortality was similar between the two cohorts. IMPLICATIONS FOR PRACTICE: Patients taking immune checkpoint inhibitors (ICIs) who had adverse events (AEs) had significantly higher health care costs and utilization, driven by inpatient stays, compared with patients who did not. Given this high cost associated with AEs and the differences in the side effect profile of ICIs versus traditional chemotherapy, it is important for physicians to be cognizant of these differences when treating patients with ICIs. Ongoing evaluation, earlier recognition, and more effective, multidisciplinary management of AEs may improve patient outcomes and reduce the need for costly inpatient stays.

Proton Pump Inhibitor Use, Hypomagnesemia and Risk of Cardiovascular Diseases: The Atherosclerosis Risk in Communities (ARIC) Study.

GOALS: The goal of this study was to evaluate whether proton pump inhibitor (PPI) use is cross-sectionally associated with hypomagnesemia and whether hypomagnesemia mediates the prospective association between PPIs and cardiovascular disease (CVD) risk. BACKGROUND: Use of PPIs has been associated with hypomagnesemia, primarily in case reports or within insurance databases. Both PPI use and low serum magnesium (Mg) have been associated with modestly higher CVD risk. Yet, the interrelation between PPI use and Mg in relation to CVD risk is unclear. STUDY: The 4436 Atherosclerosis Risk in Communities participants without prevalent CVD at visit 5 (baseline, 2011-2013) were included. Multivariable relative risk regression was used for cross-sectional analyses between PPI and hypomagnesemia prevalence (≤0.75 mmol/L). Incident CVD (defined by atrial fibrillation, coronary heart disease, CVD mortality, heart failure, stroke) was identified through 2017. Multivariable Cox regression was used to examine the PPI-CVD association. RESULTS: Participants were mean±SD aged 75±5 years; 63% were women, 23% Black, and 24% were PPI users. PPI users had 1.24-fold (95% confidence interval: 1.08-1.44) higher prevalence of hypomagnesemia than nonusers. Over a median 5 years of follow-up, 684 incident CVD events occurred. PPI users had higher CVD risk [hazard ratio (95% confidence interval) 1.31 (1.10-1.57)] than nonusers. The effect estimate was largely unchanged when hypomagnesemia was added to the model as a potential mediator. CONCLUSIONS: In this elderly community-based study, PPI users had a higher prevalence of hypomagnesemia than in nonusers. PPI users also had higher CVD risk than nonusers; however, it appears unlikely that hypomagnesemia explains associations of PPIs with CVD risk.

Increased hepatocyte growth factor levels over 2 years are associated with coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA)

Hepatocyte growth factor (HGF) is associated with subclinical and clinical atherosclerosis. However, the significance of change in HGF and development of atherosclerotic disease is unknown. In a large and diverse population-based cohort, we report that change in the biomarker HGF is an independent predictor of incident CHD.

Hepatocyte growth factor is associated with progression of atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Hepatocyte growth factor (HGF) has previously been associated with risk of stroke, coronary heart disease, and atherosclerosis. We hypothesized that higher circulating HGF is associated with greater progression of measures of atherosclerosis: coronary artery calcium (CAC) and carotid plaque. METHODS: Participants aged 45-84 years from the prospective cohort study Multi-Ethnic Study of Atherosclerosis had HGF measured at baseline (between 2000 and 2002) and were followed for progression of atherosclerosis for up to 12 years. CAC was measured at all five exams using the Agatston method. Mixed-effects models were used to examine the association of HGF and CAC progression among 6695 participants with available data. Relative risk regression was used to assess the association between HGF and new or additional carotid plaque between exams 1 and 5 in 3400 participants with available data. All point estimates were adjusted for potential confounding variables. RESULTS: Each standard deviation higher HGF at baseline was associated with 2.9 Agatston units/year greater CAC progression (95% CI: 1.6-4.2, p < 0.0001), and the magnitude of this association differed by race/ethnicity (p value for interaction by race = 0.003). Each standard deviation higher HGF at baseline was associated with a 4% higher risk of new or additional carotid plaque (95% CI: 1.01-1.08, p = 0.005). CONCLUSIONS: Higher levels of HGF were significantly associated with greater progression of atherosclerosis in this large and diverse population. Circulating HGF continues to show promise as a potential clinical biomarker for cardiovascular disease.

CYP2D6 phenotypes are associated with adverse outcomes related to opioid medications.

BACKGROUND: Variation in the CYP2D6 gene may affect response to opioids in both poor and ultrarapid metabolizers, but data demonstrating such associations have been mixed, and the impact of variants on toxicity-related symptoms (e.g., nausea) is unclear. Therefore, we examined the association between CYP2D6 phenotype and poor pain control or other adverse symptoms related to the use of opioids in a sample of primary care patients. MATERIALS AND METHODS: We identified all patients in the Mayo Clinic RIGHT Protocol who were prescribed an opioid medication between July 01, 2013 and June 30, 2015, and categorized patients into three phenotypes: poor, intermediate to extensive, or ultrarapid CYP2D6 metabolizers. We reviewed the electronic health record of these patients for indications of poor pain control or adverse symptoms related to medication use. Associations between phenotype and outcomes were assessed using Chi-square tests and logistic regression. RESULTS: Overall, 257 (25% of RIGHT Protocol participants) patients received at least one opioid prescription; of these, 40 (15%) were poor metabolizers, 146 (57%) were intermediate to extensive metabolizers, and 71 (28%) were ultrarapid metabolizers. We removed patients that were prescribed a CYP2D6 inhibitor medication (n=38). After adjusting for age and sex, patients with a poor or ultrarapid phenotype were 2.7 times more likely to experience either poor pain control or an adverse symptom related to the prescription compared to patients with an intermediate to extensive phenotype (odds ratio: 2.68; 95% CI: 1.39, 5.17; p=0.003). CONCLUSION: Our results suggest that >30% of patients with a poor or ultrarapid CYP2D6 phenotype may experience an adverse outcome after being prescribed codeine, tramadol, oxycodone, or hydrocodone. These medications are frequently prescribed for pain relief, and ~39% of the US population is expected to carry one of these phenotypes, suggesting that the population-level impact of these gene-drug interactions could be substantial.

Hepatocyte growth factor demonstrates racial heterogeneity as a biomarker for coronary heart disease.

OBJECTIVE: To determine if hepatocyte growth factor (HGF), a promising biomarker of coronary heart disease (CHD) given its release into circulation in response to endothelial damage, is associated with subclinical and clinical CHD in a racial/ethnic diverse population. METHODS: HGF was measured in 6738 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Highest mean HGF values (pg/mL) were observed in Hispanic, followed by African, non-Hispanic white, then Chinese Americans. RESULTS: In all races/ethnicities, HGF levels were associated with older age, higher systolic blood pressure (SBP) and body mass index, lower high-density lipoprotein, diabetes and current smoking. In fully adjusted models, each SD higher HGF was associated with an average increase in coronary artery calcium (CAC) of 55 Agatston units for non-Hispanic whites (p<0.001) and 51 Agatston units for African-Americans (p=0.007) but was not in the other race/ethnic groups (interaction p=0.02). There were 529 incident CHD events, and CHD risk was 41% higher in African (p<0.001), 17% in non-Hispanic white (p=0.026) and Chinese (p=0.36), and 6% in Hispanic Americans (p=0.56) per SD increase in HGF. CONCLUSION: In a large and diverse population-based cohort, we report that HGF is associated with subclinical and incident CHD. We demonstrate evidence of racial/ethnic heterogeneity within these associations, as the results are most compelling in African-Americans and non-Hispanic white Americans. We provide evidence that HGF is a biomarker of atherosclerotic disease that is independent of traditional risk factors.

Participant-perceived understanding and perspectives on pharmacogenomics: the Mayo Clinic RIGHT protocol (Right Drug, Right Dose, Right Time).

PURPOSE: To examine predictors of understanding preemptive CYP2D6 pharmacogenomics test results and to identify key features required to improve future educational efforts of preemptive pharmacogenomics testing. METHODS: One thousand ten participants were surveyed after receiving preemptive CYP2D6 pharmacogenomics test results. RESULTS: Eighty-six percent (n = 869) of patients responded. Of the responders, 98% were white and 55% were female; 57% had 4 years or more of post-secondary education and an average age of 58.9 ± 5.5 years. Twenty-six percent said that they only somewhat understood their results and 7% reported they did not understand them at all. Only education predicted understanding. The most common suggestion for improvement was the use of layperson's terms when reporting results. In addition, responders suggested that results should be personalized by referring to medications that they were currently using. Of those reporting imperfect drug adherence, most (91%) reported they would be more likely to use medication as prescribed if pharmacogenomic information was used to help select the drug or dose. CONCLUSION: Despite great efforts to simplify pharmacogenomic results (or because of them), approximately one-third of responders did not understand their results. Future efforts need to provide more examples and tailor results to the individual. Incorporation of pharmacogenomics is likely to improve medication adherence.Genet Med advance online publication 05 January 2017.

Hepatocyte Growth Factor Is Positively Associated With Risk of Stroke: The MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND AND PURPOSE: Hepatocyte growth factor (HGF) is positively associated with ischemic and hemorrhagic stroke risk factors. However, understanding the relation between HGF and stroke is in its infancy. Therefore, we sought to examine the association of circulating HGF with incident stroke using data from the MESA (Multi-Ethnic Study of Atherosclerosis). We hypothesized that circulating HGF would be positively associated with an increased risk of stroke. METHODS: Participants aged 45 to 84 years (n=6711) had HGF measured between 2000 and 2002 and were followed for incident stroke through 2013 (n=233). Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for incident stroke. A secondary analysis stratified results by adjudicated stroke type (n=183 ischemic; n=39 hemorrhagic; n=11 other). RESULTS: After adjustment for potential confounding variables, risk of stroke was 17% higher with each standard deviation increase in HGF (hazard ratio, 1.17; 95% confidence interval, 1.03-1.34). This association was mainly driven by ischemic stroke and did not change on exclusion of cardioembolic strokes, although the number of excluded cases was small. The few hemorrhagic and other types of stroke were not associated with HGF. CONCLUSIONS: Circulating HGF was positively associated with the incidence of stroke in a diverse, population-based cohort of men and women from the United States. Our findings support the hypothesis that circulating HGF is a marker of endothelial damage and suggest that HGF may have utility as a prognostic marker of stroke risk.

ABO blood group associations with markers of endothelial dysfunction in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: ABO blood type is associated with cardiovascular disease, although the underlying mechanisms are presumed to be complex. While the relationship between non-O blood types and von Willebrand Factor (vWF) is well-established, associations with cellular adhesion molecules (CAMs) across diverse populations are understudied. METHODS: We genetically inferred ABO alleles for N = 6202 participants from the Multi-Ethnic Study of Atherosclerosis. Linear regression was used to evaluate associations between major ABO allele dosages and log-transformed measurements of vWF (N = 924), soluble E-selectin (sE-selectin, N = 925), soluble P-selectin (sP-selectin, N = 2392), and soluble ICAM-1 (sICAM-1, N = 2236) by race/ethnicity. RESULTS: For the selectins, the A1 allele was associated with significantly lower levels for all races/ethnicities, with each additional allele resulting in a 28-39% decrease in sE-selectin and 10-18% decrease in sP-selectin relative to Type O subjects. However, the A2 allele demonstrated effect heterogeneity across race/ethnicity for sE-selectin, with lower levels for non-Hispanic whites (p = 0.0011) but higher levels for Hispanics (p = 0.0021). We also identified elevated sP-selectin levels for B-allele carriers solely in Hispanic participants (p = 1.0E-04). ABO-by-race/ethnicity interactions were significant for both selectins (p < 0.0125). More modest associations were observed between A1 allele dosage and levels of sICAM-1, with ABO alleles explaining 0.8-1.1% of the total phenotypic variation within race/ethnicity. ABO associations with vWF activity were consistent across race/ethnicity, with B allele carriers corresponding to the highest vWF activity levels. CONCLUSIONS: ABO blood type demonstrates complex associations with endothelial markers that are largely generalizable across diverse populations.

Integrating Pharmacogenomics into Clinical Practice: Promise vs Reality.

BACKGROUND: Limited information is available regarding primary care clinicians' response to pharmacogenomic clinical decision support (PGx-CDS) alerts integrated in the electronic health record. METHODS: In February 2015, 159 clinicians in the Mayo Clinic primary care practice were sent e-mail surveys to understand their perspectives on the implementation and use of pharmacogenomic testing in their clinical practice. Surveys assessed how the clinicians felt about pharmacogenomics and whether they thought electronic PGx-CDS alerts were useful. Information was abstracted on the number of CDS alerts the clinicians received between October 2013 and the date their survey was returned. CDS alerts were grouped into 2 categories: the alert recommended caution using the prescription, or the alert recommended an alternate prescription. Finally, data were abstracted regarding whether the clinician changed their prescription in response to the alert recommendation. RESULTS: The survey response rate was 57% (n = 90). Overall, 52% of the clinicians did not expect to use or did not know whether they would use pharmacogenomic information in their future prescribing practices. Additionally, 53% of the clinicians felt that the alerts were confusing, irritating, frustrating, or that it was difficult to find additional information. Finally, only 30% of the clinicians that received a CDS alert changed their prescription to an alternative medication. CONCLUSIONS: Our results suggest a lack of clinician comfort with integration of pharmacogenomic data into primary care. Further efforts to refine PGx-CDS alerts to make them as useful and user-friendly as possible are needed to improve clinician satisfaction with these new tools.