It is time for a new comprehensive medication review quality measure.

Medication therapy management (MTM) services include comprehensive medication reviews (CMRs), which have been completed with millions of patients since their inception in the United States. The current MTM quality measure focuses on whether CMRs were completed (ie, the CMR completion rate). However, this process measure does not assess quality of care, or patient-reported or other outcomes of CMRs, and, therefore, does not reward MTM providers for improving health outcomes. In this viewpoint article, we present 3 reasons that shape our argument for new MTM quality measures and offer recommendations on next steps to achieve this. DISCLOSURES: Dr Vaffis is an employee of Clinical Outcomes Solutions and discloses this was work was completed previously during her employment at the University of Arizona. Dr Dhatt is an employee of Janssen and discloses this was work was completed previously during her employment at the University of Arizona. Dr Anderson is an employee of The Freedom Fund and discloses this was work was completed previously during her employment at the University of Arizona. Dr Black is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Dr Campbell received funding from Pharmacy Quality Alliance, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and SinfoniaRx and discloses this work was completed previously during his employment at the University of Arizona. Dr Kolobova is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Dr Hines is an employee of Pharmacy Quality Alliance. Dr Castora-Binkley is an employee of Pharmacy Quality Alliance. Dr Nelson is an employee of Pharmacy Quality Alliance. Dr Axon received funding from Pharmacy Quality Alliance, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and SinfoniaRx. Dr Warholak received funding from Pharmacy Quality Alliance, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and SinfoniaRx and discloses this was work was completed previously during her employment at the University of Arizona.

A 12-Year Retrospective Study of the Prevalence of Anticholinergic Polypharmacy and Associated Outcomes Among Medicare Patients with Overactive Bladder in the USA.

BACKGROUND AND OBJECTIVE: Antimuscarinics, drugs with anticholinergic properties, are frequently prescribed for overactive bladder, and anticholinergic burden is associated with adverse events. The "Polypharmacy: Use of Multiple Anticholinergic Medications in Older Adults" (Poly-ACH) measure was developed by the Pharmacy Quality Alliance and is used by the Centers for Medicare and Medicaid Services. Using the Poly-ACH measure, we assessed the prevalence of anticholinergic polypharmacy among Medicare patients in the USA with overactive bladder and determined associations between polypharmacy and medical conditions, care, and spending. METHODS: This was a retrospective cohort study of Medicare beneficiaries with overactive bladder (coverage period: 2006-2017). Anticholinergic polypharmacy, measured by the Poly-ACH, was defined as concurrent use of two or more anticholinergics, each with two or more prescription claims on different dates of service for ≥ 30 cumulative days. Change in annual frequency of anticholinergic polypharmacy was assessed using logistic regression. Associations between anticholinergic polypharmacy over 3 years and falls, fractures, mental status, and medical care spending were assessed with longitudinal regression models. RESULTS: In total, 226,712 patients contributed 940,201 person-years of follow-up after overactive bladder diagnosis. The share of patients meeting the Poly-ACH definition was 3.3% in 2006 and 1.7% in 2017. Women and nursing home residents had higher risks of anticholinergic polypharmacy. Having 1 year or more of positive Poly-ACH status in the 3 years prior was associated with higher rates of all outcomes. CONCLUSIONS: Anticholinergic polypharmacy was uncommon among older adults with overactive bladder. Prevalence was higher among women and nursing home residents, and it was associated with negative outcomes, highlighting potential longitudinal implications of anticholinergic burden.

Factors associated with medication nonadherence among Medicare low-income subsidy beneficiaries with diabetes, hypertension, and/or heart failure.

BACKGROUND: Previous studies have documented factors influencing medication nonadherence among the Medicare population, but few studies have examined medication nonadherence among the Medicare low-income subsidy (LIS) population. Furthermore, little is known about the factors associated with nonadherence among this population, especially those with prevalent chronic conditions such as type 2 diabetes, hypertension, or heart failure. OBJECTIVE: To examine factors associated with the likelihood of medication nonadherence among Medicare LIS recipients with type 2 diabetes, hypertension, or heart failure. METHODS: This was a retrospective analysis of 2012-2013 Medicare Parts A, B, and D claims (most recent available for this research) linked to the Area Health Resources Files. Beneficiaries aged 65 years or older with continuous Medicare coverage and receiving any LIS were included. Individuals were categorized into full LIS or partial LIS groups. Nonadherence was determined by the proportion of days covered less than 80% for specified oral type 2 diabetes, hypertension, and heart failure medications, as defined by the Pharmacy Quality Alliance. A multivariate logistic regression was used to determine and compare individual-level and community-level characteristics associated with nonadherence among the entire study sample, the full LIS group, and the partial LIS group. RESULTS: The study sample included 505,771 Medicare beneficiaries, with 448,509 (88.7%) receiving full LIS and 57,262 (11.3%) receiving partial LIS. The proportion of individuals nonadherent was higher among the full LIS population (33.2%) than that of the partial LIS population (30.8%). Among the entire population, younger age was associated with nonadherence (OR = 0.98; 95% CI = 0.98-0.99). Men were more likely to be nonadherent than women (OR = 1.12; 95% CI = 1.11-1.14). Compared with non-Hispanic Whites, racial/ethnic minorities had higher nonadherence. Compared with beneficiaries who were non-Hispanic White, the ORs for those who were Black, Hispanic, Asian, and other were 1.41 (95% CI = 1.38-1.43), 1.58 (95% CI = 1.55-1.61), 1.08 (95% CI = 1.05-1.11), and 1.63 (95% CI = 1.56-1.70), respectively. There were higher nonadherence rates among patients living in communities with lower socioeconomic characteristics, such as a metropolitan statistical area (MSA vs non-MSA; OR = 1.05, 95% CI = 1.04-1.07). A higher risk adjustment summary score, indicating worse health status, was associated with an increased likelihood of medication nonadherence (OR = 1.21; 95% CI = 1.20-1.22). These patterns were similar among the full and partial LIS groups. CONCLUSIONS: Individual- and community-level characteristics were associated with the likelihood of medication nonadherence among Medicare LIS recipients with type 2 diabetes, hypertension, or heart failure. These characteristics included younger age, male sex, racial/ethnic minorities, living in lower socioeconomic communities, and a higher risk adjustment summary score. This study provided insight into medication nonadherence within the Medicare LIS population and identified the need to consider these factors when developing future policies to improve medication adherence. DISCLOSURES: This study was funded by the Pharmaceutical Research & Manufacturers of America (PhRMA), which was involved in the preparation and revision of the manuscript. Dougherty is employed by PhRMA. Todor was a PQA-CVS Health Foundation Scholar who was funded to work on this study. Hines is employed by Pharmacy Quality Alliance. Wang reports grants from AbbVie, Curo, Bristol Myers Squibb, and Pfizer, during the time of this study, and fees from the PhRMA Foundation for work on its Heath Outcomes Research Advisor Committee. The other authors have nothing to disclose. This study was presented as a poster at the online 2020 PQA Annual Meeting, May 7, 2020.

Effects of the Medicare Part D comprehensive medication review on medication adherence among patients with Alzheimer's disease.

OBJECTIVE: Older patients with Alzheimer's disease (AD) are challenged with adhering to complex medication regimens. We examined effects of Comprehensive Medication Review (CMR), a required Medicare Part D Medication Therapy Management (MTM) program component, on medication adherence among AD patients. METHODS: This retrospective study analyzed 100% of 2016-2017 Medicare claims covering the entire United States, linked to Area Health Resources Files. Medicare beneficiaries aged ≥65 years were included. Propensity score matching identified comparable intervention and comparison groups with the intervention defined as receiving a CMR in 2017. A difference-in-differences analysis included in multivariate logistic regressions an interaction term between CMR receipt and year 2017. The outcome measured was nonadherence to diabetes, hypertension and hyperlipidemia medications, with nonadherence defined as proportion of days covered <80% for study medications. RESULTS: Unadjusted comparisons indicated the proportion of nonadherence for intervention group members decreased from 2016 to 2017 but increased for the comparison group. In adjusted analyses, reduction in medication nonadherence among the intervention group remained higher: odds ratios for the interaction term were 0.62 (95% confidence interval [CI] = 0.54-0.71), 0.54 (95% CI = 0.50-0.58) and 0.50 (95% CI = 0.47-0.53) respectively for diabetes, hypertension and hyperlipidemia medications. This suggests that the likelihood of nonadherence in the intervention group was respectively reduced by 38%, 46% and 50% more than the comparison group. CONCLUSIONS: CMR was found to reduce nonadherence to diabetes, hypertension and hyperlipidemia medications among older Medicare beneficiaries with AD. This provides evidence that the MTM program is effective for a population with unique medication compliance challenges.

Effects of the Medicare Part D Comprehensive Medication Review on Racial and Ethnic Disparities in Medication Adherence.

Background: Substantial research has documented inequalities between US minorities and whites in meeting the eligibility criteria for the Medicare Part D medication therapy management (MTM) program. Even though the Centers for Medicare & Medicaid Services attempted to relax the eligibility criteria, a critical barrier to effective MTM reform is a lack of stronger evidence about the effects of MTM on minorities' health outcomes. Objective: To examine the effects of comprehensive medication review (CMR), an MTM core component, on racial and ethnic disparities in adherence to diabetes, hypertension, and hyperlipidemia medications among Medicare beneficiaries aged ≥65 years. Methods: This study used full-year 2017 Medicare Parts A, B, and D claims data, including MTM data, linked to the Area Health Resources Files. Racial and ethnic disparities in nonadherence to diabetes, hypertension, and hyperlipidemia medications were compared between CMR recipients and nonrecipients matched by their propensity scores. To determine the changes in racial and ethnic disparities after receiving CMR, a difference-in-differences framework was applied, by including in logistic regression analyses interaction terms between dummy variables for CMR receipt and each racial or ethnic minority group. Results: Compared with CMR nonrecipients, CMR recipients had significantly lower racial and ethnic disparities across the 3 outcome measures, with the exception of the difference between whites and blacks in nonadherence to diabetes medications. For example, compared with CMR nonrecipients, among CMR recipients the differences in the odds of nonadherence to hypertension medications were reduced, respectively, by 8% (95% confidence interval [CI], 0.88-0.96) between whites and blacks; by 18% (95% CI, 0.78-0.86) between whites and Hispanics; by 16% (95% CI, 0.77-0.91) between whites and Asians; and by 9% (95% CI, 0.85-0.98) between whites and other racial and ethnic groups. Conclusion: Receiving a CMR reduced the racial and ethnic disparities in adherence to diabetes, hypertension, and hyperlipidemia medications among Medicare beneficiaries aged ≥65 years. These findings provide critical empirical evidence that may inform the future design of the Medicare Part D MTM program, which is valuable for improving pharmacotherapy outcomes and could further realize its potential when additional people from racial and ethnic minorities are enrolled.

Exploring Racial and Ethnic Disparities in Medication Adherence Among Medicare Comprehensive Medication Review Recipients.

Background: There has been a lack of evidence on whether there are racial and ethnic disparities in medication nonadherence among individuals receiving comprehensive medication review (CMR), a required component of the Medicare Part D medication therapy management (MTM) services. Objectives: To explore racial/ethnic disparities in medication nonadherence among older MTM enrollees who received a CMR and to determine how much the identified disparities can be explained by observed characteristics. Methods: The retrospective study used 100% of the 2017 Medicare claims, including MTM data. Linked Area Health Resources Files provided community characteristics. Nonadherence was defined as proportion of days covered <80%, and was measured for diabetes, hypertension, and hyperlipidemia medications. Racial/ethnic disparities were examined by logistic regressions that included racial/ethnic minority dummy variables. A nonlinear Blinder-Oaxaca decomposition method was applied to decompose the identified disparities. Results: Compared with non-Hispanic Whites (Whites), Blacks were respectively 39% (odds ratio [OR] = 1.39, 95% confidence interval [CI] = 1.33-1.45), 27% (OR = 1.27, 95% CI = 1.22-1.32), and 43% (OR = 1.43, 95% CI = 1.39-1.47) more likely to be nonadherent to diabetes, hypertension, and hyperlipidemia medications; Hispanics were 20% (OR = 1.20, 95% CI = 1.14-1.27) more likely to be nonadherent to hyperlipidemia medications. The total portion of disparity explained was 13.42%, 7.66%, 14.87%, and 10.69% respectively for disparities in Black-White (B-W) diabetes, B-W hypertension, B-W hyperlipidemia, and Hispanic-White hyperlipidemia. The top three contributors were the proportion of married-couple families, census region, and male gender. Conclusions: A lower level of community affluence and social support, regional variations, and a lower proportion of males in Blacks and Hispanics may contribute to the disparities in medication nonadherence. The large unexplained portion of the disparity attests that nonadherence is a complex issue. The Medicare MTM program needs to implement measures to reduce disparities in medication adherence.

Racial/ethnic disparities in measure calculations for Part D Star Ratings among Medicare beneficiaries with diabetes, hypertension, and/or hyperlipidemia.

BACKGROUND: Previous literature reported racial/ethnic disparities in the measure assessment of diabetes medication adherence in the Medicare Part D Star Ratings program. OBJECTIVE: This study examined the likelihood of inclusion in measure calculation across racial/ethnic groups for adherence metrics in Part D Star Ratings among individuals with diabetes, hypertension, and/or hyperlipidemia. METHODS: This was a retrospective cross sectional analysis of a 10% random sample of 2017 Medicare claims linked to Area Health Resources Files. Inclusion in measure calculation was determined based on inclusion/exclusion criteria in adherence metrics for adherence medications for diabetes, hypertension, and hyperlipidemia in Part D Star Ratings developed by the Pharmacy Quality Alliance. Logistic regression and multinomial logistic regression were used to adjust for patient/community characteristics. RESULTS: The study sample size was 2 707 216. Compared to Non-Hispanic White (White) beneficiaries, minorities were more likely to be excluded from measure calculation among individuals with 1 condition. For example, among individuals with hypertension, compared to White individuals, the adjusted odds ratios for exclusion for Black, Hispanic, Asian/Pacific Islander and other individuals were 1.46 (95% confidence interval, or CI = 1.42-1.50), 1.38 (95% CI = 1.33-1.43), 1.28 (95% CI = 1.21-1.35), and 1.08 (95% CI = 1.02-1.15), respectively. Among individuals with more than 1 chronic condition, minorities were more likely to be included in fewer calculations for medication adherence measures. For example, among individuals with all 3 conditions, the adjusted relative risk ratios for Black, compared to White, beneficiaries for being included in 0, 1, and 2 measures, versus all 3 measures, were 2.14 (95% CI = 1.99-2.30), 1.49 (95% CI = 1.41-1.56), 1.20 (95% CI = 1.18-1.23), respectively. CONCLUSIONS: Compared to White beneficiaries, racial/ethnic minorities are more likely to be excluded from the calculation for adherence measures among individuals with diabetes, hypertension, and/or hyperlipidemia. Future studies should examine whether such disparities exacerbate existing racial/ethnic disparities in health outcomes and devise solutions for these disparities.

Association Between Medication Adherence and Healthcare Costs Among Patients Receiving the Low-Income Subsidy.

OBJECTIVES: Significant literature exists on the effects of medication adherence on reducing healthcare costs, but less is known about the effect of medication adherence among Medicare low-income subsidy (LIS) recipients. This study examined the effects of medication adherence on healthcare costs among LIS recipients with diabetes, hypertension, and/or heart failure. METHODS: This retrospective study analyzed Medicare claims data (2012-2013) linked to the Area Health Resources Files. Using measures developed by the Pharmacy Quality Alliance, adherence to 11 medication classes was studied among patients with 7 possible combinations of the diseases mentioned. Adherence was measured in 8 categories of proportion of days covered (PDC): ≥95%, 90% to <95%, 85% to <90%, 80% to <85%, 75% to <80%, 50% to <75%, 25% to <50%, and <25%. Annual Medicare costs were compared across adherence categories. A generalized linear model was used to control for patient/community characteristics. RESULTS: Among patients with only one disease, such as diabetes, patients with the lowest adherence (PDC < 25%) had $3152/year higher Medicare costs than patients with the highest adherence (PDC ≥ 95%; $11 101 vs $7949; P < .05). The adjusted costs among patients with PDC < 25% was $1893 higher than patients with PDC ≥ 95% ($9919 vs $8026; P < .05). Among patients with multiple chronic conditions, patients' adherence to medications for fewer diseases had higher costs. CONCLUSIONS: Greater medication adherence is associated with lower Medicare costs in the Medicare LIS population. Future policy affecting the LIS program should encourage better medication adherence among patients with chronic diseases.

Testing the face validity and inter-rater agreement of a simple approach to drug-drug interaction evidence assessment.

Low concordance between drug-drug interaction (DDI) knowledge bases is a well-documented concern. One potential cause of inconsistency is variability between drug experts in approach to assessing evidence about potential DDIs. In this study, we examined the face validity and inter-rater reliability of a novel DDI evidence evaluation instrument designed to be simple and easy to use. METHODS: A convenience sample of participants with professional experience evaluating DDI evidence was recruited. Participants independently evaluated pre-selected evidence items for 5 drug pairs using the new instrument. For each drug pair, participants labeled each evidence item as sufficient or insufficient to establish the existence of a DDI based on the evidence categories provided by the instrument. Participants also decided if the overall body of evidence supported a DDI involving the drug pair. Agreement was computed both at the evidence item and drug pair levels. A cut-off of ≥ 70% was chosen as the agreement threshold for percent agreement, while a coefficient > 0.6 was used as the cut-off for chance-corrected agreement. Open ended comments were collected and coded to identify themes related to the participants' experience using the novel approach. RESULTS: The face validity of the new instrument was established by two rounds of evaluation involving a total of 6 experts. Fifteen experts agreed to participate in the reliability assessment, and 14 completed the study. Participant agreement on the sufficiency of 22 of the 34 evidence items (65%) did not exceed the a priori agreement threshold. Similarly, agreement on the sufficiency of evidence for 3 of the 5 drug pairs (60%) was poor. Chance-corrected agreement at the drug pair level further confirmed the poor interrater reliability of the instrument (Gwet's AC1 = 0.24, Conger's Kappa = 0.24). Participant comments suggested several possible reasons for the disagreements including unaddressed subjectivity in assessing an evidence item's type and study design, an infeasible separation of evidence evaluation from the consideration of clinical relevance, and potential issues related to the evaluation of DDI case reports. CONCLUSIONS: Even though the key findings were negative, the study's results shed light on how experts approach DDI evidence assessment, including the importance situating evidence assessment within the context of consideration of clinical relevance. Analysis of participant comments within the context of the negative findings identified several promising future research directions including: novel computer-based support for evidence assessment; formal evaluation of a more comprehensive evidence assessment approach that requires consideration of specific, explicitly stated, clinical consequences; and more formal investigation of DDI case report assessment instruments.

Comparative Effectiveness of Medication Therapy Management Eligibility Criteria Across Racial/Ethnic Groups.

BACKGROUND/OBJECTIVES: Previous research indicates that eligibility criteria for medication therapy management (MTM) services in Medicare prescription drug (Part D) plans, defined under the Medicare Modernization Act (MMA), are associated with racial/ethnic disparities and ineffective in identifying individuals with medication utilization issues. Our study's objective was to determine the comparative effectiveness of MTM eligibility criteria under MMA and in the Affordable Care Act (ACA) in identifying patients with medication utilization issues across racial/ethnic groups. DESIGN: ACA and MMA MTM eligibility criteria were compared on proportions of eligible individuals among patients with medication utilization issues. Multinomial logistic regression was conducted to control for patient/community characteristics. Need-based and demand-based analyses were used to determine disparities due to need and demand for healthcare. Main/sensitivity analyses were conducted for the range of eligibility thresholds. SETTING: Medicare data (2012-2013) linked to Area Health Resources Files. PARTICIPANTS: A total of 964 610 patients 65 years or older. MEASUREMENTS: Medication safety/adherence measures, developed primarily by the Pharmacy Quality Alliance, were used to determine medication utilization issues. RESULTS: Higher proportions of patients were eligible based on ACA than MMA MTM eligibility criteria. For example, in 2013, proportions based on ACA and MMA MTM eligibility criteria would be 99.7% and 26.2%, respectively, in the main analysis (p < .001); in the demand-based main analysis, ACA criteria were associated with 13.6% and 9.8%, respectively, higher effectiveness than MMA criteria among non-Hispanic blacks and Hispanics than non-Hispanic whites. CONCLUSION: ACA MTM eligibility criteria are more effective than MMA criteria in identifying older patients needing MTM, particularly among minorities. J Am Geriatr Soc 67:581-587, 2019.

Associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white women diagnosed with breast cancer: the Breast Cancer Health Disparities Study.

PURPOSE: ALDH1A1, one of the main isotopes of aldehyde dehydrogenase-1 is involved in the differentiation and protection of normal hematopoietic stem cells and functions in alcohol sensitivity and dependence. We evaluated the associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white (NHW) breast cancer (BC) cases from the Breast Cancer Health Disparities Study. METHODS: Nine SNPs in ALDH1A1 were evaluated in 920 Hispanic and 1372 NHW women diagnosed with incident invasive BC. Adjusted Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were stratified by Native American (NA) ancestry and alcohol consumption. RESULTS: A total of 443 deaths occurred over a median follow-up time of 11 years. After adjusting all results for multiple comparisons, rs7027604 was significantly associated with all-cause mortality (HRAA = 1.40; 95% CI 1.13-1.73, P adj = 0.018). The rs1424482 CC genotype (HRCC = 1.69; 95% CI 1.20-2.37, P adj = 0.027) and the rs7027604 AA genotype (HRAA = 1.65; 95% CI 1.21-2.26, P adj = 0.018) were positively associated with non-BC mortality. Among long-term light drinkers, rs1888202 was associated with decreased all-cause mortality (HRCG/GG = 0.36; 95% CI 0.20-0.64), while associations were not significant among non-drinkers or moderate/heavy drinkers (P interation = 0.218). The increased risk of all-cause mortality associated with rs63319 was limited to women with low NA ancestry (HRAA = 1.53; 95% CI 1.19-1.97). CONCLUSIONS: Multiple SNPs in ALDH1A1 were associated with increased risk of mortality after BC. Future BC studies examining the relationship between ALDH1A1 and mortality should consider the modifying effects of alcohol consumption and NA ancestry.

Cigarette Smoking and Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The Breast Cancer Health Disparities Study.

OBJECTIVE: Few epidemiological studies have included Hispanics with the evaluation of the effects of cigarette smoking and breast cancer. We examined the relationship between cigarette smoking, ethnicity, and breast cancer risk using data from the Breast Cancer Health Disparities Study (BCHDS). MATERIALS AND METHODS: The BCHDS is a consortium of three population-based case-control studies, including U.S. non-Hispanic whites (NHWs) (1,525 cases; 1,593 controls), U.S. Hispanics/Native Americans (1,265 cases; 1,495 controls), and Mexican women (990 cases; 1,049 controls). Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Breast cancer risk was elevated among Mexican former smokers (OR 1.43, 95% CI 1.04-1.96) and among those who smoked ≥ 31 years (OR 1.95, 95% CI 1.13-3.35), compared to never smokers. In addition, Mexican former smokers with a history of alcohol consumption had increased breast cancer risk (OR 2.30, 95% CI 1.01-5.21). Among NHW premenopausal women, breast cancer risk was increased for smoking ≥ 20 cigarettes per day (OR 1.61, 95% CI 1.07-2.41). CONCLUSION: Our findings suggest the possibility of ethnic differences with the associations between cigarette smoking and breast cancer risk.

MAPK genes interact with diet and lifestyle factors to alter risk of breast cancer: the Breast Cancer Health Disparities Study.

Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from 3 population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 ancestry informative markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and estrogen receptor (ER)/progesterone receptor (PR) strata. MAP3K9 was associated with breast cancer overall (P(ARTP) = 0.02) with strongest association among women with the highest IA ancestry (P(ARTP) = 0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate, and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.

Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study.

Tumor necrosis factor-α (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast cancer risk among women with >70% NA ancestry (P(ARTP) = 0.0008), with TLR1 rs7696175 being the primary risk contributor (OR 1.77, 95% CI 1.25, 2.51). Overall, TLR1 rs7696175 (HR 1.40, 95% CI 1.03, 1.91; P(adj) = 0.032), TLR4 rs5030728 (HR 1.96, 95% CI 1.30, 2.95; P(adj) = 0.014), and TNFRSF1A rs4149578 (HR 2.71, 95% CI 1.28, 5.76; P(adj) = 0.029) were associated with increased breast cancer mortality. We observed several statistically significant interactions after adjustment for multiple comparisons, including interactions between our dietary oxidative balance score and CD40LG and TNFSF1A; between cigarette smoking and TLR1, TLR4, and TNF; between body mass index (BMI) among pre-menopausal women and TRAF2; and between regular use of aspirin/non-steroidal anti-inflammatory drugs and TLR3 and TRA2. In conclusion, our findings support a contributing role of certain TNF-α and TLR genes in both breast cancer risk and survival, particularly among women with higher NA ancestry. Diet and lifestyle factors appear to be important mediators of the breast cancer risk associated with these genes.

Diet and lifestyle factors interact with MAPK genes to influence survival: the Breast Cancer Health Disparities Study.

INTRODUCTION: MAPK genes are activated by a variety of factors related to growth factors, hormones, and environmental stress. METHODS: We evaluated associations between 13 MAPK genes and survival among 1,187 nonHispanic White and 1,155 Hispanic/Native American (NA) women diagnosed with breast cancer. We assessed the influence of diet, lifestyle, and genetic ancestry on these associations. Percent NA ancestry was determined from 104 Ancestry Informative Markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance. RESULTS: Associations were predominantly observed among women with lower NA ancestry. Specifically, the mitogen-activated protein kinases (MAPK) pathway was associated with all-cause mortality (P ARTP = 0.02), but not with breast cancer-specific mortality (P ARTP = 0.10). However, MAP2K1 and MAP3K9 were associated with both breast cancer-specific and all-cause mortality. MAPK12 (P ARTP = 0.05) was only associated with breast cancer-specific mortality, and MAP3K1 (P ARTP = 0.02) and MAPK1 (P ARTP = 0.05) were only associated with all-cause mortality. Among women with higher NA ancestry, MAP3K2 was significantly associated with all-cause mortality (P ARTP = 0.04). Several diet and lifestyle factors, including alcohol consumption, caloric intake, dietary folate, and cigarette smoking, significantly modified the associations with MAPK genes and all-cause mortality. CONCLUSIONS: Our study supports an association between MAPK genes and survival after diagnosis with breast cancer, especially among women with low NA ancestry. The interaction between genetic variation in the MAPK pathway with diet and lifestyle factors for all women supports the important role of these factors for breast cancer survivorship.

The good, the bad, and the different: a primer on aspects of heterogeneity of treatment effects.

The concept of heterogeneity is concerned with understanding differences within and across patients and studies. Heterogeneity of treatment effects is nonrandom variability in response to treatment and includes both benefits and harms. Because not all patients respond the same way, treatment decisions applied in a "one size fits all" fashion based on the average response observed in clinical trials may lead to suboptimal outcomes for some patients. Variation in outcomes among patients may be caused by observable and nonobservable factors. Changes in patients' health status over time can contribute to variability among patients. Assuming that the results from clinical trials are homogeneous across patients may fail to take into account clinically significant variability where some patients may receive benefit and others harm. Subgroup analyses and prediction models are 2 tools to explain variability observed within a study. Evidence synthesis with meta-analysis can provide useful information on the overall effectiveness and response among groups of patients undersampled in individual studies. Yet caution is warranted if the meta-analysis is missing studies or the individual studies comprising the meta-analysis are inherently different.For those making clinical, coverage, and reimbursement decisions at a population level, such as clinicians and pharmacy and therapeutics committee members, understanding the variation among patients, among subpopulations or populations of patients, among clinical studies, or within a meta-analysis is important to ensuring optimal patient outcomes. This article presents a variety of tools and resources to aid decision makers as they evaluate the literature to determine when clinically relevant differences exist.

Evaluation of an educational program on deciphering heterogeneity for medical coverage decisions.

BACKGROUND: It is increasingly important for decision makers, such as medical and pharmacy managers (or pharmacy therapeutics committee members and staff), to understand the variation and diversity in treatment response as decisions shift from an individual patient perspective to optimizing care for populations of patients. OBJECTIVE: To assess the effectiveness of an instructional program on heterogeneity designed for medical and pharmacy managers. METHODS: A live educational program was offered to members of the Academy of Managed Care Pharmacy at the fall 2012 educational meeting and also to medical directors and managers attending a national payer roundtable meeting in October 2012. Participants completed a retrospective pretest-posttest assessment of their knowledge, attitudes, and self-efficacy immediately following the program. Participants were offered the opportunity to participate in a follow-up assessment 6 months later. Willing participants for the follow-up assessment were contacted via e-mail and telephone. Rasch rating scale models were used to compare pre- and postscores measuring participants' knowledge about and attitude towards heterogeneity. RESULTS: A total of 49 individuals completed the retrospective pretest-posttest assessment and agreed to be a part of the program evaluation. Fifty percent (n = 25) of participants had heard of the phrase "heterogeneity of treatment effect," and 36 (72%) were familiar with the phrase "individualized treatment effect" prior to the live program. Participants reported a significant improvement in knowledge of heterogeneity (P less than 0.01) and attitudes about heterogeneity (P less than 0.01) immediately after attending the program. At the time of the educational program, participants had either never considered heterogeneity (26%) or reported not knowing (28%) whether their organizations considered it when determining basic coverage. Participants were more likely to report "sometimes" considering heterogeneity for determining necessity for individual appeals, prior authorization, tier placement for pharmaceutical therapies, and other types of medical management. At the 6-month follow-up, 21 of the 49 willing participants (43% response rate) completed the evaluation; participants continued to have a good understanding of heterogeneity, but there was no significant difference in attitudes towards heterogeneity between pre- and 6-month follow-up. CONCLUSION: A live educational program was effective in improving participants' immediate knowledge and attitudes regarding the topic of heterogeneity. Participating managed care pharmacists and medical managers indicated that heterogeneity of treatment effect was likely to be used in determining prior authorizations and determining necessity.

Racial disparity: substance dependency and psychological health problems among welfare recipients.

This study explored the racial disparity of substance dependency and psychological health among White, African American, and Hispanic Temporary Assistance to Needy Families (TANF) recipients as well as the relationship between substance dependency and psychological health. It analyzed 1,286 TANF recipients from the 2006 National Survey on Drug Use and Health data. Analysis of variance indicated that Whites were experiencing more nicotine and alcohol dependency and psychological distress than others, but African Americans and Hispanics were experiencing more cocaine dependency than Whites. Ordinary least squares regression revealed that nicotine dependency is significantly related to the psychological distress of Whites. Alcohol dependency is significantly associated with the psychological distress of three groups. Culturally competent programs are suggested.

Prescriber perceptions of a near real-time fax alert program for potential drug-drug interactions.

BACKGROUND: Health systems have developed interventions to reduce harm associated with drug-drug interactions. Pharmacy benefit managers are in an important position to identify the coprescribing of medications known to interact, since they process data on a large portion of prescription claims in the United States. Electronic health records and electronic prescribing also include alerts through their systems' clinical decision support. However, limited data are available that assess prescribers' perceptions of processes that screen for potential drug-drug interactions (PDDIs). OBJECTIVE: To determine prescribers' perceptions of near real-time fax alerts for PDDIs. METHODS: This was a 6-month prospective study where a pharmacy benefit manager distributed evidence-based summaries of 18 different PDDIs that included references and suggested management strategies. Fax alerts were individualized letters sent to the prescriber of the second drug of a PDDI pair for an individual patient. A 16-item questionnaire to assess prescribers' perceptions of the intervention accompanied each individualized PDDI evidence-based summary. RESULTS: A total of 8,075 fax alerts were distributed with 977 returning questionnaires, yielding a 12.1% response rate. There were 848 (86.8%) responses completed by physicians, and 71 (7.3%) completed by nurse practitioners. The most common PDDI fax alerts sent were for warfarin-statin (3,511, 43.5%) and warfarin-thyroid (2,111, 26.1%) interactions. 42.6% of respondents agreed or strongly agreed that fax alerts were a good way to communicate with them. However, 37.5% of respondents either agreed or strongly agreed that the fax alert was a "waste of my time." In contrast, respondents thought notification of carbamazepine-macrolide (mean 1.5 ± 0.71), ciprofloxacin-tizanidine (mean 2.3 ± 1.0), and statin-macrolide (mean 2.3 ± 1.1) was not a waste of time. Also, 59.1% of respondents either disagreed or strongly disagreed that they would prefer to receive a telephone call when interactions like this occur. Half (50.5%) of the respondents indicated their computer systems provided drug interaction alerts. Prescribers who had previously received alerts and specialists were less likely to respond to the questionnaire (OR = 0.685, P ≤ 0.0001 and OR = 0.851, P = 0.0205, respectively). CONCLUSIONS: The positive response to fax alerts by physicians varies by the component drugs of the PDDI alerts.