Publications by authors named "Purushottam W Laud"

58 Publications

Mortgage Lending Bias and Breast Cancer Survival Among Older Women in the United States.

J Clin Oncol 2021 Jun 15:JCO2100112. Epub 2021 Jun 15.

Center for Advancing Population Science, Medical College of Wisconsin, Milwaukee, WI.

Purpose: The objective was to examine the relationship between contemporary redlining (mortgage lending bias on the basis of property location) and survival among older women with breast cancer in the United States.

Methods: A redlining index using Home Mortgage Disclosure Act data (2007-2013) was linked by census tract with a SEER-Medicare cohort of 27,516 women age 66-90 years with an initial diagnosis of stage I-IV breast cancer in 2007-2009 and follow-up through 2015. Cox proportional hazards models were used to examine the relationship between redlining and both all-cause and breast cancer-specific mortality, accounting for covariates.

Results: Overall, 34% of non-Hispanic White, 57% of Hispanic, and 79% of non-Hispanic Black individuals lived in redlined tracts. As the redlining index increased, women experienced poorer survival. This effect was strongest for women with no comorbid conditions, who comprised 54% of the sample. For redlining index values of 1 (low), 2 (moderate), and 3 (high), as compared with 0.5 (least), hazard ratios (HRs) (and 95% CIs) for all-cause mortality were HR = 1.10 (1.06 to 1.14), HR = 1.27 (1.17 to 1.38), and HR = 1.39 (1.25 to 1.55), respectively, among women with no comorbidities. A similar pattern was found for breast cancer-specific mortality.

Conclusion: Contemporary redlining is associated with poorer breast cancer survival. The impact of this bias is emphasized by the pronounced effect even among women with health insurance (Medicare) and no comorbid conditions. The magnitude of this neighborhood level effect demands an increased focus on upstream determinants of health to support comprehensive patient care. The housing sector actively reveals structural racism and economic disinvestment and is an actionable policy target to mitigate adverse upstream health determinants for the benefit of patients with cancer.
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http://dx.doi.org/10.1200/JCO.21.00112DOI Listing
June 2021

Dietary Sodium Restriction Results in Tissue-Specific Changes in DNA Methylation in Humans.

Hypertension 2021 Aug 14;78(2):434-446. Epub 2021 Jun 14.

Department of Physiology, Center of Systems Molecular Medicine (X.P., C.Y., P.L., M.L.R., Y. Li, A.M.B., Yong Liu, A.W.C., D.L.M., M.L.), Medical College of Wisconsin, Milwaukee.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.17351DOI Listing
August 2021

Optimal Donor Selection for Hematopoietic Cell Transplantation Using Bayesian Machine Learning.

JCO Clin Cancer Inform 2021 05;5:494-507

Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin, Milwaukee, WI.

Purpose: Donor selection practices for matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) vary, and the impact of optimizing donor selection in a patient-specific way using modern machine learning (ML) models has not been studied.

Methods: We trained a Bayesian ML model in 10,318 patients who underwent MUD HCT from 1999 to 2014 to provide patient- and donor-specific predictions of clinically severe (grade 3 or 4) acute graft-versus-host disease or death by day 180. The model was validated in 3,501 patients from 2015 to 2016 with archived records of potential donors at search. Donor selection optimizing predicted outcomes was implemented over either an unlimited donor pool or the donors in the search archives. Posterior mean differences in outcomes from optimal donor selection versus actual practice were summarized per patient and across the population with 95% intervals.

Results: Event rates were 33% (training) and 37% (validation). Among donor features, only age affected outcomes, with the effect consistent regardless of patient features. The median (interquartile range) difference in age between the youngest donor at search and the selected donor was 6 (1-10) years, whereas the number of donors per patient younger than the selected donor was 6 (1-36). Fourteen percent of the validation data set had an approximate 5% absolute reduction in event rates from selecting the youngest donor at search versus the actual donor used, leading to an absolute population reduction of 1% (95% interval, 0 to 3).

Conclusion: We confirmed the singular importance of selecting the youngest available MUD, irrespective of patient features, identified potential for improved HCT outcomes by selecting a younger MUD, and demonstrated use of novel ML models transferable to optimize other complex treatment decisions in a patient-specific way.
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http://dx.doi.org/10.1200/CCI.20.00185DOI Listing
May 2021

An adapted two-step floating catchment area method accounting for urban-rural differences in spatial access to pharmacies.

J Pharm Health Serv Res 2021 Mar 16;12(1):69-77. Epub 2021 Jan 16.

Center for Advancing Population Science, Medical College of Wisconsin, Milwaukee, WI, USA.

Objective: To adapt the two-step floating catchment area approach to account for urban-rural differences in pharmacy access in the United States.

Methods: The urban-rural two-step floating catchment area method was described mathematically. To calculate urban-rural-two-step floating catchment area measure, census tracts and pharmacies within the study area (Southeastern Wisconsin) were classified as urban, suburban or rural, and then different catchment area sizes (2, 5 and 15 miles) were applied, based on the Centers for Medicare & Medicaid Services (CMS)' criteria for Medicare Part D service access within urban, suburban and rural areas. The urban-rural-two-step floating catchment area measures were compared to traditional two-step floating catchment area measures computed using three fixed catchment area sizes (2, 5, and 15 miles) by visually examining their spatial distributions. Associations between the four pharmacy accessibility measures and selected socio-demographics are calculated using Spearman's rank-order correlation and further compared.

Key Findings: The urban-rural two-step floating catchment area measure outperforms all the fixed catchment size measures and has the strongest Spearman correlations with the selected census variables. It also reduces the number of census tracts characterized as 'no access' when compared to the original measures. The spatial distribution of urban-rural two-step floating catchment area pharmacy access exhibits a more granular variation across the study area.

Conclusions: The results support our hypothesis that spatial access to pharmacies should account for urbanicity/rurality patterns within a region.
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http://dx.doi.org/10.1093/jphsr/rmaa022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938828PMC
March 2021

Decrease in Positivity Rate of Influenza Tests Coinciding With Outbreak of SARS-CoV-2: Data From a Southeastern Wisconsin Laboratory.

WMJ 2020 Dec;119(4):275-277

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: The SARS-CoV-2 outbreak prompted public health interventions and changes in public behavior that may have affected the 2019-2020 influenza season.

Methods: Using data from a laboratory in southeastern Wisconsin, we compared the number of weekly influenza tests and their positivity rates during the 2019-2020 influenza season with the previous 4 seasons.

Results: The number of influenza tests per week at the outset of the SARS-CoV-2 outbreak was higher than the average the previous 4 years, and positivity rates declined to 0% earlier than any of the previous 4 seasons.

Conclusion: The testing trajectory and positivity rate for influenza differed during the part of the 2019-2020 season coinciding with the SARS-CoV-2 outbreak as compared to similar periods during the previous 4 seasons.
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December 2020

Guideline-concordant treatment predicts survival: a National Cancer Database validation study of novel composite locoregional and systemic treatment scores among women with early stage breast cancer.

Breast Cancer 2021 May 4;28(3):698-709. Epub 2021 Jan 4.

Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Background: The aim of this large nationwide study was to validate two novel composite treatment scores that address guideline-concordant locoregional and systemic breast cancer care. We examined the relationship between these two scores and their association with survival.

Methods: Women with Stage I-III unilateral breast cancer were identified within the National Cancer Database. For each woman, a locoregional and a systemic treatment score (0, 1, 2) was assigned based on receipt of guideline-concordant care. Multivariable Cox regression models evaluated the association between the scores and survival.

Results: 623,756 women were treated at 1,221 different American College of Surgeons Commission on Cancer (CoC) facilities. Overall, 86% had a locoregional treatment score of 2 (most guideline-concordant), 75% had a systemic treatment score of 2, and 72% had both scores of 2. Median follow-up was 4.5 years. Compared to women with a locoregional treatment score of 2, those with a score of 1 or 0 had a 1.7-fold and 2.0-fold adjusted greater risk of death. Compared to women with a systemic treatment score of 2, those with a score of 1 or 0 had a 1.5-fold and 2.1-fold adjusted greater risk of death. Risk-adjusted 5-year overall survival was 91.6% when both scores were 2 compared to 73.4% when both scores were 0.

Conclusions: In this large national study of CoC facilities, two composite scores capturing guideline-concordant breast cancer care had independent and combined robust effects on survival. These clinically constructed novel scores are promising tools for health services research and quality-of-care studies.
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http://dx.doi.org/10.1007/s12282-020-01206-9DOI Listing
May 2021

The impact of generic aromatase inhibitors on initiation, adherence, and persistence among women with breast cancer: Applying multi-state models to understand the dynamics of adherence.

Pharmacoepidemiol Drug Saf 2020 05 20;29(5):550-557. Epub 2020 Mar 20.

Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Purpose: Clinical trials have clearly documented the survival benefit of aromatase inhibitors (AIs); however, many women fail to initiate (primary nonadherence) or remain adherent to AIs (secondary nonadherence). Prior studies have found that costs impact secondary nonadherence to medications but have failed to examine primary nonadherence. The purpose of this study is to examine primary and secondary adherence following the reduction in copays due to the introduction of generic AIs.

Methods: Using Surveillance, Epidemiology, and End Results-Medicare data, we identified 50 054 women diagnosed with incident breast cancer between 2008 and 2013. We compare women whose copays would change and those whose would not, due to the receipt of cost-sharing subsidies before and after generics were introduced using a difference-in-difference (DinD) analysis. To examine primary and secondary nonadherence, we rely on a multistate model with four states (Not yet initiated, User, Not Using, and Death). We adjusted for baseline factors using inverse probability treatment weights and then simulated adherence for 36 months following diagnosis.

Results: The generic introduction of AIs resulted in patients initiating AIs faster (DinD = -4.7%, 95%CI = -7.0, -2.3; patients not yet initiating treatment at 6-months), being more adherent (DinD ranging in absolute increase of 8.1%-10.4%) and being less likely to not be using the therapy (DinD range in absolute decrease of 1.2% at 6 months to 8.8% at 24 months) for women that do not receive a subsidy after generics were available.

Conclusions: Introduction of generic alternatives to AIs significantly reduced primary and secondary nonadherence.
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http://dx.doi.org/10.1002/pds.4995DOI Listing
May 2020

Factors associated with chronic opioid use after cervical spine surgery for degenerative conditions.

J Neurosurg Spine 2019 Oct 11:1-8. Epub 2019 Oct 11.

5Minneapolis VA Health Care System, and University of Minnesota Medical School, Minneapolis, Minnesota.

Objective: Opioids are commonly prescribed after surgery for painful spinal conditions, yet little is known about postoperative opioid use. The relationship between chronic opioid use and patient-reported outcomes and satisfaction with surgery is also unclear. The purpose of this study was to evaluate factors associated with opioid use 1 year after elective cervical spine surgery for degenerative conditions causing radiculopathy and myelopathy. The authors hypothesized that patients with preoperative opioid use would be more likely to report postoperative opioid use at 1 year, and that postoperative opioid use would be associated with patient-reported outcomes and dissatisfaction with surgery.

Methods: The authors performed a retrospective study of a prospective cohort of adult patients who underwent elective cervical spine surgery for degenerative changes causing radiculopathy or myelopathy. Patients were prospectively and consecutively enrolled from a single academic center after the decision for surgery had been made. Postoperative in-hospital pain management was conducted using a standardized protocol. The primary outcome was any opioid use 1 year after surgery. Secondary outcomes were the Neck Disability Index (NDI); 36-Item Short-Form Health Survey (SF-36) physical function (PF), bodily pain (BP), and mental component summary (MCS) scores; the modified Japanese Orthopaedic Association (mJOA) score among myelopathy patients; and patient expectations surveys. Patients with and without preoperative opioid use were compared using the chi-square and Student t-tests, and multiple logistic regression was used to study the associations between patient and surgical characteristics and postoperative opioid use 1 year after surgery.

Results: Two hundred eleven patients were prospectively and consecutively enrolled, of whom 39 were lost to follow-up for the primary outcome; 43.6% reported preoperative opioid use. Preoperative NDI and SF-36 PF and BP scores were significantly worse in the preoperative opioid cohort. More than 94% of both cohorts rated expectations of pain relief as extremely or somewhat important. At 1 year after surgery, 50.7% of the preoperative-opioid-use cohort reported ongoing opioid use, and 17.5% of patients in the no-preoperative-opioid-use cohort reported ongoing opioid use. Despite this, both cohorts reported similar improvements in NDI as well as SF-36 PF, BP, and MCS scores. More than 70% of both cohorts also reported being extremely or somewhat satisfied with pain relief after surgery. Predictors of 1-year opioid use included preoperative opioid use, duration of symptoms for more than 9 months before surgery, tobacco use, and higher comorbidity index.

Conclusions: One year after elective cervical spine surgery, patients with preoperative opioid use were significantly more likely to report ongoing opioid use. However, patients in both groups reported similar improvements in patient-reported outcomes and satisfaction with pain relief. Interventions targeted at decreasing opioid use may need to focus on patient factors such as preoperative opioid use or duration of symptoms before surgery.
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http://dx.doi.org/10.3171/2019.7.SPINE19563DOI Listing
October 2019

Prevalence and scope of advanced practice provider oncology care among Medicare beneficiaries with breast cancer.

Breast Cancer Res Treat 2020 Jan 21;179(1):57-65. Epub 2019 Sep 21.

Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: Advanced practice providers (APPs) have increasingly become members of the oncology care team. Little is known about the scope of care that APPs are performing nationally. We determined the prevalence and extent of APP practice and examined associations between APP care and scope of practice regulations, phase of cancer care, and patient characteristics.

Methods: We performed an observational study among women identified from Medicare claims as having had incident breast cancer in 2008 with claims through 2012. Outpatient APP care included at least one APP independently billing for cancer visits/services. APP scope of practice was classified as independent, reduced, or restricted. A logistic regression model with patient-level random effects was estimated to determine the probability of receiving APP care at any point during active treatment or surveillance.

Results: Among 42,550 women, 6583 (15%) received APP care, of whom 83% had APP care during the surveillance phase and 41% during the treatment phase. Among women who received APP care during a given year of surveillance, the overall proportion of APP-billed clinic visits increased with each additional year of surveillance (36% in Year 1 to 61% in Year 4). Logistic regression model results indicate that women were more likely to receive APP care if they were younger, black, healthier, had higher income status, or lived in a rural county or state with independent APP scope of practice.

Conclusions: This study provides important clinical and policy-relevant findings regarding national practice patterns of APP oncology care. Among Medicare beneficiaries with incident breast cancer, 15% received outpatient oncology care that included APPs who were billing; most of this care was during the surveillance phase. Future studies are needed to define the degree of APP oncology practice and training that maximizes patient access and satisfaction while optimizing the efficiency and quality of cancer care.
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http://dx.doi.org/10.1007/s10549-019-05447-xDOI Listing
January 2020

Racial disparities of liver cancer mortality in Wisconsin.

Cancer Causes Control 2019 Dec 17;30(12):1277-1282. Epub 2019 Sep 17.

Institute for Health & Equity, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Purpose: To calculate tract-level estimates of liver cancer mortality in Wisconsin and identify relationships with racial and socioeconomic variables.

Methods: County-level standardized mortality ratios (SMRs) of liver cancer in Wisconsin were calculated using traditional indirect adjustment methods for cases from 2003 to 2012. Tract-level SMRs were calculated using adaptive spatial filtering (ASF). The tract-level SMRs were checked for correlations to a socioeconomic advantage index (SEA) and percent racial composition. Non-spatial and spatial regression analyses with tract-level SMR as the outcome were conducted.

Results: County-level SMR estimates were shown to mask much of the variance within counties across their tracts. Liver cancer mortality was strongly correlated with the percent of Black residents in a census tract and moderately associated with SEA. In the multivariate spatially-adjusted regression analysis, only Percent Black composition remained significantly associated with an increased liver cancer SMR.

Conclusions: Using ASF, we developed a high-resolution map of liver cancer mortality in Wisconsin. This map provided details on the distribution of liver cancer that were inaccessible in the county-level map. These tract-level estimates were associated with several racial and socioeconomic variables.
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http://dx.doi.org/10.1007/s10552-019-01232-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858574PMC
December 2019

The association of pharmacy fill synchronization with breast cancer endocrine therapy adherence.

Cancer 2019 11 2;125(22):3960-3965. Epub 2019 Aug 2.

Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: One-third to one-half of patients prescribed adjuvant endocrine therapy are nonadherent during the recommended 5-year endocrine therapy course. This study investigated whether poor pharmacy synchronization of medication fills (requiring refills on different days) acts as a barrier to adherence.

Methods: A cohort of older women with stage 0 to III endocrine receptor-positive breast cancer in 2011 was identified from the Surveillance, Epidemiology, and End Result-Medicare claims-linked cancer registry. Women with endocrine therapy and at least 1 other medication fill were identified, and the 3-month synchronization of their fills was calculated as 1 minus the quotient of the number of pharmacy visits and the number of filled medications. Regression models were used to examine the association between synchronization (in quartiles adjusted for the number of medications) and adherence to endocrine therapy (defined as a medication possession ratio ≥80%) over the subsequent year.

Results: During the 3 months after the first endocrine therapy prescription, the study cohort of 3212 women had a mean of 8.6 pharmacy visits (standard deviation, 4.7) with a mean synchronization of 0.3 (standard deviation, 0.2). Those in the third (odds ratio, 1.29; 95% confidence interval, 1.04-1.59) and fourth (most) medication number-adjusted synchronization quartiles (odds ratio, 1.49; 95% confidence interval, 1.19-1.86) were more likely to be adherent than those in the least. Multivariate model predictions showed that the proportion of patients who were adherent over 1 year varied from 68.9% in the least synchronized quartile to 76.6% in the most synchronized one.

Conclusions: Prescription refill synchronization is strongly associated with adherence to endocrine therapy. Efforts to improve adherence should address this.
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http://dx.doi.org/10.1002/cncr.32433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946341PMC
November 2019

Housing discrimination and racial cancer disparities among the 100 largest US metropolitan areas.

Cancer 2019 11 9;125(21):3818-3827. Epub 2019 Jul 9.

Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: Cancer contributes substantially to the life expectancy gap between US blacks and whites, and racial cancer disparities remain stubborn to eradicate. Disparities vary geographically, suggesting that they are not inevitable.

Methods: The authors examined the relationship between housing discrimination and the size of cancer disparities across large US metropolitan statistical areas (MSAs). MSA-level cancer disparities were measured using data from the US Centers for Disease Control and Prevention. Mortgage discrimination for each MSA was estimated using the Home Mortgage Disclosure Act database, and MSA racial segregation was determined using US Census data. Patterns of housing discrimination and cancer disparities were mapped, and the associations between these place-based factors and cancer disparities across MSAs were measured.

Results: Black-to-white cancer mortality disparities (rate ratios) varied geographically, ranging from 1.50 to 0.86; 88% of mortality ratios were >1, indicating higher mortality for blacks. In areas with greater mortgage discrimination, the gap between black and white cancer mortality rates was larger (correlation coefficient [r] = 0.32; P = .001). This relationship persisted in sex-specific analyses (males, r = 0.37; P < .001; females, r = 0.23; P = .02) and in models controlling for confounders. In contrast, segregation was inconsistently associated with disparities. Adjusting for incidence disparities attenuated, but did not eliminate, the correlation between mortgage discrimination and mortality disparities (r = 0.22-0.24), suggesting that cancer incidence and survival each account for part of the mortality disparity.

Conclusions: Mortgage discrimination is associated with larger black-to-white cancer mortality disparities. Some areas are exceptions to this trend. Examination of these exceptions and of policies related to housing discrimination may offer novel strategies for explaining and eliminating cancer disparities.
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http://dx.doi.org/10.1002/cncr.32358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788939PMC
November 2019

Normative ranges of nasal airflow variables in healthy adults.

Int J Comput Assist Radiol Surg 2020 Jan 2;15(1):87-98. Epub 2019 Jul 2.

Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Purpose: Virtual surgery planning based on computational fluid dynamics (CFD) simulations of nasal airflow has the potential to improve surgical outcomes for patients with nasal airway obstruction (NAO). Virtual surgery planning requires normative ranges of airflow variables, but few studies to date have quantified inter-individual variability of nasal airflow among healthy subjects. This study reports CFD simulations of nasal airflow in 47 healthy adults.

Methods: Anatomically accurate three-dimensional nasal models were reconstructed from cone beam computed tomography scans and used for steady-state inspiratory airflow simulations with a bilateral flowrate of 250 ml/s. Normal subjective sensation of nasal patency was confirmed using the nasal obstruction symptom evaluation and visual analog scale. Healthy ranges for several CFD variables known to correlate with subjective nasal patency were computed, including unilateral airflow, nasal resistance, airspace minimal cross-sectional area (mCSA), heat flux (HF), and surface area stimulated by mucosal cooling (defined as the area where HF > 50 W/m). The normative ranges were targeted to contain 95% of the healthy population and computed using a nonparametric method based on order statistics.

Results: A wide range of inter-individual variability in nasal airflow was observed among healthy subjects. Unilateral airflow varied from 60 to 191 ml/s, airflow partitioning ranged from 23.8 to 76.2%, and unilateral mCSA varied from 0.24 to 1.21 cm. These ranges are in good agreement with rhinomanometry and acoustic rhinometry data from the literature. A key innovation of this study are the normative ranges of flow variables associated with mucosal cooling, which recent research suggests is the primary physiological mechanism of nasal airflow sensation. Unilateral HF ranged from 94 to 281 W/m, while the surface area stimulated by cooling ranged from 27.4 to 64.3 cm.

Conclusions: These normative ranges may serve as targets in future virtual surgery planning for patients with NAO.
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http://dx.doi.org/10.1007/s11548-019-02023-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939154PMC
January 2020

Factors Influencing Prescription Drug Synchronization: The Complex Role of Number of Medications.

J Manag Care Spec Pharm 2019 Jun;25(6):714-718

3 Division of Biostatistics, Institute for Health and Society and Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee.

Background: Despite the well-documented association of medication refill synchronization with medication adherence, little is known about how best to measure synchronization at pharmacy visits or about its relationship to number of medications.

Objective: To examine the relationship of a commonly cited synchronization measure with the number of prescription medications.

Methods: Using a cohort of women aged 66-90 years with stage 0-3 hormone receptor-positive breast cancer from the Surveillance, Epidemiology and End Result (SEER)-Medicare data, we identified women with pharmacy claims for at least 1 endocrine therapy prescription and at least 1 other medication fill. Twelve-month medication refill synchronization was calculated as the quotient of the number of pharmacy visits and the number of filled medications subtracted from 1. Multiple linear regression (including polynomials) was then used to assess the relationship between refill synchronization, number of medications, and other potentially influential factors.

Results: Over 47% of cohort subjects took more than 10 unique medications. Subjects made an average (SD) of 29.9 (18.0) pharmacy visits, resulting in a mean (SD) synchronization of 0.28 (0.18, range = 0.0-0.92). The number of medications, including powers through to the fourth, was strongly associated with refill synchronization, with a rapid initial rise followed by a gradual increase after 10 medications. Although patient age and race/ethnicity were not associated with synchronization, there was a significant positive association of receipt of a low-income subsidy and residence in rural areas with synchronization.

Conclusions: There is a complex relationship between refill synchronization and number of prescribed medications, and future research into synchronization should account for this.

Disclosures: This study was supported by the National Institute on Minority Health and Health Disparities under grant R01 MD010728. The authors have nothing to disclose. This study was presented as an oral abstract at the Society of General Internal Medicine Meeting; April 13, 2018; Denver, CO.
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http://dx.doi.org/10.18553/jmcp.2019.25.6.714DOI Listing
June 2019

Nonparametric competing risks analysis using Bayesian Additive Regression Trees.

Stat Methods Med Res 2020 01 7;29(1):57-77. Epub 2019 Jan 7.

Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.

Many time-to-event studies are complicated by the presence of competing risks. Such data are often analyzed using Cox models for the cause-specific hazard function or Fine and Gray models for the subdistribution hazard. In practice, regression relationships in competing risks data are often complex and may include nonlinear functions of covariates, interactions, high-dimensional parameter spaces and nonproportional cause-specific, or subdistribution, hazards. Model misspecification can lead to poor predictive performance. To address these issues, we propose a novel approach: flexible prediction modeling of competing risks data using Bayesian Additive Regression Trees (BART). We study the simulation performance in two-sample scenarios as well as a complex regression setting, and benchmark its performance against standard regression techniques as well as random survival forests. We illustrate the use of the proposed method on a recently published study of patients undergoing hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1177/0962280218822140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954340PMC
January 2020

Investigating the Association Between Advanced Practice Providers and Chemotherapy-Related Adverse Events in Women With Breast Cancer: A Nested Case-Control Study.

J Oncol Pract 2018 Oct 10:JOP1800277. Epub 2018 Oct 10.

Medical College of Wisconsin, Milwaukee, WI.

Purpose:: The effect of advanced practice provider (APP) involvement in oncology care on cancer-specific outcomes is unknown. We examined the association between team-based APP-physician care during chemotherapy and chemotherapy-related adverse events (AEs) among women with breast cancer.

Methods:: We performed separate nested case-control analyses in two national cohorts of women who received chemotherapy for incident breast cancer. Cohorts were identified from Medicare (≥ 65 years of age) and MarketScan (18 to 64 years of age) data. Cases experienced a chemotherapy-related AE (emergency room visit and/or hospitalization). Controls were matched 1:1 on the basis of each patient's age, comorbidities, census region, state's APP scope of practice regulations, and observation period from chemotherapy initiation to first AE. APP exposure (any outpatient claim billed by an APP during the observation period) was assessed for each matched pair member.

Results:: Among the 1,948 cases in the Medicare cohort, 225 (12%) had APP exposure before the first chemotherapy-related AE, compared with 213 controls (11%; P = .54). Among the 725 cases in the MarketScan cohort, 52 (7%) had APP exposure compared with 65 controls (9%; P = .21). In the matched case-control analysis, there was no association between outpatient APP exposure during chemotherapy and AEs in either cohort (Medicare: OR, 1.06 [95% CI, 0.87 to 1.30]; MarketScan: OR, 0.76 [95% CI, 0.50 to 1.14]).

Conclusion:: Our results suggest that team-based APP-physician care that includes an APP who is billing independently, at least for certain patients receiving chemotherapy, may be a viable strategy to safely leverage the scarce oncology workforce to increase access and delivery of cancer care.
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http://dx.doi.org/10.1200/JOP.18.00277DOI Listing
October 2018

Transcriptomic analysis reveals inflammatory and metabolic pathways that are regulated by renal perfusion pressure in the outer medulla of Dahl-S rats.

Physiol Genomics 2018 06 30;50(6):440-447. Epub 2018 Mar 30.

Department of Physiology, Medical College of Wisconsin , Milwaukee, Wisconsin.

Studies exploring the development of hypertension have traditionally been unable to distinguish which of the observed changes are underlying causes from those that are a consequence of elevated blood pressure. In this study, a custom-designed servo-control system was utilized to precisely control renal perfusion pressure to the left kidney continuously during the development of hypertension in Dahl salt-sensitive rats. In this way, we maintained the left kidney at control blood pressure while the right kidney was exposed to hypertensive pressures. As each kidney was exposed to the same circulating factors, differences between them represent changes induced by pressure alone. RNA sequencing analysis identified 1,613 differently expressed genes affected by renal perfusion pressure. Three pathway analysis methods were applied, one a novel approach incorporating arterial pressure as an input variable allowing a more direct connection between the expression of genes and pressure. The statistical analysis proposed several novel pathways by which pressure affects renal physiology. We confirmed the effects of pressure on p-Jnk regulation, in which the hypertensive medullas show increased p-Jnk/Jnk ratios relative to the left (0.79 ± 0.11 vs. 0.53 ± 0.10, P < 0.01, n = 8). We also confirmed pathway predictions of mitochondrial function, in which the respiratory control ratio of hypertensive vs. control mitochondria are significantly reduced (7.9 ± 1.2 vs. 10.4 ± 1.8, P < 0.01, n = 6) and metabolomic profile, in which 14 metabolites differed significantly between hypertensive and control medullas ( P < 0.05, n = 5). These findings demonstrate that subtle differences in the transcriptome can be used to predict functional changes of the kidney as a consequence of pressure elevation.
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http://dx.doi.org/10.1152/physiolgenomics.00034.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032288PMC
June 2018

Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet.

Theranostics 2018 5;8(6):1468-1480. Epub 2018 Feb 5.

Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.

Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood, and it is difficult to assess blood pressure salt-sensitivity clinically. We examined urinary levels of metabolites in 103 participants of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial after nearly 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol per day). Targeted chromatography/mass spectrometry analysis was performed in 24 h urine samples for 47 amino metabolites and 10 metabolites related to the tricarboxylic acid cycle. The effect of an identified metabolite on blood pressure was examined in Dahl salt-sensitive rats. Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations of 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine with systolic blood pressure and cystine with diastolic blood pressure. The differences in homocysteine levels between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries, which could be developed as markers or therapeutic targets for salt-sensitive hypertension.
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http://dx.doi.org/10.7150/thno.22018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858161PMC
January 2019

Decision making and uncertainty quantification for individualized treatments using Bayesian Additive Regression Trees.

Stat Methods Med Res 2019 04 18;28(4):1079-1093. Epub 2017 Dec 18.

1 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.

Individualized treatment rules can improve health outcomes by recognizing that patients may respond differently to treatment and assigning therapy with the most desirable predicted outcome for each individual. Flexible and efficient prediction models are desired as a basis for such individualized treatment rules to handle potentially complex interactions between patient factors and treatment. Modern Bayesian semiparametric and nonparametric regression models provide an attractive avenue in this regard as these allow natural posterior uncertainty quantification of patient specific treatment decisions as well as the population wide value of the prediction-based individualized treatment rule. In addition, via the use of such models, inference is also available for the value of the optimal individualized treatment rules. We propose such an approach and implement it using Bayesian Additive Regression Trees as this model has been shown to perform well in fitting nonparametric regression functions to continuous and binary responses, even with many covariates. It is also computationally efficient for use in practice. With Bayesian Additive Regression Trees, we investigate a treatment strategy which utilizes individualized predictions of patient outcomes from Bayesian Additive Regression Trees models. Posterior distributions of patient outcomes under each treatment are used to assign the treatment that maximizes the expected posterior utility. We also describe how to approximate such a treatment policy with a clinically interpretable individualized treatment rule, and quantify its expected outcome. The proposed method performs very well in extensive simulation studies in comparison with several existing methods. We illustrate the usage of the proposed method to identify an individualized choice of conditioning regimen for patients undergoing hematopoietic cell transplantation and quantify the value of this method of choice in relation to the optimal individualized treatment rule as well as non-individualized treatment strategies.
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http://dx.doi.org/10.1177/0962280217746191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028324PMC
April 2019

Fractures in a nationwide population-based cohort of users of breast cancer hormonal therapy.

J Cancer Surviv 2018 04 15;12(2):268-275. Epub 2017 Dec 15.

Center for Patient Care and Outcomes Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: Although users of aromatase inhibitors have higher total fracture risk in some randomized trials, little is known about their risk outside of clinical trials or in older higher-risk cohorts.

Methods: In a population-based retrospective cohort study, we identified all older US Medicare D prescription drug insurance plan-enrolled women who had initial breast cancer surgery in 2006-2008 and began hormonal therapy (an aromatase inhibitor (AI) or tamoxifen) within the subsequent year. Total nonvertebral and hip fractures through 2012 were identified using a validated algorithm. The association of fracture outcomes with hormonal therapy type was assessed using competing risk regression models that accounted for differences in measured baseline covariates. Treatment assignment bias was reduced using inverse probability of treatment weighting computed from propensity scores.

Results: Among 23,378 women taking hormonal therapy (23.2% aged 80 or over), there were 3000 total and 436 hip fractures. Although AI users were younger and had lower comorbidity, after propensity score weighting, these and other covariates were balanced. Total nonvertebral risk was higher for users of AIs compared with tamoxifen, HR 1.11 (1.02-1.21), but the small increase in risk for hip fracture was not statistically significant, HR 1.04 (0.84-1.30).

Conclusions: Although total nonvertebral fracture risk was higher among AI users, differences in hip fractures were not significant in a large population-based cohort of older women.

Implications For Cancer Survivors: Use of aromatase inhibitors by older women is associated with high risk for nonvertebral fracture that is increased compared with use of tamoxifen. Fracture risk should be assessed among patients taking these medications.
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http://dx.doi.org/10.1007/s11764-017-0666-4DOI Listing
April 2018

Prevalence and Consequences of Axillary Lymph Node Dissection in the Era of Sentinel Lymph Node Biopsy for Breast Cancer.

Med Care 2018 01;56(1):78-84

Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee, WI.

Background: Despite clear guidelines for its use and wide adoption, no population-based study has examined the extent to which patients with early stage breast cancer are benefiting from sentinel lymph node biopsy (SLNB) by being spared a potentially avoidable axillary lymph node dissection (ALND) and its associated morbidity.

Objective: Examine variation in type of axillary surgery performed by surgeon volume; investigate the extent and consequences of potentially avoidable ALND.

Research Design/subjects: Observational study of older women with pathologically node-negative stage I-II invasive breast cancer who underwent surgery in a SEER state in 2008-2009.

Measures: Surgeon annual volume of breast cancer cases and type of axillary surgery were determined by Medicare claims. An estimated probability of excess lymphedema due to ALND was calculated.

Results: Among 7686 pathologically node-negative women, 49% underwent ALND (either initially or after SLNB) and 25% were operated on by low-volume surgeons. Even after adjusting for demographic and tumor characteristics, women treated by higher volume surgeons were less likely to undergo ALND [medium volume: odds ratio, 0.69 (95% confidence interval, 0.51-0.82); high volume: odds ratio, 0.59 (95% confidence interval, 0.45-0.76)]. Potentially avoidable ALND cases were estimated to represent 21% of all expected lymphedema cases.

Conclusions: In this pathologically node-negative population-based breast cancer cohort, only half underwent solely SLNB. Patients treated by low-volume surgeons were more likely to undergo ALND. Resources and guidelines on the appropriate training and competency of surgeons to assure the optimal performance of SLNB should be considered to decrease rates of potentially avoidable ALND and lymphedema.
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http://dx.doi.org/10.1097/MLR.0000000000000832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725235PMC
January 2018

A Bayesian subgroup analysis using collections of ANOVA models.

Biom J 2017 Jul 20;59(4):746-766. Epub 2017 Mar 20.

Department of Mathematics, University of Texas, Austin, TX, 78712, USA.

We develop a Bayesian approach to subgroup analysis using ANOVA models with multiple covariates, extending an earlier work. We assume a two-arm clinical trial with normally distributed response variable. We also assume that the covariates for subgroup finding are categorical and are a priori specified, and parsimonious easy-to-interpret subgroups are preferable. We represent the subgroups of interest by a collection of models and use a model selection approach to finding subgroups with heterogeneous effects. We develop suitable priors for the model space and use an objective Bayesian approach that yields multiplicity adjusted posterior probabilities for the models. We use a structured algorithm based on the posterior probabilities of the models to determine which subgroup effects to report. Frequentist operating characteristics of the approach are evaluated using simulation. While our approach is applicable in more general cases, we mainly focus on the 2 × 2 case of two covariates each at two levels for ease of presentation. The approach is illustrated using a real data example.
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http://dx.doi.org/10.1002/bimj.201600064DOI Listing
July 2017

Medicare D Subsidies and Racial Disparities in Persistence and Adherence With Hormonal Therapy.

J Clin Oncol 2016 12 24;34(36):4398-4404. Epub 2016 Oct 24.

Alana Biggers, University of Illinois-Chicago, Chicago, IL; and Yushu Shi, John Charlson, Elizabeth C. Smith, Alicia J. Smallwood, Ann B. Nattinger, Purushottam W. Laud, and Joan M. Neuner, Medical College of Wisconsin, Milwaukee, WI.

Purpose To investigate the role of out-of-pocket cost supports through the Medicare Part D Low-Income Subsidy on disparities in breast cancer hormonal therapy persistence and adherence by race or ethnicity. Methods A nationwide cohort of women age ≥ 65 years with a breast cancer operation between 2006 and 2007 and at least one prescription filled for oral breast cancer hormonal therapy was identified from all Medicare D enrollees. The association of race or ethnicity with nonpersistence (90 consecutive days with no claims for a hormonal therapy prescription) and nonadherence (medication possession rate < 80%) was examined. Survival analyses were used to account for potential differences in age, comorbidity, or intensity of other treatments. Results Among the 25,111 women in the study sample, 77% of the Hispanic and 70% of the black women received a subsidy compared with 21% of the white women. By 2 years, 69% of black and 70% of Hispanic patients were persistent compared with 61% of white patients. In adjusted analyses, patients in all three unsubsidized race or ethnicity groups had greater discontinuation than subsidized groups (white patients: hazard ratio [HR], 1.83; 95% CI, 1.70 to 1.95; black patients: HR, 2.09; 95% CI, 1.73 to 2.51; Hispanic patients: HR, 3.00; 95% CI, 2.37 to 3.89). Racial or ethnic persistence disparities that were present for unsubsidized patients were not present or reversed among subsidized patients. All three subsidized race or ethnicity groups also had higher adherence than all three unsubsidized groups, although with the smallest difference occurring in black women. Conclusion Receipt of a prescription subsidy was associated with substantially improved persistence to breast cancer hormonal therapy among white, black, and Hispanic women and lack of racial or ethnic disparities in persistence. Given high subsidy enrollment among black and Hispanic women, policies targeted at low-income patients have the potential to also substantially reduce racial and ethnic disparities.
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http://dx.doi.org/10.1200/JCO.2016.67.3350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455308PMC
December 2016

Bone Mineral Density Testing Disparities Among Patients With Breast Cancer Prescribed Aromatase Inhibitors.

J Natl Compr Canc Netw 2016 07;14(7):875-80

From the Department of Medicine, Hematology-Oncology Division; Center for Patient Care and Outcomes Research; Division of Biostatistics, Institute for Health and Society; and Department of Medicine, General Internal Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. From the Department of Medicine, Hematology-Oncology Division; Center for Patient Care and Outcomes Research; Division of Biostatistics, Institute for Health and Society; and Department of Medicine, General Internal Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

Objectives: Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with early-stage, estrogen receptor-positive breast cancer. We designed our study to determine whether women initiating adjuvant therapy with an AI underwent baseline bone mineral density testing, as well as what factors predicted adherence with testing guidelines.

Methods: Medicare Parts A, B, and D claims were used to identify a cohort of women aged 67 years and older with incident breast cancer in 2006 and 2007 who started AI therapy. Medicare claims provided information about bone density testing, as well as demographic and other treatment data through 2012. We also ascertained which patients were treated with bisphosphonates and studied the relationship of bisphosphonate therapy with bone density testing.

Results: Approximately two-thirds of patients had baseline bone density testing. Older age, comorbidity, low income, and black race were associated with lower rates of baseline bone density testing. Testing rates decreased substantially with increasing age from 73% for women aged 67 to 70 years to 51% for those 85 years of age and older (adjusted odds ratio for not being tested, 2.48 [Cl, 2.17-2.82]). The proportion of women who had neither bone density testing nor bisphosphonate therapy increased with age as well.

Conclusions: Despite the importance of age as a risk factor for fractures, older women starting treatment with AIs for treatment of breast cancer are less likely to undergo recommended bone density assessment.
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http://dx.doi.org/10.6004/jnccn.2016.0092DOI Listing
July 2016

New spatially continuous indices of redlining and racial bias in mortgage lending: links to survival after breast cancer diagnosis and implications for health disparities research.

Health Place 2016 07 9;40:34-43. Epub 2016 May 9.

Center for Patient Care and Outcomes Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509, USA; Division of General Internal Medicine, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509, USA.

Racial health disparities continue to be a serious problem in the United States and have been linked to contextual factors, including racial segregation. In some cases, including breast cancer survival, racial disparities appear to be worsening. Using the Home Mortgage Disclosure Act (HMDA) database, we extend current spatial analysis methodology to derive new, spatially continuous indices of (1) racial bias in mortgage lending and (2) redlining. We then examine spatial patterns of these indices and the association between these new measures and breast cancer survival among Black/African American women in the Milwaukee, Wisconsin metropolitan area. These new measures can be used to examine relationships between mortgage discrimination and patterns of disease throughout the United States.
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http://dx.doi.org/10.1016/j.healthplace.2016.04.014DOI Listing
July 2016

Breast and Colorectal Cancer Survival Disparities in Southeastern Wisconsin.

WMJ 2016 Feb;115(1):17-21

Background: Cancer health disparities by race, ethnicity, socioeconomic status, and geography are a top public health priority. Breast and colorectal cancer, in particular, have been shown to exhibit significant disparities and contribute a large proportion of morbidity and mortality from cancer. In addition, breast and colorectal cancer offer targets for prevention and control, including nutrition, physical activity, screening, and effective treatments to prolong and enhance the quality of survival. However, despite the investment of significant time and resources over many years, breast and colorectal cancer disparities persist, and in some cases, may be growing.

Methods: This paper examines breast and colorectal cancer survival disparities in an 8-county region in southeastern Wisconsin, including the City of Milwaukee. Cox proportional hazards models were used to examine survival trends, and a new adaptation of adaptive spatial filtering--a disease mapping method--was used to examine spatial patterns of survival.

Results: Disparities by race and ethnicity are revealed, and spatial analyses identify specific areas within the study region that have lower than expected survival rates.

Conclusions: Cancer control efforts in southeastern Wisconsin should focus on black/African American and Hispanic/Latina women to reduce breast cancer survival disparities, and black/African American populations to reduce colorectal cancer disparities. Evidence indicates that targeted interventions may be needed to serve populations in the Milwaukee and Kenosha metropolitan areas, as well as areas of Walworth, Ozaukee, and Waukesha counties.
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February 2016

Nonparametric survival analysis using Bayesian Additive Regression Trees (BART).

Stat Med 2016 07 7;35(16):2741-53. Epub 2016 Feb 7.

Division of Biostatistics, Medical College of Wisconsin, Milwaukee, U.S.A.

Bayesian additive regression trees (BART) provide a framework for flexible nonparametric modeling of relationships of covariates to outcomes. Recently, BART models have been shown to provide excellent predictive performance, for both continuous and binary outcomes, and exceeding that of its competitors. Software is also readily available for such outcomes. In this article, we introduce modeling that extends the usefulness of BART in medical applications by addressing needs arising in survival analysis. Simulation studies of one-sample and two-sample scenarios, in comparison with long-standing traditional methods, establish face validity of the new approach. We then demonstrate the model's ability to accommodate data from complex regression models with a simulation study of a nonproportional hazards scenario with crossing survival functions and survival function estimation in a scenario where hazards are multiplicatively modified by a highly nonlinear function of the covariates. Using data from a recently published study of patients undergoing hematopoietic stem cell transplantation, we illustrate the use and some advantages of the proposed method in medical investigations. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.6893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899272PMC
July 2016

The introduction of generic aromatase inhibitors and treatment adherence among Medicare D enrollees.

J Natl Cancer Inst 2015 Aug 12;107(8). Epub 2015 May 12.

Center for Patient Care and Outcomes Research (JMN, SK, JC, EMW, ECS, AJS, PWL, LEP), Division of Hematology and Oncology, Department of Medicine (SK, JC), Division of Biostatistics, Department of the Institute for Health and Society (PWL), Division of General Internal Medicine, Department of Medicine (JMN, AB, LEP), Medical College of Wisconsin, Milwaukee, WI.

Background: Aromatase inhibitors (AIs) substantially reduce breast cancer mortality in clinical trials, but high rates of nonadherence to these long-term oral therapies have reduced their impact outside of trials. We examined the association of generic AI availability with AI adherence among a large national breast cancer cohort.

Methods: Using a quasi-experimental prepost design, we examined the effect of generic AI introductions (7/2010 and 4/2011) on adherence among a national cohort of women with incident breast cancer in 2006 and 2007 who were enrolled in the Medicare D pharmaceutical coverage program. Medicare D claims were used to calculate AI adherence, defined as a medication possession ratio of 80% or more of eligible days, over 36 months. Multivariable logistic regression models estimated with generalized estimating equations were applied to longitudinal adherence data to control for possible confounders, including receipt of a Medicare D low-income subsidy, and to account for repeated measures. All statistical tests were two-sided.

Results: Sixteen thousand four hundred sixty-two Medicare D enrollees were eligible. Adherence declined throughout the study. However, among women without a subsidy, the median quarterly out-of-pocket cost of anastrozole fell from $183 in the fourth quarter of 2009 to $15 in 2011, and declines in adherence were attenuated with generic AI introductions. Regression-adjusted adherence probabilities were estimated to be 5.4% higher after generic anastrozole was introduced in 2010 and 11% higher after generic letrozole/exemestane was introduced in 2011. Subsidy recipients had higher adherence rates throughout the study.

Conclusions: The introduction of generic medications attenuated the decline in adherence to AIs over three years of treatment among breast cancer survivors not receiving low-income subsidies for Medicare D coverage.
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http://dx.doi.org/10.1093/jnci/djv130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580559PMC
August 2015

The introduction of generic aromatase inhibitors and treatment adherence among Medicare D enrollees.

J Natl Cancer Inst 2015 Aug 12;107(8). Epub 2015 May 12.

Center for Patient Care and Outcomes Research (JMN, SK, JC, EMW, ECS, AJS, PWL, LEP), Division of Hematology and Oncology, Department of Medicine (SK, JC), Division of Biostatistics, Department of the Institute for Health and Society (PWL), Division of General Internal Medicine, Department of Medicine (JMN, AB, LEP), Medical College of Wisconsin, Milwaukee, WI.

Background: Aromatase inhibitors (AIs) substantially reduce breast cancer mortality in clinical trials, but high rates of nonadherence to these long-term oral therapies have reduced their impact outside of trials. We examined the association of generic AI availability with AI adherence among a large national breast cancer cohort.

Methods: Using a quasi-experimental prepost design, we examined the effect of generic AI introductions (7/2010 and 4/2011) on adherence among a national cohort of women with incident breast cancer in 2006 and 2007 who were enrolled in the Medicare D pharmaceutical coverage program. Medicare D claims were used to calculate AI adherence, defined as a medication possession ratio of 80% or more of eligible days, over 36 months. Multivariable logistic regression models estimated with generalized estimating equations were applied to longitudinal adherence data to control for possible confounders, including receipt of a Medicare D low-income subsidy, and to account for repeated measures. All statistical tests were two-sided.

Results: Sixteen thousand four hundred sixty-two Medicare D enrollees were eligible. Adherence declined throughout the study. However, among women without a subsidy, the median quarterly out-of-pocket cost of anastrozole fell from $183 in the fourth quarter of 2009 to $15 in 2011, and declines in adherence were attenuated with generic AI introductions. Regression-adjusted adherence probabilities were estimated to be 5.4% higher after generic anastrozole was introduced in 2010 and 11% higher after generic letrozole/exemestane was introduced in 2011. Subsidy recipients had higher adherence rates throughout the study.

Conclusions: The introduction of generic medications attenuated the decline in adherence to AIs over three years of treatment among breast cancer survivors not receiving low-income subsidies for Medicare D coverage.
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http://dx.doi.org/10.1093/jnci/djv130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580559PMC
August 2015

Characterization of biological pathways associated with a 1.37 Mbp genomic region protective of hypertension in Dahl S rats.

Physiol Genomics 2014 Jun 8;46(11):398-410. Epub 2014 Apr 8.

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;

The goal of the present study was to narrow a region of chromosome 13 to only several genes and then apply unbiased statistical approaches to identify molecular networks and biological pathways relevant to blood-pressure salt sensitivity in Dahl salt-sensitive (SS) rats. The analysis of 13 overlapping subcongenic strains identified a 1.37 Mbp region on chromosome 13 that influenced the mean arterial blood pressure by at least 25 mmHg in SS rats fed a high-salt diet. DNA sequencing and analysis filled genomic gaps and provided identification of five genes in this region, Rfwd2, Fam5b, Astn1, Pappa2, and Tnr. A cross-platform normalization of transcriptome data sets obtained from our previously published Affymetrix GeneChip dataset and newly acquired RNA-seq data from renal outer medullary tissue provided 90 observations for each gene. Two Bayesian methods were used to analyze the data: 1) a linear model analysis to assess 243 biological pathways for their likelihood to discriminate blood pressure levels across experimental groups and 2) a Bayesian graphical modeling of pathways to discover genes with potential relationships to the candidate genes in this region. As none of these five genes are known to be involved in hypertension, this unbiased approach has provided useful clues to be experimentally explored. Of these five genes, Rfwd2, the gene most strongly expressed in the renal outer medulla, was notably associated with pathways that can affect blood pressure via renal transcellular Na(+) and K(+) electrochemical gradients and tubular Na(+) transport, mitochondrial TCA cycle and cell energetics, and circadian rhythms.
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http://dx.doi.org/10.1152/physiolgenomics.00179.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042181PMC
June 2014
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