Data-driven automated classification algorithms for acute health conditions: applying PheNorm to COVID-19 disease.

OBJECTIVES: Automated phenotyping algorithms can reduce development time and operator dependence compared to manually developed algorithms. One such approach, PheNorm, has performed well for identifying chronic health conditions, but its performance for acute conditions is largely unknown. Herein, we implement and evaluate PheNorm applied to symptomatic COVID-19 disease to investigate its potential feasibility for rapid phenotyping of acute health conditions. MATERIALS AND METHODS: PheNorm is a general-purpose automated approach to creating computable phenotype algorithms based on natural language processing, machine learning, and (low cost) silver-standard training labels. We applied PheNorm to cohorts of potential COVID-19 patients from 2 institutions and used gold-standard manual chart review data to investigate the impact on performance of alternative feature engineering options and implementing externally trained models without local retraining. RESULTS: Models at each institution achieved AUC, sensitivity, and positive predictive value of 0.853, 0.879, 0.851 and 0.804, 0.976, and 0.885, respectively, at quantiles of model-predicted risk that maximize F1. We report performance metrics for all combinations of silver labels, feature engineering options, and models trained internally versus externally. DISCUSSION: Phenotyping algorithms developed using PheNorm performed well at both institutions. Performance varied with different silver-standard labels and feature engineering options. Models developed locally at one site also worked well when implemented externally at the other site. CONCLUSION: PheNorm models successfully identified an acute health condition, symptomatic COVID-19. The simplicity of the PheNorm approach allows it to be applied at multiple study sites with substantially reduced overhead compared to traditional approaches.

Factors that have an Impact on Abbreviated New Drug Application (ANDA) Submissions.

BACKGROUND: Increasing generic drug price competition by facilitating abbreviated new drug applications (ANDA) submission may help patients have access to affordable care. This study examined factors associated with first ANDA submission for the brand drug to be copied [the "reference listed drug" (RLD)]. METHODS: This study used several data sources from 1/1/2011 to 12/31/2017, including FDA's Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book), internal ANDA submission data, FDA's Product-Specific Guidances (PSGs), National Drug Code, and IQVIA National Sales Perspectives. Two Cox proportional hazard models were separately performed to determine factors associated with first ANDA submissions for groups of ANDAs for RLDs with "new chemical entity" (NCE) exclusivity that were submitted on the first lawfully permissible date NCE ANDAs, and non-NCE ANDA groups. RESULTS: For NCE group, annual market sales were the only factor associated with increased likelihood of first ANDA submission. Specifically, adjusted hazard ratio (HR) for RLDs with annual sales > $250 million was nearly 5 times higher than those with annual sales < $10 million (HR 4.74; Confidence Interval [CI] 1.85-12.13) suggesting RLDs with higher sales are more likely to have ANDA submissions. For the non-NCE group, annual market sales (HR 2.40; CI 1.09-5.25, sales > $100-250 million compared with sales < $10 million) and PSG availability were associated with increased likelihood of first ANDA submission. Being an ANDA for a complex drug product was associated with decreased likelihood of submission for both NCE (HR 0.51; CI 0.26-0.99) and non-NCE groups (HR 0.62; CI 0.39-0.98). CONCLUSION: Given the impact of regulatory-related factors, particularly PSG availability prior to ANDA submission, the findings provide opportunities to address high drug prices with specific FDA actions. Specifically, timely development of PSGs, including those for complex generics, and research prioritizing complex generics may facilitate ANDA submission; and thus, promote drug price competition.

Predictive Analysis of First Abbreviated New Drug Application Submission for New Chemical Entities Based on Machine Learning Methodology.

Generic drug products are approved by the US Food and Drug Administration (FDA) through Abbreviated New Drug Applications (ANDAs). The ANDA review and approval involves multiple offices across the FDA. Forecasting ANDA submissions can critically inform resource allocation and workload management. In this work, we used machine learning (ML) methodologies to predict the time to first ANDA submissions referencing new chemical entities following their earliest lawful ANDA submission dates. Drug product information, regulatory factors, and pharmacoeconomic factors were used as modeling inputs. The random survival forest ML method, as well as the conventional Cox model, was used for ANDA submission predictions. The ML method outperformed the conventional Cox regression model in predictive performance that was adequately assessed by both internal and external validations. In conclusion, it can potentially serve as an effective forecasting tool for strategic workload and research planning for generic applications.

Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or ß-blockers in Older Adults With Breast Cancer.

PURPOSE: Although clinical trials have provided some data on the benefit of angiotensin-converting enzyme inhibitors (ACEIs) or ß-blockers (BBs) in patients with chemotherapy-induced cardiotoxicity, evidence of ACEIs/BBs on prevention of trastuzumab and/or anthracycline-induced cardiotoxicity outside trials is limited. MATERIALS AND METHODS: A cohort study of 142,990 women (66 y and above) newly diagnosed with breast cancer from 2001 to 2009 was conducted using the Surveillance, Epidemiology, and End Results-Medicare-linked database. The ACEI/BB exposure was defined as filled prescription(s) before or after the initiation of trastuzumab/anthracyclines. The nonexposed group was defined as those who had never been prescribed ACEIs/BBs. Cumulative rates of cardiotoxicity and all-cause mortality were estimated and marginal structural Cox models were used to determine factors associated with cardiotoxicity and all-cause mortality adjusting for baseline covariates and use of chemotherapy. All statistical tests were 2 sided. RESULTS: The final sample included 6542 women. Adjusted hazard ratio for cardiotoxicity and all-cause mortality for the ACEI/BB exposed group were 0.77 (95% confidence interval, 0.62-0.95) and 0.79 (95% confidence interval, 0.70-0.90) compared with the nonexposed group, respectively. Starting ACEIs/BBs≤6 months after the initiation of trastuzumab/anthracyclines and having exposed duration≥6 months were also associated with decreased risk of cardiotoxicity and all-cause mortality. Baseline characteristics, including age, non-Hispanic black, advanced cancer, region, comorbidity, preexisting cardiovascular conditions, lower socioeconomic status, and concomitant treatment were significantly associated with an elevated risk of all-cause mortality and/or cardiotoxicity (all P<0.05). CONCLUSIONS: ACEIs/BBs show favorable effects on preventing cardiotoxicity and improving survival in female breast cancer patients undergoing trastuzumab/anthracycline treatment.

Patterns of psychiatric emergency department utilization among community-dwelling Medicare beneficiaries under 65.

This study estimated patterns and trends in all-cause (any reason, including psychiatry related) and psychiatric emergency department (ED) utilization among Medicare beneficiaries under 65 who were residing in community settings (i.e., noninstitutionalized or in their own homes). Medicare beneficiaries under the age of 65 enrolled in Medicare for Social Security Disability Insurance (SSDI) due to permanent physical or mental disabilities are a population with poor health conditions and high utilization of health services; however, this vulnerable population has received limited attention from researchers and policymakers compared to the Medicare beneficiaries 65 years and older. Data from the 2002-2009 Medicare Current Beneficiary Survey (MCBS) with linked Medicare administrative claims data were used to select a total of 4,864 Medicare beneficiaries under the age of 65 with a total of 10,384 person-years (weighted n = 30,086,846 person-years). We found that trends in all-cause and psychiatric ED utilization among the young and disabled Medicare beneficiaries remained stable, but trends in the proportion of all-cause ED visits that were psychiatric related increased, and trends in the proportion of psychiatric ED visits resulting in a psychiatric inpatient stay decreased over time. Factors associated with a higher likelihood of psychiatric ED utilization included younger age, residence in the Northeast region, lower education level, Medicare-Medicaid dual eligibility, use of psychotropic medication, and greater number of chronic and psychiatric conditions. These findings highlight the need for policies, programs, and system interventions designed to reduce future psychiatric ED events and improve the access and quality of community mental health services for the community-dwelling, young, and disabled Medicare population. (PsycINFO Database Record

Cardiotoxicity in targeted therapy for breast cancer: A study of the FDA adverse event reporting system (FAERS).

Purpose Cancer chemotherapy-induced cardiotoxicity is concerning. Certain anthracyclines and targeted therapies are known to have potential for cardiotoxicity, but existing trial evidence is inadequate to understand real-world patterns of cardiotoxicity with newer targeted therapies and their common combinations with older agents. This study evaluated chemotherapy-related cardiotoxicity reports for targeted therapies and their combinations in breast cancer patients. Methods The US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 2004 through September 2012 was used to summarize characteristics of reported cardiotoxicity events and their health outcomes. Disproportionality analyses with reporting odds ratios (ROR) and 95% confidence intervals (95% CI) were conducted to detect event signals using a case/non-case method for each targeted therapy and combination. Results A total of 59,739 cases of cardiotoxicity reports were identified; 937 cases identified targeted therapy as the suspect drug. Trastuzumab had the highest number of reports followed by bevacizumab and lapatinib. Proportions of reports of death and disability outcomes for each targeted therapy were approximately 20-25% of the total reports of serious events. Trastuzumab had the highest ROR as a single agent (ROR = 5.74; 95% CI = 5.29-6.23) or combination use of cyclophosphamide (ROR = 16.83; 95% CI = 13.32-21.26) or doxorubicin (ROR = 17.84; 95% CI = 13.77-23.11). Relatively low cardiotoxicity reporting rates were found with lapatinib, regardless of use with combination therapy. Conclusions Analysis of FAERS data identified signals for adverse cardiotoxicity events with targeted therapies and their combinations. Practitioners should consider factors that may increase the likelihood of cardiotoxicity when assessing treatment. Findings support continued surveillance, risk factor identification, and comparative studies.

Factors associated with psychotropic prescriptions, psychiatric hospitalization, and spending among Medicare beneficiaries under 65.

BACKGROUND: Medicare beneficiaries under 65 are a medically heterogenous population with significant psychiatric health service utilization. Patterns of psychiatric health services utilization and spending have not been well studied in this population. OBJECTIVE: To estimate and compare annual trends in psychotropic prescriptions, psychiatric hospitalization, and total Medicare spending between Medicare beneficiaries <65 and those ≥ 65. We also identified factors associated with these outcomes among Medicare beneficiaries under 65. METHODS: This serial cross-sectional study used 2006-2009 Medicare Current Beneficiary Survey (MCBS) data linked with Medicare claims. Psychotropic prescription and psychiatric hospitalization were measured using claims data. Total annual Medicare spending included reimbursements from Medicare Parts A, B, and D. Repeated person-year data were analyzed using generalized estimating equation (GEE) models to examine associations between factors and outcomes among beneficiaries <65, controlling for covariates. RESULTS: Over one-third of beneficiaries <65 used at least one psychotropic prescription annually. Annual prevalence of psychotropic prescription and psychiatric hospitalization was higher among beneficiaries <65 than those ≥ 65 (threefold and ten-fold, respectively), as well as Medicare spending. The annual prevalence of psychiatric hospitalization decreased over time among beneficiaries <65. Antidepressants were the most prevalently prescribed psychotropic drug class among beneficiaries <65. Factors associated with psychiatric services utilization and spending among beneficiaries <65 included demographics and health insurance access, self-reported health, smoking status, and comorbidities (all P < 0.05). CONCLUSIONS: Our findings highlight the special psychiatric health care needs of Medicare beneficiaries under 65 and call for the attention of policy makers and clinicians to this understudied population.

Treatment patterns among breast cancer patients in the United States using two national surveys on visits to physicians' offices and hospital outpatient departments.

BACKGROUND: Despite the availability of previous studies, little research has examined how types of anti-neoplastic agents prescribed differ among various populations and health care characteristics in ambulatory settings, which is a primary method of providing care in the U.S. Understanding treatment patterns can help identify possible disparities and guide practice or policy change. OBJECTIVES: To characterize patterns of anti-neoplastic agents prescribed to breast cancer patients in ambulatory settings and identify factors associated with receipt of treatment. METHODS: A cross-sectional analysis using the National Ambulatory Medical Care Survey data in 2006-2010 was conducted. Breast cancer treatments were categorized by class and further grouped as chemotherapy, hormone, and targeted therapy. A visit-level descriptive analysis using visit sampling weights estimated national prescribing trends (n = 2746 breast cancer visits, weighted n = 28,920,657). Multiple logistic regression analyses identified factors associated with anti-neoplastic agent used. RESULTS: The proportion of visits in which anti-neoplastic agent(s) was/were documented remained stable from 2006 to 2010 (20.47% vs. 24.56%; P > 0.05). Hormones were commonly prescribed (29.69%) followed by mitotic inhibitors (9.86%) and human epidermal growth factor receptor2 inhibitors (5.34%). Patients with distant stage were more likely than patients with in-situ stage to receive treatment (Adjusted Odds Ratio [OR] = 2.79; 95% CI, 1.04-7.77), particularly chemotherapy and targeted therapy. Patients with older age, being ethnic minorities, having comorbid depression, and having U.S. Medicaid insurance were less likely to receive targeted therapy (P < 0.05). Patients with older age, having comorbid obesity and osteoporosis were less likely to receive chemotherapy, while patients seen in hospital-based settings and settings located in metropolitan areas were more likely to receive chemotherapy (P < 0.05). CONCLUSIONS: Anti-neoplastic treatment patterns differ among breast cancer patients treated in ambulatory settings. Factors predicting treatment include certain socio-demographics, cancer stages, comorbidities, metropolitan areas, and setting.

Interventions for adherence with oral chemotherapy in hematological malignancies: A systematic review.

BACKGROUND: Poor adherence to treatment for chronic diseases including some hematological malignancies impedes health outcomes and increases costs. Oral chemotherapy is an emerging trend that raises concern about nonadherence problems in these targeted patients. OBJECTIVES: This systematic literature review explores evidence and gaps in the literature regarding interventions to enhance adherence with prescribed oral chemotherapy in patients with hematological malignancies. METHODS: Searches of databases and abstracts from conferences were performed for 1987 to January 2013 using a modified Cochrane method. Studies measuring interventions to improve adherence alone or together with clinical, humanistic, and economic outcomes were included. Assessment of methodological quality was performed for each retained study. RESULTS: The literature search generated 6 studies that met inclusion criteria. Four of these reported a statistically significant increase in the adherence outcome, compared with baseline. Tailored and educational interventions were widely used among the retained studies. Post-intervention adherence rates were 41-96.1%; intervention groups yielded higher rates than comparison groups. Two studies reported statistically significant improvement in clinical outcomes (cytogenetic response and survival time). One study reported that severity of illness was associated with survival time but not with adherence. Studies that used both tailored and educational interventions showed significant relationship between adherence and clinical outcomes; however, the study that used dosage simplification did not. None of the studies explored humanistic or economic outcomes. CONCLUSIONS: Interventions to improve adherence with oral chemotherapies in hematological malignancies remain limited. Though they were heterogeneous in nature, interventions tested in the retained studies suggested a positive impact on the adherence outcome; some established a significant relationship between adherence and clinical outcomes. The results yielded limited evidences regarding characteristics of a specific intervention, but supported a general structure for methods to improve adherence and other outcomes in real-life settings. Further rigorous methodological studies are needed to fully examine impact on adherence and clinical outcomes.

Prevalence of depressive symptoms and predictors of treatment among U.S. adults from 2005 to 2010.

OBJECTIVES: To determine nationally representative estimates of the prevalence of depressive symptoms and factors associated with treatment among those with moderate to severe symptoms. METHODS: A cross-sectional, retrospective analysis of adults age≥18 years in the 2005-2010 National Health and Nutrition Examination Survey data who responded to the Patient Health Questionnaire (PHQ-9) was conducted (n=13,320). Depressive symptoms and severity were defined by PHQ-9 scores. Depression treatment was defined as either receiving antidepressants or seeing a mental health professional. Multivariable logistic regression analyses using population weights identified factors associated with having depressive symptoms and receipt of any treatment. RESULTS: The prevalence of depressive symptoms increased from 20.92% to 25.66% over 6 years. Among patients with moderate to severe depression, 38.66% received treatment. Multivariable analyses found that being female, other Hispanic, younger age, having certain chronic comorbidities or previous hospitalization, no health insurance and in poverty status were associated with having depressive symptoms (P<.05). Among patients with moderate to severe depression, being female, white, younger age, having comorbidities (arthritis and hypertension) or previous hospitalization were associated with receipt of treatment (P<.05). CONCLUSIONS: The prevalence of depressive symptoms is high, and only a small portion of patients with moderate to severe depression received treatments. Treatment disparities exist and need improvement.

Evaluation of medication therapy management services for patients with cardiovascular disease in a self-insured employer health plan.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality in the United States, representing the highest total expenditures among major diseases. To improve CVD-associated outcomes, medication therapy management (MTM) services have been included in essential health benefit packages offered by various health plans. Nevertheless, the impact of such MTM services on outcomes is still unclear, especially from the perspective of the self-insured employer.  OBJECTIVES: To (a) compare economic outcomes between patients who received and those who did not receive MTM services from the self-insured employer's perspective and (b) compare clinical outcomes before and after receiving MTM services.  METHODS: This study consisted of 2 pre- and post-retrospective designs: (1) a cohort study with comparison groups and (2) a cohort study within group comparison. Patients were beneficiaries aged 19 years or older who were diagnosed with CVD conditions according to ICD-9-CM codes and continuously enrolled in a public university-sponsored insurance plan between 2008-2010. Patients were divided into MTM and non-MTM groups. The first MTM encounter was assigned as the index date for the MTM group. Match-paired patients who did not receive MTM services were randomly assigned the index date based on age category, gender, and comorbidity. Measures for pharmacy, medical, and total expenditures were obtained from medical and pharmacy claims. Paired t-tests and independent t-tests using data generated from 1000 bootstraps compared mean cost difference within and between groups. The return on investment (ROI) was calculated by dividing the average net benefit from MTM services by the average cost of MTM services. Clinical parameters, including blood pressure (BP) and body mass index (BMI), were retrieved from electronic medical records from a pharmacist-provided clinic where MTM services took place. Paired-t tests were used to compare the mean difference between baseline and endpoint values. Further, this study examined changes in the proportion of patients who achieved an individualized treatment goal for BP and BMI. The study also quantified the improvement in disease stages after the index date using the McNemar's test. Statistical analyses were performed by using SAS software version 9.2 with statistical significance level of 0.05.   RESULTS: A total of 63 patients and 62 match-paired patients were included in the MTM group and the non-MTM group, respectively. The mean cost (SD) per patient in the MTM group during the 6 months post-index period for CVD-related pharmacy, all-cause medical, and total expenditures was lower than the 6 months pre-index period by $22.0 (19.1), $79.2 (99.6), and $75.1 (136.2), respectively. In contrast, the mean cost (SD) for the non-MTM group increased during the 6 months post-index date by $10.7 (24.2), $246.4 (248.4), and $289.0 (269.5) for pharmacy, medical, and total expenditure, respectively. When comparing the 2 groups, the MTM group had statistically significantly lower costs per patient for pharmacy expenditures (difference of -31.9 ± 25.1, P less than 0.0001), medical expenditures (difference of -$325.6 ± 271.2, P less than 0.0001), and total direct expenditures (difference of -$359.3 ± 219.2, P less than 0.0001). Given the net benefit of MTM services ($359.3) and the average cost of MTM service ($134.6), the ROI was $1.67 per $1 in MTM cost. Regarding clinical outcomes, while no statistically significant differences were observed in clinical outcomes, MTM services demonstrated clinical benefits. At the post-index period, the percentage of patients who had achieved their goals increased from 55% to 70% for BP and from 13.0% to 21.7% for normal BMI compared with the pre-index period. In terms of the extent of improvement in disease stages, clinical improvements in the stages of hypertension (χ2 =12.77, P less than 0.05) as well as BMI (χ2 =6.39, P less than 0.05) at the endpoint were observed.  CONCLUSIONS: Cardiovascular-related pharmacy, all-cause medical, and total expenditures were statistically lower among beneficiaries who received MTM services compared with those who did not. In addition, MTM services had a positive ROI and demonstrated clinical significances by the increasing number of patients who achieved treatment goals and improved disease stages for hypertension and BMI.