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The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Background: Timing of initiation of screening for breast cancer is controversial in the United States.Objective: To determine the threshold relative risk (RR) at which the harm-benefit ratio of screening women aged 40 to 49 years equals that of biennial screening for women aged 50 to 74 years.Design: Comparative modeling study.Data Sources: Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and medical literature.Target Population: A contemporary cohort of women eligible for routine screening.Time Horizon: Lifetime.Perspective: Societal.Intervention: Mammography screening starting at age 40 versus 50 years with different screening methods (film, digital) and screening intervals (annual, biennial).Outcome Measures: Benefits: life-years gained, breast cancer deaths averted; harms: false-positive mammography findings; harm-benefit ratios: false-positive findings/life-years gained, false-positive findings/deaths averted.Results Of Base-case Analysis: Screening average-risk women aged 50 to 74 years biennially yields the same false-positive findings/life-years gained as biennial screening with digital mammography starting at age 40 years for women with a 2-fold increased risk above average (median threshold RR, 1.9 [range across models, 1.5 to 4.4]). The threshold RRs are higher for annual screening with digital mammography (median, 4.3 [range, 3.3 to 10]) and when false-positive findings/deaths averted is used as an outcome measure instead of false-positive findings/life-years gained. The harm-benefit ratio for film mammography is more favorable than for digital mammography because film has a lower false-positive rate.Results Of Sensitivity Analysis: The threshold RRs changed slightly when a more comprehensive measure of harm was used and were relatively insensitive to lower adherence assumptions.Limitation: Risk was assumed to influence onset of disease without influencing screening performance.Conclusion: Women aged 40 to 49 years with a 2-fold increased risk have similar harm-benefit ratios for biennial screening mammography as average-risk women aged 50 to 74 years. Threshold RRs required for favorable harm-benefit ratios vary by screening method, interval, and outcome measure.Primary Funding Source: National Cancer Institute. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer.Methods: Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models.Findings: 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45).Interpretation: Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer.Funding: Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation. [ABSTRACT FROM AUTHOR]

Background: Once-monthly paliperidone palmitate (PP1M) is a long-acting injectable antipsychotic approved for the treatment of schizophrenia and schizoaffective disorder (SCA) in adults., Objective: To assess treatment patterns and schizophrenia/SCA-related hospitalization following payer rejection, patient reversal, or payment of an initial PP1M claim., Methods: This was a retrospective cohort study using the IQVIA Formulary Impact Analyzer database linked to the Medical Claims, Hospital Charge Detail Master, and Experian consumer databases. Patients with schizophrenia/SCA and ≥1 PP1M pharmacy claim from January 1, 2018, to February 28, 2022, were identified and stratified into 3 cohorts based on the transaction status of the initial PP1M claim (index date): rejected (payer not approved), reversed (payer approved, patient abandoned), and paid (payer approved, patient filled). Patient characteristics during the 12 months before the index date, subsequent treatment patterns, and schizophrenia/SCA-related hospitalization for patients with >6 months of follow-up were assessed by cohort., Results: The rejected, reversed, and paid cohorts included 1,260, 1,046, and 1,686 patients, respectively. Across these cohorts, the mean ages ranged between 39.2 and 44.5 years; more than half were male (50.8%-51.6%) and White (50.6%-58.3%); 19.8%-24.6% of patients had a Quan-Charlson Comorbidity Index score of ≥2. Rates of prior atypical oral and long-acting injectable antipsychotic use ranged between 76.4%-80.3% and 7.8%-12.7%, respectively. Among patients with ≥6 months of follow-up, 52.2% in the rejected and 53.1% in the reversed cohorts had a subsequent paid PP1M claim during the study period; the median (quartile 1-quartile 3) time to the first paid PP1M claim was 22 (5-74) days for rejection and 11 (1-41) days for reversal. In the rejected and reversed cohorts, 10.2% (n = 111) and 9.8% (n = 90) of patients, respectively, did not receive any paid claim for an antipsychotic after the initial PP1M rejection/reversal. The prevalence of schizophrenia/SCA-related hospitalization during follow-up was similar between patients with a paid (7.4%) and rejected PP1M claim (7.0%; P = 0.689) but higher among patients with a reversed claim (10.8%; P = 0.004). After adjusting for confounders, patients in the reversed cohort were 39% more likely to have a schizophrenia/SCA-related hospitalization than those in the paid cohort (odds ratio = 1.39; 95% CI = 1.03-1.87)., Conclusions: Payer rejection and patient reversal of initial PP1M claims is a form of primary nonadherence and may influence patient trajectory. Data from this study suggest that patient reversal of PP1M may lead to an increased risk of schizophrenia/SCA-related hospitalizations, potentially caused by missed or delayed treatment. Policy initiatives that remove barriers to primary adherence or fulfillment may help improve patients' clinical outcomes.

This retrospective study was conducted to evaluate all-cause healthcare resource utilization (HCRU) and costs in commercially insured patients living with pulmonary arterial hypertension (PAH) and explore end-of-life (EOL)-related HCRU and costs. Data from the IQVIA PharMetrics® Plus database (October 2014 to May 2020) were analyzed to identify adults (≥18 years) with PAH (PAH cohort) and those without PH (non-PH cohort). Patients were required to have data for ≥12 months before (baseline) and ≥6 months after (follow-up) the first observed PH diagnosis (index date) for PAH cohort or pseudo index date for non-PH cohort. A PAH EOL cohort was similarly constructed using a broader data window (October 2014 to March 2022) and ≥1 month of follow-up. Annualized all-cause HCRU and costs during follow-up were compared between PAH and non-PH cohorts after 1:1 matching on propensity scores derived from patient characteristics. EOL-related HCRU and costs were explored within 30 days and 6 months before the death date and estimated by a claims-based algorithm in PAH EOL cohort. The annual all-cause total ($183,616 vs. $20,212) and pharmacy ($115,926 vs. $7862; both p  < 0.001) costs were 8 and 14 times higher, respectively, in the PAH cohort versus matched non-PH cohort ( N  = 386 for each). In PAH EOL cohort ( N  = 28), the mean EOL-related costs were $48,846 and $167,524 per patient within 30 days and 6 months before the estimated death, respectively. Hospitalizations contributed 58.8%-70.8% of the EOL-related costs. The study findings indicate substantial HCRU and costs for PAH. While pharmacy costs were one of the major sources, hospitalization was the primary driver for EOL-related costs., Competing Interests: T. W., D. R., and D. L. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. A. N., D. T., N. F. S., and X. Z. are employees of IQVIA, Inc., which received consulting fees for conducting this study. N. P. was an employee of IQVIA at the time of study conduct. S. N. has received consulting fees and serves on the advisory board for Merck & Co., Inc., United Therapeutics Corporation, Bellerophon Therapeutics, Third Pole Therapeutics and F. Hoffmann‐La Roche AG., (© 2024 Merck Sharp & Dohme LLC. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Aims: This study described treatment patterns, healthcare resource utilization (HRU) and costs among advanced or metastatic non-small cell lung cancer (a/mNSCLC) patients with different epidermal growth factor receptor ( EGFR) mutation types., Materials and Methods: This retrospective study leveraged NeoGenomics NeoNucleus linked with IQVIA PharMetrics Plus between 01 January 2016 to 30 April 2021 (study period). Patients with evidence of a/mNSCLC between 01 July 2016 to 31 March 2021 (selection window) with EGFR test results indicating exon 19 deletion (exon19del), exon 21 L858R (L858R), or exon 20 insertion (exon20i) mutations were included; date of first observed evidence of a/mNSCLC was the index date. Treatment patterns, all-cause HRU and costs during ≥1 month follow-up were reported for each cohort (exon19del, L858R, and exon20i)., Results: A total of 106 exon19del, 75 L858R, and 13 exon20i patients met the study criteria. The prevalence of hospitalization was highest in the exon20i cohort (76.9%), followed by L858R (62.7%) and exon19del (55.7%) cohorts. A higher proportion of patients had evidence of hospice/end-of-life care in the exon20i (30.8%) and L858R (29.3%) cohorts relative to the exon19del cohort (22.6%). The exon20i cohort had higher median total healthcare costs per patient per month ($27,069) relative to exon19del ($17,482) and L858R ($17,763). EGFR tyrosine kinase inhibitors (TKI) were the most frequently observed treatment type for exon19del and L858R cohorts, while chemotherapy was the most observed treatment in exon20i cohort., Limitations: The sample size for the study cohorts was small, thus no statistical comparisons were conducted., Conclusions: This is one of the first real-world studies to describe HRU and costs among a/mNSCLC patients by specific EGFR mutation type. HRU and costs varied between EGFR mutation types and were highest among exon20i cohort, potentially reflecting higher disease burden and unmet need among patients with this mutation.

Background: Obesity-related complications (ORCs) are associated with high costs for healthcare systems. We assessed the relationship between comorbidity burden, represented by both number and type of 14 specific ORCs, and total healthcare costs over time in people with obesity in the USA., Methods: Adults (≥ 18 years old) identified from linked electronic medical records and administrative claims databases, with a body mass index measurement of 30-< 70 kg/m 2 between 1 January 2007 and 31 March 2012 (earliest measurement: index date), and with continuous enrolment for ≥ 1 year pre index (baseline year) and ≥ 8 years post index, were included. Individuals were grouped by type and number of ORCs during the pre-index baseline year. The primary outcome was annual total adjusted direct per-person healthcare costs., Results: Of 28,583 included individuals, 12,686 had no ORCs, 7242 had one ORC, 4180 had two ORCs and 4475 had three or more ORCs in the baseline year. Annual adjusted direct healthcare costs increased with the number of ORCs and over the 8-year follow-up. Outpatient costs were the greatest contributor to baseline annual direct costs, irrespective of the number of ORCs. For specific ORCs, costs generally increased gradually over the follow-up; the largest percentage increases from year 1 to year 8 were observed for chronic kidney disease (+ 78.8%) and type 2 diabetes (+ 47.8%)., Conclusions: In a US real-world setting, the number of ORCs appears to be a cost driver in people with obesity, from the time of initial obesity classification and for at least the following 8 years., (© 2023. The Author(s).)

Rationale: There is a lack of real-world characterization of healthcare costs and associated cost drivers in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (PH-COPD)., Objectives: To examine (1) excess healthcare resource utilization (HCRU) and associated costs in patients with PH-COPD compared to COPD patients without PH; and (2) patient characteristics that are associated with higher healthcare costs in patients with PH-COPD., Methods: This study analyzed data from the IQVIA PharMetrics ® Plus database (OCT2014-MAY2020). Patients with PH-COPD were identified by a claims-based algorithm based on PH diagnosis (ICD-10-CM: I27.0, I27.2, I27.20, I27.21, I27.23) after COPD diagnosis. Patients aged ≥40 years and with data available ≥12 months before (baseline) and ≥6 months after (follow-up) the first observed PH diagnosis were included. Patients with other non-asthma chronic pulmonary diseases, PH associated with other causes, cancer, left-sided heart failure (HF), PH before the first observed COPD diagnosis, or right-sided/unspecified HF during baseline were excluded. Patients in the PH-COPD cohort were matched 1:1 to COPD patients without PH based on propensity scores derived from baseline patient characteristics. Annualized all-cause and COPD/PH-related (indicated by a primary diagnosis of COPD or PH) HCRU and costs during follow-up were compared between the matched cohorts. Baseline patient characteristics associated with higher total costs were examined in a generalized linear model in the PH-COPD cohort., Results: A total of 2,224 patients with PH-COPD were identified and matched to COPD patients without PH. Patients with PH-COPD had higher all-cause HCRU and annual healthcare costs ($51,435 vs. $18,412, p<0.001) than matched COPD patients without PH. Among patients with PH-COPD, costs were primarily driven by hospitalizations (57%), while COPD/PH-related costs accounted for 13% of all-cause costs. Having a higher comorbidity burden and a prior history of COPD exacerbation were major risk factors for higher total all-cause costs among patients with PH-COPD., Conclusions: Treatment strategies focusing on preventing hospitalizations and managing comorbidities may help reduce the burden of PH-COPD., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates and Steven D. Nathan 2023.)

Objectives: Real-world data evaluating weight changes in people living with HIV (PLWH) following switch to integrase strand transfer inhibitor (INSTI), specifically bictegravir (BIC), are limited. This retrospective cohort study analyzed weight changes upon switching to INSTI from non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) in treatment-experienced PLWH., Methods: Adult PLWH (≥18 years) treated with NNRTI or PI (non-switch cohorts) and those switching to INSTI (switch cohorts) between January 1, 2014 and August 31, 2019 were identified using IQVIA's Ambulatory Electronic Medical Records linked to a prescription drug claims database. The associations of switching to INSTI and individual INSTI agents with having ≥5% weight gain at 12 months of follow-up were evaluated, adjusting for demographics and baseline clinical characteristics., Results: At 12 months of follow-up, PLWH in the NNRTI-INSTI switch cohort ( n  = 508) were more likely to have ≥5% weight gain over 12 months compared to the NNRTI non-switch cohort ( n  = 614; odds ratio, OR [95% CI], 1.7 [1.2-2.4]). Switching from NNRTI to dolutegravir (DTG: OR [95% CI], 2.1 [1.4-3.0]) or BIC (2.0 [1.0-4.2]) resulted in significantly higher odds of ≥5% weight gain. PI-INSTI switch ( n  = 295) and non-switch ( n  = 228) cohorts had similar proportions of PLWH with ≥5% (21.1-23.4%) or ≥10% (7.8-7.9%) weight gain, and no significant association was found between switching from PI to INSTI and weight gain., Conclusion: Weight gain and related metabolic health of PLWH switching from NNRTI to DTG or BIC should be closely monitored by clinicians. Further research is needed to assess other metabolic outcomes in PLWH remaining on PI and those who switch from PI to INSTI.

Background: Treatment guidelines recommend integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) regimens for treatment naïve people living with HIV (PLWH) in the United States (US). This retrospective database study compared weight changes following initiation of INSTI-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based ART in treatment-naïve PLWH., Methods: Adult (≥18 years) PLWH initiated on INSTI, NNRTI, or PI plus ≥2 nucleoside reverse transcriptase inhibitors (NRTI) between 1 January 2014 to 31 August 2019 were identified in IQVIA's Ambulatory Electronic Medical Records (AEMR) linked to prescription drug claims (LRx). Weight changes over up to 36 months (M) of follow-up were compared among PLWH on INSTI- vs. NNRTI- and PI-based ART separately using non-linear mixed effect models, adjusting for demographics and baseline clinical characteristics., Results: The INSTI, NNRTI, and PI cohorts included 931, 245, and 124 PLWH, respectively. For all three cohorts, the majority were male (78.2-81.2%) and overweight/obese (53.6-61.6%) at baseline; 40.8-45.2% of the groups were African American. The INSTI vs. NNRTI/PI cohorts were younger (median age: 38 years vs. 44 years/46 years), had lower weight at ART initiation (mean: 80.9 kg vs. 85.7 kg/85.0 kg), and had higher TAF usage during follow-up (55.6% vs. 24.1%/25.8%; all p  < .05). Multivariate models showed higher weight gain among PLWH in INSTI vs. NNRTI and PI cohorts during treated follow-up (estimated weight gain after 36 M: 7.1 kg vs. 3.8 kg and 3.8 kg, both p  < .05)., Conclusion: Study findings highlight the need to monitor an increase in weight and potential metabolic complications among PLWH starting ART with INSTI.

Introduction: A twice-daily single inhaler triple therapy consisting of budesonide/glycopyrrolate/formoterol fumarate (BGF) was approved by the US Food and Drug Administration (FDA) in July 2020 as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The objective of this AURA study is to describe patient characteristics, exacerbation and treatment history, and healthcare resource utilization (HCRU) before BGF initiation to better inform treatment decisions for prescribers., Methods: This retrospective cohort study leveraged data of all payer types from IQVIA's Longitudinal Prescription Data (LRx) linked to Medical Data (Dx). Patients with COPD who had ⩾1 LRx claim for BGF between 1 October 2020 and 30 September 2021 were included. The date of first BGF claim was the index date. Patient demographic and clinical characteristics, history of COPD exacerbation or related event, treatment history, and HCRU were assessed during the 12 months before index (baseline)., Results: We identified 30,339 patients with COPD initiating BGF (mean age: 68.2 years; 57.1% female; 67.6% Medicare). Unspecified COPD (J44.9; 74.0%) was the most commonly coded COPD phenotype. The most prevalent respiratory conditions/symptoms were dyspnea (50.8%), lower respiratory tract infection (25.3%), and sleep apnea (19.0%). Uncomplicated hypertension (58.8%), dyslipidemia (43.9%), cardiovascular disease (41.4%), and heart failure (19.9%) were the most prevalent nonrespiratory conditions. During the 12-month baseline, 57.9% of patients had evidence of a COPD exacerbation or related event, and 14.9% had ⩾1 COPD-related emergency department (ED) visit; 21.0% of patients had evidence of prior triple therapy use, while 54.3% had ⩾1 oral corticosteroid (OCS) fill. Among OCS users, 29.9% had cumulative exposures >1000 mg [median [Q1-Q3] exposure: 520 (260-1183) mg]., Conclusion: This real-world data analysis indicates that BGF is being initiated in patients with COPD experiencing symptoms and exacerbations despite current therapy, and among patients who have various chronic comorbidities, most often cardiopulmonary-related.

Background: Seasonal influenza poses a substantial clinical and economic burden in the United States and vulnerable populations, including the elderly and those with comorbidities, are at elevated risk for influenza-related medical complications., Methods: We conducted a retrospective cohort study using the IQVIA PharMetrics® Plus claims database in two stages. In Stage 1, we identified patients with evidence of medically-attended influenza during influenza seasons from October 1, 2014 to May 31, 2018 (latest available data for Stage 1) and used a multivariable logistic regression model to identify patient characteristics that predicted 30-day influenza-related hospitalization. The findings from Stage 1 informed high-risk subgroups of interest for Stage 2, where we selected cohorts of influenza patients during influenza seasons from October 1, 2014 to March 1, 2019 and used 1:1 propensity score matching to patients without influenza with similar high-risk characteristics to compare influenza-attributable rates of all-cause hospital and emergency department (ED) visits during follow-up (30-day and in the index influenza season)., Results: In Stage 1, more than 1.6 million influenza cases were identified, of which 18,509 (1.2%) had a hospitalization. Elderly age was associated with 9 times the odds of hospitalization (≥65 years vs. 5-17 years; OR = 9.4, 95% CI 8.8-10.1) and select comorbidities were associated with 2-3 times the odds of hospitalization. In Stage 2, elderly influenza patients with comorbidities had 3 to 7 times higher 30-day hospitalization rates compared to matched patients without influenza, including patients with congestive heart failure (41.0% vs.7.9%), chronic obstructive pulmonary disease (34.6% vs. 6.1%), coronary artery disease (22.8% vs. 3.8%), and late-stage chronic kidney disease (44.1% vs. 13.1%; all p < 0.05)., Conclusions: The risk of influenza-related complications is elevated in the elderly, especially those with certain underlying comorbidities, leading to excess healthcare resource utilization. Continued efforts, beyond currently available vaccines, are needed to reduce influenza burden in high-risk populations., (© 2022. The Author(s).)

Objective: To evaluate societal outcomes including unemployment and homelessness among US veterans with schizophrenia with a history of relapse., Methods: A retrospective cohort study was conducted using US Veterans Health Administration (VHA) data from January 1, 2013, to September 30, 2019. Veterans with ≥ 2 diagnoses of schizophrenia, schizotypal disorder, and/or schizoaffective disorders ( ICD-9-CM 295.xx, ICD-10-CM F20.x, F21, or F25.x) during the study period on different days were identified. The index date was the earliest observed diagnosis. Two cohorts were created and propensity score matched: (1) the relapse cohort of veterans with ≥ 1 prior relapse, defined as hospitalization or emergency department visit associated with a schizophrenia diagnosis during the 12-month preindex period, and (2) the nonrelapse cohort of veterans with no evidence of relapse during the preindex period. The frequencies of unemployment, divorce, homelessness, incarceration, and premature death were compared between matched cohorts using standardized mean difference (SMD ≥ 0.1 indicating imbalance)., Results: Each cohort included 16,862 veterans (92.0% male, 57.0% White, median age of 58-59 years). In the relapse cohort, 67.4% and 42.0% of veterans had a history of substance use disorder and non-schizophrenia mental health disorder, respectively, compared to 43.5% and 23.8% in the matched nonrelapse cohort (both SMD > 0.1). The relapse cohort had a higher frequency of unemployment (75.4% vs 71.4%), divorce (35.6% vs 33.7%), homelessness (38.9% vs 23.7%), incarceration (0.6% vs 0.4%), and premature death (23.3% vs 16.9%) compared to the nonrelapse cohort (all SMD > 0.1)., Conclusions: Schizophrenia relapse is associated with increased adverse societal outcomes in the VHA population., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

This retrospective observational study evaluated outpatient treatment patterns among patients with molecular-based viral diagnostic testing for suspected upper respiratory tract infections in the United States. Patients with a respiratory viral test were identified from 1 August 2016 to 1 July 2019 in a large national reference laboratory database linked to IQVIA's prescription and medical claims databases. Antibiotic and influenza antiviral treatment patterns were reported up to 7 days post-test result. Predictors of antibiotic utilization were assessed using multivariable logistic regression. Among 9561 patients included in the study, 24.6% had evidence of ≥1 filled antibiotic prescription. Antibiotic utilization was higher in patients who tested negative for all viral targets (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.17-1.50) and patients positive for non-influenza viruses (OR, 1.28; 95% CI, 1.09-1.51) compared with those influenza-positive only. Age ≥ 50 years and location outside of the northeast United States also predicted antibiotic utilization. Influenza antivirals were more common in influenza-positive patients compared with patients with other test results (32.5% vs. 3.6-9.0%). Thus, in this real-world study, antibiotic utilization was elevated in patients positive for non-influenza viruses, although antibiotics would generally not be indicated. Further research on pairing diagnostic tools with outpatient antibiotic stewardship programs is needed.

Background: The burden associated with schizophrenia is substantial. Impacts on the individual, healthcare system, and society may be particularly striking within the veteran population due to the presence of physical and mental health comorbidities. Disease burden is also influenced by a complex interplay between social determinants of health and health disparities. The objective of the current study was to compare non-healthcare societal outcomes between veterans with and without schizophrenia in the United States Veterans Health Administration (VHA)., Methods: A retrospective cohort study was conducted using the VHA database (01/2013-09/2019; study period). Veterans with schizophrenia (≥2 diagnoses of ICD-9295.xx, ICD-10 F20.x, F21, and/or F25.x during the study period) were identified; the index date was the earliest observed schizophrenia diagnosis. Veterans with schizophrenia were propensity score-matched to those without schizophrenia using baseline characteristics. A 12-month baseline and variable follow-up period were applied. The frequency of unemployment, divorce, incarceration, premature death, and homelessness were compared between the matched cohorts using standardized mean difference (SMD). Risk of unemployment and homelessness were estimated using logistic regression models., Results: A total of 102,207 veterans remained in each cohort after matching (91% male; 61% White [per AMA]; median age, 59 years). Among veterans with schizophrenia, 42% had a substance use disorder and 30% had mental health-related comorbidities, compared with 25 and 15%, respectively, of veterans without schizophrenia. Veterans with schizophrenia were more likely to experience unemployment (69% vs. 41%; SMD: 0.81), divorce (35% vs. 28%; SMD: 0.67), homelessness (28% vs. 7%; SMD: 0.57), incarceration (0.4% vs. 0.1%; SMD: 0.47), and premature death (14% vs. 12%; SMD < 0.1) than veterans without schizophrenia. After further adjustments, the risk of unemployment and of homelessness were 5.4 and 4.5 times higher among veterans with versus without schizophrenia. Other predictors of unemployment included Black [per AMA] race and history of substance use disorder; for homelessness, younger age (18-34 years) and history of mental health-related comorbidities were additional predictors., Conclusion: A greater likelihood of adverse societal outcomes was observed among veterans with versus without schizophrenia. Given their elevated risk for unemployment and homelessness, veterans with schizophrenia should be a focus of targeted, multifactorial interventions to reduce disease burden., (© 2022. The Author(s).)

Background: This study examined MDD treatment regimens received during the first observed and treated major depressive episode (MDE) among US veterans., Methods: This retrospective study, conducted using the Veterans Health Administration (VHA) database, supplemented with Medicare Part A/B/D data, included adults with ≥1 MDD diagnosis (index date) between 10/1/2015-2/28/2017 and ≥1 line of therapy (LOT) within the first observed complete MDE. Patient baseline (6-month pre-index) characteristics and up to six LOTs received during the first observed and treated MDE were assessed., Results: Of 40,240 veterans with MDD identified (mean age: 50.9 years, 83.9% male, 63.4% White, 88.6% non-Hispanic), hypertension (27.5%), hyperlipidemia (20.8%), and post-traumatic stress disorder (17.5%) were the most common baseline comorbidities. During the first observed and treated MDE, patients received a mean of 1.6 ± 1.0 LOTs, with 14.6% of patients receiving ≥3 LOTs. SSRI-monotherapy was the most commonly observed regimen in the first six LOTs, followed by SNRI-monotherapy in LOT 1 and antidepressants augmented by anticonvulsants in the remaining five LOTs. The antidepressant class of the previous LOT was commonly used in the subsequent LOT. SSRI-SSRI-SSRI was the most common LOT1-to-LOT3 sequencing pattern among patients receiving ≥3 LOTs., Limitations: The study findings are limited to data in the VHA database and may not be generalizable to the non-veteran US population., Conclusions: During the first observed and treated MDE, SSRI-monotherapy was the most common therapy in the first six LOTs. Cycling within SSRI class was the leading sequencing pattern of the first three LOTs among veterans who received ≥3 LOTs., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Biologics have expanded the treatment options in the management of patients with moderate-to-severe psoriasis. The objective of this study was to describe patient characteristics and previous treatments in psoriasis patients newly treated with guselkumab, secukinumab, or ixekizumab., Methods: This retrospective study included patients ≥ 18 years old with psoriasis in the USA who were newly treated with guselkumab, secukinumab, or ixekizumab between 1 July 2017 and 31 March 2019 in the Modernizing Medicine Data Services database (MMDS). Patients were indexed on their first prescription or injection record of guselkumab, secukinumab, or ixekizumab, and three mutually exclusive cohorts were created. Patients were required to have evidence of moderate-to-severe psoriasis, defined as Physician Global Assessment (PGA) score of 3 or 4, or body surface area (BSA) ≥ 10% on index date or within 12 months before index. Baseline characteristics, including treatment history, were reported for each cohort., Results: The study population included 461 guselkumab, 619 secukinumab, and 375 ixekizumab patients. The median age across cohorts was 51-52 years. Median baseline BSA ranged from 15% to 20%; 16.1-29.3% of patients had a PGA of 4 and over half of patients were obese prior to index. Approximately 40% of patients had comorbid cardiovascular disease and 20.8-24.2% of patients had a psychiatric disorder. About half of patients in each cohort had prior biologic use, of which adalimumab was most common (28.2-34.9%) across the cohorts., Conclusion: This real-world study describes the characteristics of patients with moderate-to-severe psoriasis receiving biologic treatments., (© 2022. The Author(s).)

Objectives: To understand real-world implementation of the updated CDC HIV diagnostic testing algorithm., Study Design: Retrospective database analysis., Methods: Using data from Quest Diagnostics, we identified patients with at least 1 HIV-1/HIV-2 antibody differentiation test (BioRad Geenius HIV 1/2 Supplemental Assay [Geenius]) between January 1 and December 31, 2017. Study measures included Health Insurance Portability and Accountability Act-compliant patient demographics, test results, test frequency, and sequence relative to the CDC HIV diagnostic algorithm, including HIV-1 RNA Qualitative Assay (Aptima) or HIV-2 nucleic acid test (NAT)., Results: A total of 26,319 patients were identified (mean [SD] age, 40.7 [14.3] years; 66.4% male), with 28,954 Geenius tests, 7234 Aptima tests, and 298 HIV-2 NATs. In 26.4% of test sequences, the Geenius results were indeterminate or negative and required subsequent confirmatory NATs. A total of 8.5% of patients had more than 1 Geenius test in 2017, and 11.2% of the time, results of the first and second tests differed. A total of 74.2% of test sequences matched the CDC-recommended algorithm., Conclusions: Our study findings suggest that the CDC HIV diagnostic algorithm is complex and may pose suboptimal testing efficiency. Opportunities to improve diagnostic efficiency by reducing indeterminate results and repeat tests are warranted.

Objective: To evaluate frequency, severity and costs of flares in US patients with newly diagnosed SLE., Methods: Adults diagnosed with SLE between January 2005 and December 2014 were identified from US commercial claims data linked to electronic medical records. Disease and flare severity during 1 year after diagnosis were classified as mild, moderate or severe using a claims-based algorithm. Study outcomes included frequency and severity of flares stratified by disease severity during the 1-year post-diagnosis period and all-cause healthcare costs of flares by severity at 30, 60 and 90 days after flare., Results: Among 2227 patients, 26.3%, 51.0% and 22.7% had mild, moderate and severe SLE, respectively. The overall annual flare rate was 3.5 and increased with disease severity: 2.2, 3.7 and 4.2, respectively, for mild, moderate and severe SLE (p<0.0001). Patients with severe SLE had a higher annual severe flare rate (0.6) compared with moderate (0.1) or mild SLE (0; p<0.0001). Mean total all-cause costs at 30, 60 and 90 days after flare were $16 856, $22 252 and $27 468, respectively, for severe flares (mild flares: $1672, $2639 and $3312; moderate flares: $3831, $6225, $8582; (p<0.0001, all time points)). Inpatient costs were the primary driver of the increased cost of severe flares., Conclusions: Flare frequency and severity in newly diagnosed patients with SLE increase with disease severity. After a flare, healthcare costs increase over the following 90 days by disease severity. Preventing flares or reducing flare rates and duration may improve outcomes and reduce healthcare costs., Competing Interests: Competing interests: ERH, BD, XW and MJ are employees of AstraZeneca. AMN is an employee of IQVIA and was paid by AstraZeneca to conduct this research study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the economic burden of patients with SLE by disease severity in the USA 1 year before and after diagnosis., Methods: Patients aged ≥18 years with a first SLE diagnosis (index date) between January 2005 and December 2014 were identified from administrative commercial claims data linked to electronic medical records (EMRs). Disease severity during the year after diagnosis was classified as mild, moderate, or severe using claims-based algorithms and EMR data. Healthcare resource utilisation (HCRU) and all-cause healthcare costs (2017 US$) were reported for 1 year pre-diagnosis and post-diagnosis. Generalised linear modelling examined all-cause costs over 1 year post-index, adjusting for baseline demographics, clinical characteristics, Charlson Comorbidity Index and 1 year pre-diagnosis costs., Results: Among 2227 patients, 26.3% had mild, 51.0% moderate and 22.7% severe SLE. Mean per-patient costs were higher for patients with moderate and severe SLE compared with mild SLE during the year before diagnosis: mild US$12 373, moderate $22 559 and severe US$39 261 (p<0.0001); and 1-year post-diagnosis period: mild US$13 415, moderate US$29 512 and severe US$68 260 (p<0.0001). Leading mean cost drivers were outpatient visits (US$13 566) and hospitalisations (US$10 252). Post-diagnosis inpatient utilisation (≥1 stay) was higher for patients with severe (51.2%) and moderate (22.4%) SLE, compared with mild SLE (12.8%), with longer mean hospital stays: mild 0.47 days, moderate 1.31 days and severe 5.52 days (p<0.0001)., Conclusion: HCRU and costs increase with disease severity in the year before and after diagnosis; leading cost drivers post-diagnosis were outpatient visits and hospitalisations. Earlier diagnosis and treatment may improve health outcomes and reduce HCRU and costs., Competing Interests: Competing interests: MJ, BD, XW and ERH are employees of AstraZeneca. AMN is an employee of IQVIA and was paid by AstraZeneca to conduct this research study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In 2015, Boehringer Ingelheim (BI) created a support program for patients with idiopathic pulmonary fibrosis (IPF) treated with nintedanib, to help patients obtain their prescription, learn about their disease and medication, and provide support in the management of their IPF. The purpose of this study was to measure the impact of the program on nintedanib persistence among patients with IPF newly treated with the medication., Methods: A retrospective cohort analysis of BI Pharmaceuticals, Inc.'s Specialty Pharmacy (SP) database was conducted. Patients at least 18 years of age, newly treated with nintedanib from April 1, 2015 to January 31, 2018, and with at least one diagnosis of IPF were included in the study; earliest nintedanib prescription was the index date. Patients were classified into two mutually exclusive cohorts: enrolled in the patient support program within 60 days of index or not enrolled in the program at any time. The cohorts were compared in terms of patient characteristics, time to nintedanib discontinuation (a gap of more than 60 days between refills), and proportion of persistent patients at 6, 12, 18, and 24 months after index. Time to discontinuation was compared between the cohorts using Kaplan-Meier analysis. A multivariable Cox proportional hazards model assessed the impact of program participation on time to discontinuation within the first 12 months., Results: A total of 3114 enrolled and 9388 non-enrolled patients were identified. The proportion of patients persistent on nintedanib was higher among enrolled patients throughout the post-index period (57.8% vs. 49.7% at 6 months, 34.7% vs. 28.9% at 12 months; p < 0.05). In adjusted analyses, being enrolled in the program was associated with a 21% decreased hazard of discontinuing nintedanib over the first-year post-index [hazard ratio (HR) = 0.79, 95% CI 0.75-0.83, p < 0.05)., Conclusion: Real-world evidence suggests a persistence benefit for patients with IPF treated with nintedanib who are enrolled in the patient support program., (© 2021. The Author(s).)

Objectives: Gonadotropin-releasing hormone analogs are the treatment of choice for central precocious puberty (CPP). This study characterizes patients treated with histrelin implant or leuprolide injection., Methods: A US claims database was used to identify patients aged ≤20 years with ≥1 histrelin or leuprolide claim (index treatment) between April 2010 and November 2017 and continuous enrollment ≥3 months before and ≥12 months after the index treatment date., Results: Overall, 4,217 patients (histrelin, n=1,001; leuprolide, n=3,216) were identified. The percentage of patients with CPP diagnosis was greater in the histrelin (96.5%) vs. leuprolide (68.8%; p<0.0001) cohort. In patients with CPP (histrelin, n=966; leuprolide, n=2,214), mean age at treatment initiation was similar for histrelin (9.0 ± 2.0 years) and leuprolide (9.1 ± 2.3 years), with >50% of patients aged 6-9 years. Mean treatment duration was significantly longer for histrelin (26.7 ± 14.8 months) vs. leuprolide (14.1 ± 12.1 months; p<0.0001), and was longer in younger patient groups. More patients switched from leuprolide to histrelin (12.3%) than vice versa (3.6%; p<0.0001). Median annual total treatment costs were slightly lower for the histrelin cohort ($23,071 [interquartile range, $16,833-$31,050]) than the leuprolide cohort ($27,021 [interquartile range, $18,314-$34,995]; p<0.0001)., Conclusions: Patients with CPP treated with histrelin had a longer duration of treatment, lower rates of index treatment discontinuation, and lower annual treatment costs vs. those treated with leuprolide., (© 2021 Lawrence A. Silverman et al., published by De Gruyter, Berlin/Boston.)

Background: The epidemiologic impact of hereditary angioedema (HAE) is difficult to quantify, due to misclassification in retrospective studies resulting from non-specific diagnostic coding. The aim of this study was to identify cohorts of patients with HAE-1/2 by evaluating structured and unstructured data in a US ambulatory electronic medical record (EMR) database., Methods: A retrospective feasibility study was performed using the GE Centricity EMR Database (2006-2017). Patients with ≥ 1 diagnosis code for HAE-1/2 (International Classification of Diseases, Ninth Revision, Clinical Modification 277.6 or International Classification of Diseases, Tenth Revision, Clinical Modification D84.1) and/or ≥ 1 physician note regarding HAE-1/2 and ≥ 6 months' data before and after the earliest code or note (index date) were included. Two mutually exclusive cohorts were created: probable HAE (≥ 2 codes or ≥ 2 notes on separate days) and suspected HAE (only 1 code or note). The impact of manually reviewing physician notes on cohort formation was assessed, and demographic and clinical characteristics of the 2 final cohorts were described., Results: Initially, 1691 patients were identified: 190 and 1501 in the probable and suspected HAE cohorts, respectively. After physician note review, the confirmed HAE cohort comprised 254 patients and the suspected HAE cohort decreased to 1299 patients; 138 patients were determined not to have HAE and were excluded. The overall false-positive rate for the initial algorithms was 8.2%. Across final cohorts, the median age was 50 years and > 60% of patients were female. HAE-specific prescriptions were identified for 31% and 2% of the confirmed and suspected HAE cohorts, respectively., Conclusions: Unstructured EMR data can provide valuable information for identifying patients with HAE-1/2. Further research is needed to develop algorithms for more representative HAE cohorts in retrospective studies.

Background: Attainment of asthma-specific US Healthcare Effectiveness Data and Information Set (HEDIS) quality measures may be associated with improved clinical outcomes and reduced economic burden., Objective: We examined the relationship between the attainment of HEDIS measures asthma medication ratio (AMR) and medication management for people with asthma (MMA) on clinical and economic outcomes., Methods: This retrospective claims database analysis linked to ambulatory electronic medical records enrolled US patients aged ≥5 years with persistent asthma between May 2015 and April 2017. The attainment of AMR ≥0.5 and MMA ≥75% was determined over a 1-year premeasurement period. Asthma exacerbations and asthma-related health care costs were evaluated during the subsequent 12-month measurement period, comparing patients attaining 1 or both measures with those not attaining either., Results: In total, 32,748 patients were included, 75.2% of whom attained AMR (n = 24,388) and/or MMA (n = 12,042) during the premeasurement period. Fewer attainers of 1 or more HEDIS measures had ≥1 asthma-related hospitalizations, emergency department visit, corticosteroid burst, or exacerbation (4.9% vs 7.3%; 9.6% vs 18.2%; 43.8% vs 51.6%; 14.3% vs 23.3%, respectively; all P < .001) compared with nonattainers. In adjusted analyses, HEDIS attainment was associated with a lower likelihood of exacerbations (odds ratio: 0.63, [95% confidence interval: 0.60-0.67]; P < .001). The attainment of ≥1 HEDIS measures lowered total and asthma-related costs, and asthma exacerbation-related health care costs per patient relative to nonattainers (cost ratio: 0.87, P < .001; 0.96, P = .02; and 0.59, P < .001, respectively). Overall and asthma-specific costs were lower for patients attaining AMR, but not MMA., Conclusions: HEDIS attainment was associated with significantly improved asthma outcomes and lower asthma-specific costs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The aim of this real-world study was to measure the benefit of the Aerobika oscillating positive expiratory pressure (OPEP) device when added to standard of care (defined as incentive spirometry [IS]) for post-operative patients., Methods: Adults aged ≥ 18 years who were hospitalized for cardiac, thoracic or upper abdominal surgery between 1 September 2013 and 30 April 2017 were identified from IQVIA's Hospital Charge Detail Master (CDM) database; the index date was the date of the first hospitalization for surgery. The control cohort (IS) included patients who had ≥ 1 CDM record within 12 months prior to the index date and ≥ 1 record after discharge, evidence of IS use during index hospitalization and no evidence of use of a PEP or OPEP device at any time during the study period. The Aerobika OPEP cohort was selected in a similar manner, except that patients were required to have evidence of Aerobika OPEP use during the index hospitalization. Aerobika OPEP patients were 1:1 matched to IS patients using propensity score (PS) matching. Hospital readmissions and costs were measured at 30 days post-discharge from the index hospitalization., Results: After PS matching, 144 patients were included in each cohort. At 30 days post-discharge, compared to the control (IS) cohort there were significantly fewer patients in the Aerobika OPEP cohort with ≥ 1 all-cause re-hospitalizations (13.9 vs. 22.9%; p = 0.042). The patients in the Aerobika OPEP cohort also had a shorter mean length of stay (± standard deviation) (1.25 ± 4.04 vs. 2.60 ± 8.24 days; p = 0.047) and lower total unadjusted mean all-cause cost per patient ($3670 ± $13,894 vs. $13,775 ± $84,238; p = 0.057). Adjusted analyses suggested that hospitalization costs were 80% lower for the Aerobika OPEP cohort versus the IS cohort (p = 0.001)., Conclusion: Our results suggest that the addition of the Aerobika OPEP device to standard of care (IS) is beneficial in the post-operative setting., Funding: Trudell Medical International.

Background: The Georgetown University-Albert Einstein College of Medicine breast cancer simulation model (Model GE) has evolved over time in structure and function to reflect advances in knowledge about breast cancer, improvements in early detection and treatment technology, and progress in computing resources. This article describes the model and provides examples of model applications., Methods: The model is a discrete events microsimulation of single-life histories of women from multiple birth cohorts. Events are simulated in the absence of screening and treatment, and interventions are then applied to assess their impact on population breast cancer trends. The model accommodates differences in natural history associated with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) biomarkers, as well as conventional breast cancer risk factors. The approach for simulating breast cancer natural history is phenomenological, relying on dates, stage, and age of clinical and screen detection for a tumor molecular subtype without explicitly modeling tumor growth. The inputs to the model are regularly updated to reflect current practice. Numerous technical modifications, including the use of object-oriented programming (C++), and more efficient algorithms, along with hardware advances, have increased program efficiency permitting simulations of large samples., Results: The model results consistently match key temporal trends in US breast cancer incidence and mortality., Conclusion: The model has been used in collaboration with other CISNET models to assess cancer control policies and will be applied to evaluate clinical trial design, recurrence risk, and polygenic risk-based screening.

Background: Since their inception in 2000, the Cancer Intervention and Surveillance Network (CISNET) breast cancer models have collaborated to use a nationally representative core of common input parameters to represent key components of breast cancer control in each model. Employment of common inputs permits greater ability to compare model output than when each model begins with different input parameters. The use of common inputs also enhances inferences about the results, and provides a range of reasonable results based on variations in model structure, assumptions, and methods of use of the input values. The common input data are updated for each analysis to ensure that they reflect the most current practice and knowledge about breast cancer. The common core of parameters includes population rates of births and deaths; age- and cohort-specific temporal rates of breast cancer incidence in the absence of screening and treatment; effects of risk factors on incidence trends; dissemination of plain film and digital mammography; screening test performance characteristics; stage or size distribution of screen-, interval-, and clinically- detected tumors by age; the joint distribution of ER/HER2 by age and stage; survival in the absence of screening and treatment by stage and molecular subtype; age-, stage-, and molecular subtype-specific therapy; dissemination and effectiveness of therapies over time; and competing non-breast cancer mortality., Method and Results: In this paper, we summarize the methods and results for the common input values presently used in the CISNET breast cancer models, note assumptions made because of unobservable phenomena and/or unavailable data, and highlight plans for the development of future parameters., Conclusion: These data are intended to enhance the transparency of the breast CISNET models.

Importance: Given recent advances in screening mammography and adjuvant therapy (treatment), quantifying their separate and combined effects on US breast cancer mortality reductions by molecular subtype could guide future decisions to reduce disease burden., Objective: To evaluate the contributions associated with screening and treatment to breast cancer mortality reductions by molecular subtype based on estrogen-receptor (ER) and human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)., Design, Setting, and Participants: Six Cancer Intervention and Surveillance Network (CISNET) models simulated US breast cancer mortality from 2000 to 2012 using national data on plain-film and digital mammography patterns and performance, dissemination and efficacy of ER/ERBB2-specific treatment, and competing mortality. Multiple US birth cohorts were simulated., Exposures: Screening mammography and treatment., Main Outcomes and Measures: The models compared age-adjusted, overall, and ER/ERBB2-specific breast cancer mortality rates from 2000 to 2012 for women aged 30 to 79 years relative to the estimated mortality rate in the absence of screening and treatment (baseline rate); mortality reductions were apportioned to screening and treatment., Results: In 2000, the estimated reduction in overall breast cancer mortality rate was 37% (model range, 27%-42%) relative to the estimated baseline rate in 2000 of 64 deaths (model range, 56-73) per 100 000 women: 44% (model range, 35%-60%) of this reduction was associated with screening and 56% (model range, 40%-65%) with treatment. In 2012, the estimated reduction in overall breast cancer mortality rate was 49% (model range, 39%-58%) relative to the estimated baseline rate in 2012 of 63 deaths (model range, 54-73) per 100 000 women: 37% (model range, 26%-51%) of this reduction was associated with screening and 63% (model range, 49%-74%) with treatment. Of the 63% associated with treatment, 31% (model range, 22%-37%) was associated with chemotherapy, 27% (model range, 18%-36%) with hormone therapy, and 4% (model range, 1%-6%) with trastuzumab. The estimated relative contributions associated with screening vs treatment varied by molecular subtype: for ER+/ERBB2-, 36% (model range, 24%-50%) vs 64% (model range, 50%-76%); for ER+/ERBB2+, 31% (model range, 23%-41%) vs 69% (model range, 59%-77%); for ER-/ERBB2+, 40% (model range, 34%-47%) vs 60% (model range, 53%-66%); and for ER-/ERBB2-, 48% (model range, 38%-57%) vs 52% (model range, 44%-62%)., Conclusions and Relevance: In this simulation modeling study that projected trends in breast cancer mortality rates among US women, decreases in overall breast cancer mortality from 2000 to 2012 were associated with advances in screening and in adjuvant therapy, although the associations varied by breast cancer molecular subtype.

Background: There are no publicly available tools designed specifically to assist policy makers to make informed decisions about the optimal ages of breast cancer screening initiation for different populations of US women., Objective: To use three established simulation models to develop a web-based tool called Mammo OUTPuT., Methods: The simulation models use the 1970 US birth cohort and common parameters for incidence, digital screening performance, and treatment effects. Outcomes include breast cancers diagnosed, breast cancer deaths averted, breast cancer mortality reduction, false-positive mammograms, benign biopsies, and overdiagnosis. The Mammo OUTPuT tool displays these outcomes for combinations of age at screening initiation (every year from 40 to 49), annual versus biennial interval, lifetime versus 10-year horizon, and breast density, compared to waiting to start biennial screening at age 50 and continuing to 74. The tool was piloted by decision makers (n = 16) who completed surveys., Results: The tool demonstrates that benefits in the 40s increase linearly with earlier initiation age, without a specific threshold age. Likewise, the harms of screening increase monotonically with earlier ages of initiation in the 40s. The tool also shows users how the balance of benefits and harms varies with breast density. Surveys revealed that 100% of users (16/16) liked the appearance of the site; 94% (15/16) found the tool helpful; and 94% (15/16) would recommend the tool to a colleague., Conclusions: This tool synthesizes a representative subset of the most current CISNET (Cancer Intervention and Surveillance Modeling Network) simulation model outcomes to provide policy makers with quantitative data on the benefits and harms of screening women in the 40s. Ultimate decisions will depend on program goals, the population served, and informed judgments about the weight of benefits and harms.

Background: Biennial screening is generally recommended for average-risk women aged 50 to 74 years, but tailored screening may provide greater benefits., Objective: To estimate outcomes for various screening intervals after age 50 years based on breast density and risk for breast cancer., Design: Collaborative simulation modeling using national incidence, breast density, and screening performance data., Setting: United States., Patients: Women aged 50 years or older with various combinations of breast density and relative risk (RR) of 1.0, 1.3, 2.0, or 4.0., Intervention: Annual, biennial, or triennial digital mammography screening from ages 50 to 74 years (vs. no screening) and ages 65 to 74 years (vs. biennial digital mammography from ages 50 to 64 years)., Measurements: Lifetime breast cancer deaths, life expectancy and quality-adjusted life-years (QALYs), false-positive mammograms, benign biopsy results, overdiagnosis, cost-effectiveness, and ratio of false-positive results to breast cancer deaths averted., Results: Screening benefits and overdiagnosis increase with breast density and RR. False-positive mammograms and benign results on biopsy decrease with increasing risk. Among women with fatty breasts or scattered fibroglandular density and an RR of 1.0 or 1.3, breast cancer deaths averted were similar for triennial versus biennial screening for both age groups (50 to 74 years, median of 3.4 to 5.1 vs. 4.1 to 6.5 deaths averted; 65 to 74 years, median of 1.5 to 2.1 vs. 1.8 to 2.6 deaths averted). Breast cancer deaths averted increased with annual versus biennial screening for women aged 50 to 74 years at all levels of breast density and an RR of 4.0, and those aged 65 to 74 years with heterogeneously or extremely dense breasts and an RR of 4.0. However, harms were almost 2-fold higher. Triennial screening for the average-risk subgroup and annual screening for the highest-risk subgroup cost less than $100 000 per QALY gained., Limitation: Models did not consider women younger than 50 years, those with an RR less than 1, or other imaging methods., Conclusion: Average-risk women with low breast density undergoing triennial screening and higher-risk women with high breast density receiving annual screening will maintain a similar or better balance of benefits and harms than average-risk women receiving biennial screening., Primary Funding Source: National Cancer Institute.

Background: Controversy persists about optimal mammography screening strategies., Objective: To evaluate screening outcomes, taking into account advances in mammography and treatment of breast cancer., Design: Collaboration of 6 simulation models using national data on incidence, digital mammography performance, treatment effects, and other-cause mortality., Setting: United States., Patients: Average-risk U.S. female population and subgroups with varying risk, breast density, or comorbidity., Intervention: Eight strategies differing by age at which screening starts (40, 45, or 50 years) and screening interval (annual, biennial, and hybrid [annual for women in their 40s and biennial thereafter]). All strategies assumed 100% adherence and stopped at age 74 years., Measurements: Benefits (breast cancer-specific mortality reduction, breast cancer deaths averted, life-years, and quality-adjusted life-years); number of mammograms used; harms (false-positive results, benign biopsies, and overdiagnosis); and ratios of harms (or use) and benefits (efficiency) per 1000 screens., Results: Biennial strategies were consistently the most efficient for average-risk women. Biennial screening from age 50 to 74 years avoided a median of 7 breast cancer deaths versus no screening; annual screening from age 40 to 74 years avoided an additional 3 deaths, but yielded 1988 more false-positive results and 11 more overdiagnoses per 1000 women screened. Annual screening from age 50 to 74 years was inefficient (similar benefits, but more harms than other strategies). For groups with a 2- to 4-fold increased risk, annual screening from age 40 years had similar harms and benefits as screening average-risk women biennially from 50 to 74 years. For groups with moderate or severe comorbidity, screening could stop at age 66 to 68 years., Limitation: Other imaging technologies, polygenic risk, and nonadherence were not considered., Conclusion: Biennial screening for breast cancer is efficient for average-risk populations. Decisions about starting ages and intervals will depend on population characteristics and the decision makers' weight given to the harms and benefits of screening., Primary Funding Source: National Institutes of Health., Competing Interests: Potential Conflicts of Interest: None disclosed

Purpose: BRCA1/2 counseling and mutation testing is recommended for high-risk women, but geographic barriers exist, and no data on the costs and yields of diverse delivery approaches are available., Methods: We performed an economic evaluation with a randomized clinical trial comparing telephone versus in-person counseling at 14 locations (nine geographically remote). Costs included fixed overhead, variable staff, and patient time costs; research costs were excluded. Outcomes included average per-person costs for pretest counseling; mutations detected; and overall counseling, testing, and disclosure. Sensitivity analyses were performed to assess the impact of uncertainty., Results: In-person counseling was more costly per person counseled than was telephone counseling ($270 [range, $180 to $400] v $120 [range, $80 to $200], respectively). Counselors averaged 285 miles round-trip to deliver in-person counseling to the participants (three participants per session). There were no differences by arm in mutation detection rates (approximately 10%); therefore, telephone counseling was less costly per positive mutation detected than was in-person counseling ($37,160 [range, $36,080 to$38,920] v $40,330 [range, $38,010 to $43,870]). In-person counseling would only be less costly than telephone counseling if the most favorable assumptions were applied to in personc ounseling and the least favorable assumptions were applied to telephone counseling., Conclusion: In geographically underserved areas, telephone counseling is less costly than in-person counseling., (Copyright © 2016 by American Society of Clinical Oncology.)

Introduction: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides mammograms and diagnostic services for low-income, uninsured women aged 40-64 years. Mammography facilities within the NBCCEDP gradually shifted from plain-film to digital mammography. The purpose of this study is to assess the impact of replacing film with digital mammography on health effects (deaths averted, life-years gained [LYG]); costs (for screening and diagnostics); and number of women reached., Methods: NBCCEDP 2010 data and data representative of the program's target population were used in two established microsimulation models. Models simulated observed screening behavior including different screening intervals (annual, biennial, irregular) and starting ages (40, 50 years) for white, black, and Hispanic women. Model runs were performed in 2012., Results: The models predicted 8.0-8.3 LYG per 1,000 film screens for black women, 5.9-7.5 for white women, and 4.0-4.5 for Hispanic women. For all race/ethnicity groups, digital mammography had more LYG than film mammography (2%-4%), but had higher costs (34%-35%). Assuming a fixed budget, 25%-26% fewer women could be served, resulting in 22%-24% fewer LYG if all mammograms were converted to digital. The loss in LYG could be reversed to an 8%-13% increase by only including biennial screening., Conclusions: Digital could result in slightly more LYG than film mammography. However, with a fixed budget, fewer women may be served with fewer LYG. Changes in the program, such as only including biennial screening, will increase LYG/screen and could offset the potential decrease in LYG when shifting to digital mammography., (Copyright © 2015 American Journal of Preventive Medicine. All rights reserved.)

Background: Molecular characterization of breast cancer allows subtype-directed interventions. Estrogen receptor (ER) is the longest-established molecular marker., Methods: We used six established population models with ER-specific input parameters on age-specific incidence, disease natural history, mammography characteristics, and treatment effects to quantify the impact of screening and adjuvant therapy on age-adjusted US breast cancer mortality by ER status from 1975 to 2000. Outcomes included stage-shifts and absolute and relative reductions in mortality; sensitivity analyses evaluated the impact of varying screening frequency or accuracy., Results: In the year 2000, actual screening and adjuvant treatment reduced breast cancer mortality by a median of 17 per 100000 women (model range = 13-21) and 5 per 100000 women (model range = 3-6) for ER-positive and ER-negative cases, respectively, relative to no screening and no adjuvant treatment. For ER-positive cases, adjuvant treatment made a higher relative contribution to breast cancer mortality reduction than screening, whereas for ER-negative cases the relative contributions were similar for screening and adjuvant treatment. ER-negative cases were less likely to be screen-detected than ER-positive cases (35.1% vs 51.2%), but when screen-detected yielded a greater survival gain (five-year breast cancer survival = 35.6% vs 30.7%). Screening biennially would have captured a lower proportion of mortality reduction than annual screening for ER-negative vs ER-positive cases (model range = 80.2%-87.8% vs 85.7%-96.5%)., Conclusion: As advances in risk assessment facilitate identification of women with increased risk of ER-negative breast cancer, additional mortality reductions could be realized through more frequent targeted screening, provided these benefits are balanced against screening harms., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: This study examines the effect of past tobacco control policies and projects the effect of future policies on smoking and snus use prevalence and associated premature mortality in Sweden., Methods: The established SimSmoke model was adapted with population, smoking rates and tobacco control policy data from Sweden. SimSmoke evaluates the effect of taxes, smoke-free air, mass media, marketing bans, warning labels, cessation treatment and youth access policies on smoking and snus prevalence and the number of deaths attributable to smoking and snus use by gender from 2010 to 2040., Results: Sweden SimSmoke estimates that significant inroads to reducing smoking and snus prevalence and premature mortality can be achieved through tax increases, especially when combined with other policies. Smoking prevalence can be decreased by as much as 26% in the first few years, reaching a 37% reduction within 30 years. Without effective tobacco control policies, almost 54 500 lives will be lost in Sweden due to tobacco use by the year 2040., Conclusion: Besides presenting the benefits of a comprehensive tobacco control strategy, the model identifies gaps in surveillance and evaluation that can help better focus tobacco control policy in Sweden., (© The Author 2013. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: US breast cancer mortality is declining, but thousands of women still die each year., Methods: Two established simulation models examine 6 strategies that include increased screening and/or treatment or elimination of obesity versus continuation of current patterns. The models use common national data on incidence and obesity prevalence, competing causes of death, mammography characteristics, treatment effects, and survival/cure. Parameters are modified based on obesity (defined as BMI  ≥  30 kg/m(2) ). Outcomes are presented for the year 2025 among women aged 25+ and include numbers of cases, deaths, mammograms and false-positives; age-adjusted incidence and mortality; breast cancer mortality reduction and deaths averted; and probability of dying of breast cancer., Results: If current patterns continue, the models project that there would be about 50,100-57,400 (range across models) annual breast cancer deaths in 2025. If 90% of women were screened annually from ages 40 to 54 and biennially from ages 55 to 99 (or death), then 5100-6100 fewer deaths would occur versus current patterns, but incidence, mammograms, and false-positives would increase. If all women received the indicated systemic treatment (with no screening change), then 11,400-14,500 more deaths would be averted versus current patterns, but increased toxicity could occur. If 100% received screening plus indicated therapy, there would be 18,100-20,400 fewer deaths. Eliminating obesity yields 3300-5700 fewer breast cancer deaths versus continuation of current obesity levels., Conclusions: Maximal reductions in breast cancer deaths could be achieved through optimizing treatment use, followed by increasing screening use and obesity prevention., (© 2013 American Cancer Society.)

Obesity affects multiple points along the breast cancer control continuum from prevention to screening and treatment, often in opposing directions. Obesity is also more prevalent in Blacks than Whites at most ages so it might contribute to observed racial disparities in mortality. We use two established simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate the impact of obesity on race-specific breast cancer outcomes. The models use common national data to inform parameters for the multiple US birth cohorts of Black and White women, including age- and race-specific incidence, competing mortality, mammography characteristics, and treatment effectiveness. Parameters are modified by obesity (BMI of ≥ 30 kg/m(2)) in conjunction with its age-, race-, cohort- and time-period-specific prevalence. We measure age-standardized breast cancer incidence and mortality and cases and deaths attributable to obesity. Obesity is more prevalent among Blacks than Whites until age 74; after age 74 it is more prevalent in Whites. The models estimate that the fraction of the US breast cancer cases attributable to obesity is 3.9-4.5 % (range across models) for Whites and 2.5-3.6 % for Blacks. Given the protective effects of obesity on risk among women <50 years, elimination of obesity in this age group could increase cases for both the races, but decrease cases for women ≥ 50 years. Overall, obesity accounts for 4.4-9.2 % and 3.1-8.4 % of the total number of breast cancer deaths in Whites and Blacks, respectively, across models. However, variations in obesity prevalence have no net effect on race disparities in breast cancer mortality because of the opposing effects of age on risk and patterns of age- and race-specific prevalence. Despite its modest impact on breast cancer control and race disparities, obesity remains one of the few known modifiable risks for cancer and other diseases, underlining its relevance as a public health target.

Background: Black women in the District of Columbia (DC) have the highest breast cancer mortality in the US. Local cancer control planners are interested in how to most efficiently reduce this mortality., Methods: An established simulation model was adapted to reflect the experiences of Black women in DC and estimate the past and future impact of changes in use of screening and adjuvant treatment., Results: The model estimates that the observed reduction in mortality that occurred from 1975 to 2007 attributable to screening, treatment, and both was 20.2%, 25.7%, and 41.0% respectively. The results suggest that, by 2020, breast cancer mortality among Black women in DC could be reduced by 6% more by initiating screening at age 40 vs. age 50. Screening annually may also reduce mortality to a greater extent than biennially, albeit with a marked increase in false positive screening rates., Conclusion: This study demonstrates how modeling can provide data to assist local planners as they consider different cancer control policies based on their individual populations.

Objective: To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism and the PROGINS allele., Design: Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies., Setting: An international ovarian cancer consortium including studies from Australia, Europe, and the United States., Patient(s): Five thousand eight hundred twelve white female controls, of whom 348 had endometriosis, from eight ovarian cancer case-control studies., Intervention(s): None., Main Outcome Measure(s): Genotypes for the +331C/T single nucleotide polymorphism and PROGINS allele and a history of endometriosis., Result(s): The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (odds ratio=0.65; 95% confidence interval: 0.43-0.98), whereas there was no association between the PROGINS allele and endometriosis (odds ratio=0.94, 95% confidence interval 0.76-1.16)., Conclusion(s): Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced progesterone (P) receptor A to P receptor B ratio, and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease., (Copyright © 2011. Published by Elsevier Inc.)

Background: U.S. Black women have higher breast cancer mortality rates than White women despite lower incidence. The aim of this study is to investigate how much of the mortality disparity can be attributed to racial differences in natural history, uptake of mammography screening, and use of adjuvant therapy., Methods: Two simulation models use common national race, and age-specific data for incidence, screening and treatment dissemination, stage distributions, survival, and competing mortality from 1975 to 2010. Treatment effectiveness and mammography sensitivity are assumed to be the same for both races. We sequentially substituted Black parameters into the White model to identify parameters that drive the higher mortality for Black women in the current time period., Results: Both models accurately reproduced observed breast cancer incidence, stage and tumor size distributions, and breast cancer mortality for White women. The higher mortality for Black women could be attributed to differences in natural history parameters (26-44%), use of adjuvant therapy (11-19%), and uptake of mammography screening (7-8%), leaving 38% to 46% unexplained., Conclusion: Black women appear to have benefited less from cancer control advances than White women, with a greater race-related gap in the use of adjuvant therapy than screening. However, a greater portion of the disparity in mortality appears to be due to differences in natural history and undetermined factors., Impact: Breast cancer mortality may be reduced substantially by ensuring that Black women receive equal adjuvant treatment and screening as White women. More research on racial variation in breast cancer biology and treatment utilization is needed., (©2011 AACR.)

Studies indicate that estrogen receptor beta, encoded by the ESR2 gene on chromosome 14q, may play a role in ovarian carcinogenesis. Using the genetic structure data generated by the Breast and Prostate Cohort Consortium (BPC3), we have comprehensively characterized the role of haplotype diversity in ESR2 and risk of ovarian cancer. Five haplotypes with a frequency of > or =5% were observed in White subjects and five haplotype tagging SNPs (htSNP) were selected to capture the locus diversity with a minimum R(h)(2) of 0.81. The htSNPs were genotyped in 574 White controls, 417 White invasive ovarian cancer cases, and 123 White borderline ovarian cancer cases from case-control studies carried out in Los Angeles County from 1994 through 2004. No statistically significant association was observed between the five htSNPs and related haplotypes and risk of ovarian cancer overall. Haplotype D was associated with a nonstatistically significant increased risk of invasive ovarian cancer overall (odds ratio, 1.38; 95% confidence interval, 0.93-2.02; P = 0.11) relative to the most common haplotype and a statistically significant increased risk of invasive clear cell ovarian cancer (odds ratio, 3.88; 95% confidence interval, 1.28-11.73; P = 0.016). Haplotype D was also reported by the BPC3 to be associated with increased risk of breast cancer. This haplotype warrants further investigation to rule out any effect with invasive ovarian cancer risk.