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Background: Evidence shows underutilization of cancer genetics services. To explore the reasons behind this underutilization, this study evaluated characteristics of women who were referred for genetic counseling and/or had undergone BRCA1/2 testing. Methods: An ovarian cancer risk perception study stratified 16,720 eligible women from the Henry Ford Health System into average-, elevated-, and high-risk groups based on family history. We randomly selected 3,307 subjects and interviewed 2,524 of them (76.3% response rate). Results: Among the average-, elevated-, and high-risk groups, 2.3, 10.1, and 20.2%, respectively, reported genetic counseling referrals, and 0.8, 3.3, and 9.5%, respectively, reported having undergone BRCA testing. Personal breast cancer history, high risk, and perceived ovarian cancer risk were associated with both referral and testing. Discussion of family history with a doctor predicted counseling referral, whereas belief that family history influenced risk was the strongest BRCA testing predictor. Women perceiving their cancer risk as much higher than other women their age were twice as likely (95% confidence interval: 2.0–9.6) to report genetic counseling referral. Conclusion: In a health system with ready access to cancer genetic counseling and BRCA testing, women who were at high risk underutilized these services. There were strong associations between perceived ovarian cancer risk and genetic counseling referral, and between a belief that family history influenced risk and BRCA testing. Genet Med advance online publication 19 June 2014

Background: To assess value, industry organizations often use list or net prices to calculate average prices per patient or price per QALY. However, this methodology requires numerous assumptions which need to be validated and can be challenging to ascertain. A better approach is to use fully adjudicated net prices and real-world clinical outcomes data for value assessments. Aims: We sought to demonstrate the impact on value analyses of using list vs. net prices. Methods: Using the IBM Access and Value Connect solution, patients in the IBM MarketScan Commercial Database between 1 October 2016 and 30 September 2017 with a psoriasis diagnosis were identified. To demonstrate an example of impact on value assessments, we calculated the mean per-patient-per-month (PPPM) cost associated with apremilast and compared that to the net price calculation reported in the 2018 Plaque Psoriasis Condition Update by the Institute for Clinical and Economic Review (ICER), based on per-unit dosing and discount assumptions. Results: We identified 4169 patients with a psoriasis diagnosis during the study period. The adjudicated claims PPPM cost for US health plans was $20,821 with a mean duration of exposure to apremilast of 243 days and including concomitant psoriasis medications. This is approximately $10,000 less than the net price presented in the 2018 ICER report ($30,807 Year 1, $31,018 Year 2) . Numerous additional differences between the real-world performance data and ICER evidence report were identified. Conclusions: Our analysis found that using a fully adjudicated net price: (1) allowed direct comparison of prices amongst therapies quickly and easily; and (2) facilitated a more accurate reflection of price versus value when used alongside analysis of the real-world clinical outcomes data. We recommend that net prices and real-world data be used for value assessments whenever possible. Value assessment organizations should incorporate the numerous data sets and tools available to improve transparency, accuracy and ease of analysis.

Introduction Identification of adverse events and determination of their seriousness ensures timely detection of potential patient safety concerns. Adverse event seriousness is a key factor in defining reporting timelines and is often performed manually by pharmacovigilance experts. The dramatic increase in the volume of safety reports necessitates exploration of scalable solutions that also meet reporting timeline requirements. Objective The aim of this study was to develop an augmented intelligence methodology for automatically identifying adverse event seriousness in spontaneous, solicited, and medical literature safety reports. Deep learning models were evaluated for accuracy and/or the F1 score against a ground truth labeled by pharmacovigilance experts. Methods Using a stratified random sample of safety reports received by Celgene, we developed three neural networks for addressing identification of adverse event seriousness: (1) a binary adverse-event level seriousness classifier; (2) a classifier for determining seriousness categorization at the adverse-event level; and (3) an annotator for identifying seriousness criteria terms to provide supporting evidence at the document level. Results The seriousness classifier achieved an accuracy of 83.0% in post-marketing reports, 92.9% in solicited reports, and 86.3% in medical literature reports. F1 scores for seriousness categorization were 77.7 for death, 78.9 for hospitalization, and 75.5 for important medical events. The seriousness annotator achieved an F1 score of 89.9 in solicited reports, and 75.2 in medical literature reports. Conclusions The results of this study indicate that a neural network approach can provide an accurate and scalable solution for potentially augmenting pharmacovigilance practitioner determination of adverse event seriousness in spontaneous, solicited, and medical literature reports.

The identification of women with early-stage breast cancer who will develop distant metastasis may improve clinical management. The transcriptional regulator Enhancer of Zeste-2 (EZH2) is overexpressed in invasive breast carcinoma compared with benign breast tissues, with maximal expression in breast cancer metastasis. In this article, our purpose was to investigate the performance of EZH2 protein detection as a predictor of metastasis in women with early-stage breast cancer, which is unknown. We developed a cohort of 480 women with stage I–IIA breast cancer diagnosed between 1996 and 2002 and recorded detailed sociodemographic, clinical, and pathological information. Tumors were histologically characterized and arrayed in tissue microarrays containing 1,443 samples. The nuclear EZH2 expression was investigated by immunohistochemistry and was scored as 1–2 (negative and weak) or 3–4 (moderate and strong) using a validated scoring schema. Scores 1–2 were considered low EZH2; scores 3–4 were considered high EZH2. In this study, we found that after a median follow up of 9 years (range 0.04–14.5 years) 46 of 480 patients (9.6%) developed distant metastasis. High EZH2 was associated with larger size, high histological grade, negative hormone receptors, and first degree family history of breast and/or ovarian carcinoma. While EZH2 could not predict survival in the entire cohort, high EZH2 was a predictor of disease-specific survival in patients with early-stage disease and first degree family history (log rank P value 0.05). Importantly, in this group of patients, high EZH2 was an independent predictor of distant metastasis up to 15 years after primary carcinoma diagnosis (hazard ratio 6.58, 95% CI: 1.40–30.89, P  = 0.016) providing survival information above and beyond currently used prognosticators. In conclusion, EZH2 may be a useful biomarker of long-term metastatic risk in women with familial early-stage breast cancer, and warrant further validation studies.

Background This study examined predictors and behaviors of pregnancy-related smoking among women who belonged to a private health maintenance organization and the recall accuracy of pregnancy-related smoking behaviors after 6-years. Methods A cohort of 725 pregnant women was followed for six years. Major predictors for smoking behavior before, during, and one-year following pregnancy were determined. In addition, accuracy of recall six years postpartum of smoking behavior at the time of pregnancy and one-year postpartum was tested. Results Mother’s education, asthma status, amount of pre-pregnancy smoking, gravidity, and father’s smoking status were important in the prediction of pregnancy associated smoking. Agreement for recall of smoking behavior during pregnancy (6 year recall) and one-year postpartum (5 year recall) were 90% and 91%, respectively. Conclusions Despite potentially adverse outcomes, a proportion of women continue to smoke throughout pregnancy. A number of variables proved to be important predictors of pregnancy associated smoking behavior. These factors should be considered by smoking cessation programs targeting women of reproductive age. Additionally, there was substantial agreement for maternal recall at six years postpartum of smoking behavior at the time of pregnancy and one-year postpartum. This should be considered in retrospective study designs that are primarily based on maternal recall of smoking behaviors before, during, and following pregnancy.

Background Acquisition of metabolic alterations has been shown to be essential for the unremitting growth of cancer, yet the relation of such alterations to chemosensitivity has not been investigated. In the present study our aim was to identify the metabolic alterations that are specifically associated with platinum resistance in ovarian cancer. A global metabolic analysis of the A2780 platinum-sensitive and its platinum-resistant derivative C200 ovarian cancer cell line was performed utilizing ultra-high performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy. Per-metabolite comparisons were made between cell lines and an interpretive analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic library and the Ingenuity exogenous molecule library. Results We observed 288 identified metabolites, of which 179 were found to be significantly different ( t -test p < 0.05) between A2780 and C200 cells. Of these, 70 had increased and 109 had decreased levels in platinum resistant C200 cells. The top altered KEGG pathways based on number or impact of alterations involved the cysteine and methionine metabolism. An Ingenuity Pathway Analysis also revealed that the methionine degradation super-pathway and cysteine biosynthesis are the top two canonical pathways affected. The highest scoring network of altered metabolites was related to carbohydrate metabolism, energy production, and small molecule biochemistry. Compilation of KEGG analysis and the common network molecules revealed methionine and associated pathways of glutathione synthesis and polyamine biosynthesis to be most significantly altered. Conclusion Our findings disclose that the chemoresistant C200 ovarian cancer cells have distinct metabolic alterations that may contribute to its platinum resistance. This distinct metabolic profile of platinum resistance is a first step towards biomarker development for the detection of chemoresistant disease and metabolism-based drug targets specific for chemoresistant tumors.

Background: Evaluating changes to historical treatment costs is critical for healthcare professionals to make informed business decisions. However, real-world clinical and cost outcome data is challenging to use regularly without significant data science knowledge or resources. Aims: This study sought to demonstrate the potential value in user-friendly analytics tools to identify drivers of costs and outcomes. Methods: The IBM Access and Value Connect solution was used to analyze a patient cohort of metastatic breast cancer (mBC) patients treated in the most recent 12, 36, and 60 months in the IBM MarketScan; Commercial and Medicare Supplement Database. We used the interactive visual explorer tool to quickly (<15 min) determine the mean total per-patient-per-month (PPPM) cost associated with mBC overall and for select side-effects by age group (45-54, 55-64, 65-74, and 75+), and generated histograms for mean total PPPM overall and for leukopenia and neutropenia by age group for each study period. Results: The mean total PPPM across all mBC patients ranged from $6,562 for the 75+ age group at 60 months to $14,201 for the 45-54 age group at 12 months. For those who experienced leukopenia, the mean total PPPM ranged from $10,319 for the 75+ age group at 60 months to $19,598 for the 45-55 age group at 60 months. Similarly, for those who experienced neutropenia, the mean total PPPM ranged from $10,593 for the 65-74 age group at 60 months to $21,784 for the 45-54 age group at 12 months. Conclusions: These methods show that it is possible to make PPPM costs easily available without data science, clinical, or programming knowledge with interactive, visual analytics. The results showed that in general PPPM costs are higher for younger patients overall and among those who experience leukopenia or neutropenia. This is likely due to the practice to aggressively treat younger patients.

Purpose Many studies suggest a role for cholesterol in cancer development. Serum cholesterol levels have been observed to be low in newly diagnosed lymphoma cases. The objective of these analyses was to examine the time-varying relationship of cholesterol with lymphomagenesis in the 10 years prior to diagnosis by lymphoma subtype. Methods Participants were selected from the combined membership of six National Cancer Institute-funded Cancer Research Network health plans from 1998 to 2008, excluding members with human immunodeficiency virus, cancer (except lymphoma), or organ transplants. Incident lymphoma cases within this population were ascertained and matched with up to five controls. Total serum cholesterol, high-density lipoprotein, and low-density lipoprotein were collected from plan databases. Multilevel, multivariable longitudinal models were fit after choosing the best polynomial order by deviance statistics for selected lymphoma histotypes to examine pre-diagnosis cholesterol trajectories: Hodgkin lymphoma ( n  = 519) and all non-Hodgkin lymphomas combined ( n  = 12,635) as well as six subtypes of the latter. Results For all categories, lymphoma cases had statistically significantly lower estimated total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels than controls in the years prior to diagnosis/index date. Between-group differences were most pronounced 3–4 years prior to diagnosis, when cases’ cholesterol levels declined steeply. Conclusions This analysis is the first to examine changes in serum cholesterol for a decade prior to lymphoma diagnosis. A drop in cholesterol levels was evident several years before diagnosis. Our results suggest that cholesterol-related pathways have an important relationship with lymphomagenesis and low cholesterol could be a preclinical lymphoma marker.

Background: Advances in technology have made individual access to personal genetic information foreseeable in the near future. Policy makers and the media forecast that the ready availability of personal genetic profiles would benefit both the individual and the health care system by improving outcomes and decreasing cost. However, there is a significant gap between having access to genetic data and either wanting or understanding the information it provides. Objective: Our primary aim was to evaluate, using a population-based sample of healthy adults, whether gender, race and education status influences interest and participation in a multiplex genetic susceptibility test. Methods: Healthy, insured individuals, 25–40 years of age, were approached via a large, integrated health system in which primary and specialty care is available. Study participants were offered personalized genetic risk information on 8 common chronic health conditions. Social groups historically known not to participate in genetic research (men, African Americans and those from lower education neighborhoods) were oversampled. We describe the recruitment outcomes and testing decisions of these social groups. Results: We found that even among those with access to health care, African Americans were less likely to participate in the multiplex genetic susceptibility test, while those from higher education neighborhoods were more likely to participate. Conclusions: Our results suggest that large social groups will likely be underrepresented in research in personalized genomics even when robust population-based recruitment strategies are employed.

•The inclusion of the larger dataset is explicitly detailed to the reviewers.•The analyses were dichotomized on the medians of cumulative exposure among the statins-exposed individuals.•The use of exact test and their p-values has been added to the Material and Methods section.•The results of the sensitivity analysis which persons on statins for <6 months are reported.•The results remain consistent with a significant inverse association between statin use and HCC. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are medications widely prescribed to reduce cholesterol levels. Observational studies in high-risk populations, mostly in Asia, have suggested that statins are associated with a reduced risk of hepatocellular carcinoma (HCC). The current study sought to evaluate the association of statin use and HCC in a U.S.-based, low-risk, general population. A nested case–control study was conducted among members of the Health Alliance Plan HMO of the Henry Ford Health System enrolled between 1999 and 2010. Electronic pharmacy records of statin use were compared among tumor registry-confirmed cases of HCC (n=94) and controls (n=468) matched on age, sex, diagnosis date, and length of HMO enrolment. In multivariate analyses, ever-use of statins was significantly inversely associated with development of HCC (Odds ratio (OR): 0.32, 95%CI: 0.15–0.67). No clear dose–response relationship was evident as statin use for <2 years (OR=0.32, 95%CI=0.13–0.83) and >2 years (OR=0.31, 95CI%=0.12–9.81) resulted in very similar ORs. The use of statins among populations in low-risk HCC areas may be associated with decreased risk of HCC.