Supplementary Table 1 from Association between Genetic Variants in the 8q24 Cancer Risk Regions and Circulating Levels of Androgens and Sex Hormone–Binding Globulin

PURPOSE:In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research. METHODS:We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization). RESULTS:Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms. CONCLUSIONS:We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies.

During 2017, opioids were associated with 47,600 deaths in the United States, approximately one third of which involved a prescription opioid (1). Amid concerns that overprescribing to patients with acute pain remains an essential factor underlying misuse, abuse, diversion, and unintentional overdose, several states have restricted opioid analgesic prescribing (2,3). To characterize patterns of opioid analgesic use for acute pain in primary care settings before the widespread implementation of limits on opioid prescribing (2,3), patients filling an opioid analgesic prescription for acute pain were identified from a 2014 database of commercial claims. Using a logistic generalized additive model, the probability of obtaining a refill was estimated as a function of the initial number of days supplied. Among 176,607 patients with a primary care visit associated with an acute pain complaint, 7.6% filled an opioid analgesic prescription. Among patients who received an initial 7-day supply, the probability of obtaining an opioid analgesic prescription refill for nine of 10 conditions was <25%. These results suggest that a ≤7-day opioid analgesic prescription might be sufficient for most, but not all, patients seen in primary care settings with acute pain who appear to need opioid analgesics. However, treatment strategies should account for patient and condition characteristics, which might alternatively reduce or extend the anticipated duration of benefit from opioid analgesic therapy.

IMPORTANCE Many stakeholders are working to improve the safe use of immediate-release (IR) and extended-release/long-acting (ER/LA) opioid analgesics. However, little information exists regarding the relative use of these 2 formulations in chronic pain management. OBJECTIVES To describe the distribution of IR and ER/LA opioid analgesic therapy duration and examine adding and switching patterns among patients receiving long-term IR opioid analgesic therapy, defined as at least 90 consecutive days of IR formulation use. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study of 169 million individuals receiving opioid analgesics from across 90% of outpatient retail pharmacies in the United States from January 1, 2003, to December 31, 2014, using the IQVIA Health Vector One: Data Extract Tool. Analyses were conducted from March 2015 to June 2017. EXPOSURES Receipt of dispensed IR or ER/LA opioid analgesic prescription. MAIN OUTCOMES AND MEASURES Distribution of therapy frequency and duration of IR and ER/LA opioid analgesic use, and annual proportions of patients receiving long-term IR opioid analgesic therapy who added an ER/LA formulation while continuing to use an IR formulation, switched to an ER/LA formulation, or continued receiving IR opioid analgesic therapy only. RESULTS Among the 169 280 456 patients included in this analysis, 168 315 458 patients filled IR formulations and 10 216 570 patients filled ER/LA formulations. A similar percentage of women received ER/LA (55%) and IR (56%) formulations, although those receiving ER/LA formulations (72%) were more likely to be aged 45 years or older compared with those receiving IR formulations (46%). The longest opioid analgesic episode duration was 90 days or longer for 11563 089 patients (7%) filling IR formulations and 3103 777 patients (30%) filling ER/LA formulations. The median episode duration was 5 days (interquartile range, 3-10 days) for patients using IR formulations and 30 days (interquartile range, 21-74 days) for patients using ER/LA formulations. From January 1. 2003, to December 31, 2014, a small and decreasing proportion of patients with long-term IR opioid analgesic therapy added (3.8% in 2003 to 1.8% in 2014) or switched to (1.0% in 2003 to 0.5% in 2014) an ER/LA formulation. CONCLUSIONS AND RELEVANCE Most patients receiving opioid analgesics, whether for short or extended periods, use IR formulations. Once receiving long-term IR opioid analgesic therapy, patients are unlikely to add or switch to an ER/LA formulation.

This chapter focuses on the central role of information visualization in health analytics. From the early x-rays to 3D volume visualizations, rapid progress has been made. However, the most exciting growth is now in the area of information visualization, which offers interactive environments and analytic processes that help support exploration of electronic health record (EHR) data, monitoring, or insight discovery. For example, a health organization might want to investigate patterns of drug prescriptions in patients with asthma and compare prescribing practices with current guidelines. Temporal patterns are critical to this analysis, and interactive visualizations are beginning to support powerful temporal queries, present rich result summaries, and offer fluid interactions to identify the clinically relevant patterns hidden in the data. Visualization should soon help clinicians identify cohorts of patients who match selection criteria for clinical trials or need to be brought back to the office. Visualization can also reveal data quality problems, which are common when repurposing clinical data for secondary analysis. After a quick summary of the state-of-the-art of information visualization systems for exploring and querying EHR data, we describe in detail one recent system (EventFlow) developed by the Human-Computer Interaction Lab at the University of Maryland and illustrate its use with an asthma prescription study example.

Background: Chronic inflammation has been linked to cancers, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of several cancers. To further refine the magnitude of NSAID-related associations, in particular for cancers related to inflammation, such as alcohol-, infection-, obesity-, and smoking-related cancers, as well as for less common cancers, we evaluated the use of NSAIDs and cancer risk in a very large cohort. We used propensity scores to account for potential selection bias and hypothesized that NSAID use is associated with decreased cancer incidence.Methods: We conducted a prospective study among 314,522 participants in the NIH-AARP Diet and Health Study. Individuals who completed the lifestyle questionnaire, which included NSAID use, in 1996-1997 were followed through 2006. Information on cancer incidence was ascertained by linking to cancer registries and vital status databases.Findings: During 2,715,994 person-years of follow-up (median 10.1 person-years), there were 51,894 incident cancers. Compared with non-users of NSAIDs, individuals who reported use in the 12 months prior to interview had a significantly lower risk of all inflammation-related cancer, alcohol-related, infection-related, obesity-related, and smoking-related cancers [hazard ratio (HR) (95% CI)) 0.90 (0.87-0.93), 0.80 (0.74-0.85), 0.82 (0.78-0.87), 0.88 (0.84-0.92), and 0.88 (0.85-0.92) respectively)].Conclusions: After accounting for potential selection bias, our data showed an inverse association between NSAID use and alcohol-related, infection-related, obesity-related, and smoking-related cancers and support the hypothesis that inflammation is related to an increased risk of certain cancers.

This chapter focuses on the central role of information visualization in health analytics. From the early x-rays to 3D volume visualizations rapid progress has been made, but the most exciting growth is now in the area of information visualization which offer interactive environments and analytic processes that help support exploration of EHR data, monitoring, or insight discovery. For example, a health organization might want to investigate patterns of drug prescriptions in patients with asthma, and compare prescribing practices with current guidelines. Temporal patterns are critical to this analysis, and interactive visualizations are beginning to support powerful temporal queries, present rich result summaries, and offer fluid interactions to identify the clinically relevant patterns hidden in the data. Visualization should soon help clinicians identify cohorts of patients who match selection criteria for clinical trials, or need to be brought back to the office. Visualization can also reveal data quality problems, which are common when repurposing clinical data for secondary analysis. After a quick summary of the state-of-the-art of information visualization systems for exploring and querying EHR data, we describe in detail one recent system (EventFlow) developed by the Human-Computer Interaction Lab at the University of Maryland, and illustrate its use with an asthma prescription study example.

The Food and Drug Administration and Department of Defense were interested in detecting sub-optimal use of long-acting beta-agonists (LABAs) in asthmatics within the Military Health System (MHS). Visualizing the patterns of asthma medication use surrounding a LABA prescription is a quick way to detect possible sub-optimal use for further evaluation. Analysis of 100 asthma patients was conducted in EventFlow to display and summarize timepoint and interval data. Epidemiologists reported that EventFlow was a powerful tool for rapidly visualizing possible patterns of sub-optimal LABA use that can be targeted for intervention.

Metabolomic profiling has identified, sarcosine, a derivative of the amino acid glycine, as an important metabolite involved in the etiology or natural history of prostate cancer. We examined the association between serum sarcosine levels and risk of prostate cancer in 1122 cases (813 non-aggressive and 309 aggressive) and 1112 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Sarcosine was quantified using high-throughput liquid chromatography-mass spectrometry. A significantly increased risk of prostate cancer was observed with increasing levels of sarcosine (odds ratio [OR] for the highest quartile of exposure [Q4] versus the lowest quartile [Q1] = 1.30, 95% confidence interval [CI]: 1.02, 1.65; P-trend 0.03). When stratified by disease aggressiveness, we observed a stronger association for non-aggressive cases (OR for Q4 versus Q1 = 1.44, 95% CI: 1.11, 1.88; P-trend 0.006) but no association for aggressive prostate cancer (OR for Q4 versus Q1 = 1.03, 95% CI: 0.73, 1.47; P-trend 0.89). Although not statistically significant, temporal analyses showed a stronger association between sarcosine and prostate cancer for serum collected closer to diagnosis, suggesting that sarcosine may be an early biomarker of disease. Interestingly, the association between sarcosine and prostate cancer risk was stronger among men with diabetes (OR = 2.66, 95% CI: 1.04, 6.84) compared with those without reported diabetes (OR = 1.23, 95% CI: 0.95-1.59, P-interaction = 0.01). This study found that elevated levels of serum sarcosine are associated with an increased prostate cancer risk and evidence to suggest that sarcosine may be an early biomarker for this disease.

Abstract Introduction and Objective: Existing epidemiologic data do not support an association between circulating levels of sex steroid hormones and risk of prostate cancer. Although it has been suggested that the combined action of androgens and estrogens'specifically their balance'may play a key role in prostate carcinogenesis, epidemiologic studies to evaluate this hypothesis are sparse, have assessed a limited number of sex steroid hormones, and have provided inconsistent results. We investigated associations between serum sex hormones'with a particular focus on estrogen metabolites'and risk of aggressive prostate cancer. Study Population, Design and Methods: In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we measured 15 parent serum estrogens (estrone and estradiol) and estrogen metabolites, including those in the C-2, -4, or 16 hydroxylation pathways, using a liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay. Cases (n=195) were defined as non-Hispanic white men diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7) between and 1994 and 2009 who were 55–70 years at diagnosis. Controls (n=195) were non-Hispanic white men who were free from prostate cancer for the duration of follow-up and frequency-matched to cases by age at study entry (5-yr intervals), time since baseline screen (1-yr time windows) and year of blood draw. Only cases and controls included in a previous study that measured serum androgens and sex-hormone binding globulin (SHBG) were eligible. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI). Results: Individual parent estrogens and individual estrogen metabolites were unrelated to risk of aggressive prostate cancer; with the exception of a non-linear inverse relationship between cancer and levels of methylated catechols, namely 2- and 4-methoxyestrone. However, there was an increased risk of aggressive prostate cancer associated with an increasing ratio of 2:16 hydroxyestrone (fourth vs. first quartile: OR 2.44, 95% CI 1.34–4.45, p trend=0.001) and a strong trend of decreasing prostate cancer risk with an increasing ratio of estradiol to testosterone (fourth vs. first quartile: OR 0.27, 95% CI 0.12–0.59, p trend=0.003). Conclusion: We observed a strong protective effect of higher serum estradiol to testosterone levels in relation to risk of aggressive prostate cancer. Men with higher concentrations of methylated catechols in the 2- and 4-hydroxylation pathway may have a reduced risk of aggressive prostate cancer, while those with higher ratios of 2:16 hydroxyestrone may be at increased risk. These findings suggest a role for sex steroid hormone metabolism in prostate carcinogenesis. Citation Format: Amanda Black, Paul F. Pinsky, Robert L. Grubb, III, Roni T. Falk, Ann W. Hsing, Lisa W. Chu, Tamra E. Meyer, Tim Veenstra, Xia Xu, Kai Yu, Louise A. Brinton, Robert N. Hoover, Michael B. Cook. Estrogen metabolism in relation to the risk of aggressive prostate cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A53.

Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation‐related genes.

AIM:To determine the rate ratio of neuropsychiatric hospitalizations in new users of varenicline compared to new users of nicotine replacement therapy (NRT) patch in the Military Health System (MHS).DESIGN, SETTING AND PARTICIPANTS:Varenicline (n = 19,933) and NRT patch (n = 15,867) users who initiated therapy from 1 August 2006 to 31 August 2007 within the MHS were included in this retrospective cohort study. After matching according to propensity scores, 10,814 users remained in each cohort. The study population included those with and without a history of neuropsychiatric disease.MEASUREMENTS:Patients were followed for neuropsychiatric hospitalizations defined by primary neuropsychiatric discharge diagnosis using ICD-9 codes from in-patient administrative claims. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated after propensity score matching on exposure for socio-demographic factors, health-care utilization, comorbidities, medication history and neuropsychiatric history.FINDINGS:There was no increase in the rate of neuropsychiatric hospitalizations in patients treated with varenicline compared to NRT patch when followed for 30 days (propensity-score matched HR = 1.14, 95% CI: 0.56-2.34). Results were similar after 60 days of follow-up.CONCLUSIONS:There does not appear to be an increase in neuropsychiatric hospitalizations with varenicline compared with nicotine replacement therapy patch over 30 or 60 days after drug initiation.

ABSTRACTPurposeWe report the annual trend, distribution, and determinants of acetaminophen overdose using data from the Military Health System. We also assess the proportion of individuals with an acetaminophen overdose who received a prescription for any acetaminophen‐containing medication prior to their event.MethodsDiagnostic International Classification of Diseases, 9th revision (ICD‐9) codes from inpatient medical encounters were used to identify patients with acetaminophen overdose. We used Poisson regression to estimate adjusted prevalence ratios (aPRs) for associations between selected socio‐demographic characteristics and acetaminophen overdose. Pharmacy records for individuals with an acetaminophen overdose were obtained to evaluate the proportion who received a prescription for any acetaminophen‐containing medication prior to their overdose.ResultsAnnual age‐adjusted and sex‐adjusted prevalence of acetaminophen overdose increased by 38.5% from 2004 to 2008. Acetaminophen overdose was significantly more common in female subjects than in male subjects (aPR = 3.24, 95%CI = 2.97–3.55). Individuals aged 15–17 and 18–24 also were significantly more likely to have an overdose compared with those aged 45–64 (aPR = 6.06, 95%CI = 5.25–7.00 and aPR = 4.58, 95%CI = 4.01–5.23, respectively). Among active duty service members, acetaminophen overdose was six times more common in junior enlisted service members than in officers (aPR = 6.06, 95%CI = 3.90–9.40). The proportion of individuals with an inpatient overdose who had any prescription for an acetaminophen‐containing medication in the 365, 30, and 7 days before the overdose was 53.3%, 23.7%, and 16.3%, respectively.ConclusionsIdentification of at‐risk populations will aid the military in ongoing efforts to decrease medication misuse. Findings suggest a potential need for improved labeling of over‐the‐counter medications and medication safety education efforts for unintentional acetaminophen overdose and continued efforts to identify individuals at risk for intentional overdose. Published 2012. This article is a US Government work and is in the public domain in the USA.

While sarcosine was recently identified as a potential urine biomarker for prostate cancer, further studies have cast doubt on its utility to diagnose this condition. The inconsistent results may be due to the fact that alanine and sarcosine coelute on an HPLC reversed-phase column and the mass spectrometer cannot differentiate between the two isomers, since the same parent/product ions are generally used to measure them. In this study, we developed a high-throughput liquid chromatography-mass spectrometry (LC-MS) method that resolves sarcosine from alanine isomers, allowing its accurate quantification in human serum and urine. Assay reproducibility was determined using the coefficient of variation (CV) and intraclass correlation coefficient (ICC) in serum aliquots from 10 subjects and urine aliquots from 20 subjects across multiple analytic runs. Paired serum/urine samples from 42 subjects were used to evaluate sarcosine serum/urine correlation. Both urine and serum assays gave high sensitivity (limit of quantitation of 5 ng/mL) and reproducibility (serum assay, intra- and interassay CVs < 3% and ICCs > 99%; urine assay, intra-assay CV = 7.7% and ICC = 98.2% and interassay CV = 12.3% and ICC = 94.2%). In conclusion, this high-throughput LC-MS method is able to resolve sarcosine from α- and β-alanine and is useful for quantifying sarcosine in serum and urine samples.

Serum lipids, diabetes, and obesity, individual components of metabolic syndrome, are associated with biliary tract cancer and stone risk, but the associations of metabolic syndrome or insulin resistance with biliary tract cancers and stones are not well studied. In this population-based case-control study in Shanghai, China (627 biliary tract cancers, 1037 biliary stones, and 959 controls), metabolic syndrome was defined as the presence of any three of the five components, including high waist circumference, high triglycerides, low high-density lipoprotein cholesterol (HDL), high blood pressure, and diabetes. Insulin resistance and β-cell function were assessed, using homeostasis assessment models. Metabolic syndrome was significantly associated with gallbladder cancer (odds ratio (OR)=2.75, 95% confidence interval (95% CI)=1.82–4.15) and biliary stones (OR=1.64, 95% CI=1.24–2.16), with a significant dose effect with increasing number of metabolic syndrome components (P trend <0.0001). The observed association persisted among subjects without a history of diabetes. The association between insulin resistance and gallbladder cancer was borderline (P trend=0.06). There was a significant inverse association between β-cell function and gallbladder cancer risk (P trend <0.001). Our findings suggest that metabolic syndrome and insulin resistance have a role in the aetiology of biliary tract cancers and biliary stones, and if confirmed, they imply that lifestyle control of these factors may lower the risk of biliary stones and biliary tract cancer.

Objective To evaluate the associations between dietary carbohydrate, glycemic index (GI), glycemic load (GL), and incident prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Methods Between September 1993 and September 2000, 38,343 men were randomized to the screening arm of the trial at one of 10 PLCO centers. A food frequency questionnaire administered at baseline assessed usual dietary intake over the preceding 12 months. Prostate cancer was ascertained by medical follow-up of suspicious screening results and annual mailed questionnaires and confirmed with medical records. Cox proportional hazards regression was used to model the associations of carbohydrate, GI, and GL with prostate cancer risk. Results During follow-up (median = 9.2 years), 2,436 incident prostate cancers were identified among 30,482 eligible participants. Overall, there were no associations of baseline carbohydrate, GI, or GL with incident prostate cancer in minimally or fully adjusted models. There were no associations when the 228 advanced and 2,208 non-advanced cancers were analyzed separately. Conclusions Dietary carbohydrate, GI, and GL were not associated with incident prostate cancer in PLCO. The narrow range of GI in this cohort may have limited our ability to detect associations, an issue that future studies should address.

Abstract Background: Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder. Methods: To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone), and sex hormone–binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels. Results: Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 × 10−3) and bioavailable testosterone (P < 6.3 × 10−4). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05). Conclusions: These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels. Impact: These results might provide some clues for the strong link between 8q24 and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 19(7); 1848–54. ©2010 AACR.