Health systems are stewards of patient electronic health record (EHR) data with extraordinarily rich depth and breadth, reflecting thousands of diagnoses and exposures. Measures of genomic variation ...integrated with EHRs offer a potential strategy to accurately stratify patients for risk profiling and discover new relationships between diagnoses and genomes. The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine. PRS for 12 cancer traits were calculated using summary statistics from the NHGRI-EBI catalog. A total of 1,711 synthetic case-control studies was used for PheWAS analyses. There were 13,490 (47.7%) patients with at least one cancer diagnosis in this study sample. PRS exhibited strong association for several cancer traits they were designed for, including female breast cancer, prostate cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, and thyroid cancer. Phenome-wide significant associations were observed between PRS and many non-cancer diagnoses. To differentiate PRS associations driven by the primary trait from associations arising through shared genetic risk profiles, the idea of “exclusion PRS PheWAS” was introduced. Further analysis of temporal order of the diagnoses improved our understanding of these secondary associations. This comprehensive PheWAS used PRS instead of a single variant.
Few studies have assessed postoperative trends in opioid cessation and predictors of persistent opioid use after total knee arthroplasty (TKA) and total hip arthroplasty (THA). Preoperatively, 574 ...TKA and THA patients completed validated, self-report measures of pain, functioning, and mood and were longitudinally assessed for 6 months after surgery. Among patients who were opioid naive the day of surgery, 8.2% of TKA and 4.3% of THA patients were using opioids at 6 months. In comparison, 53.3% of TKA and 34.7% of THA patients who reported opioid use the day of surgery continued to use opioids at 6 months. Patients taking >60 mg oral morphine equivalents preoperatively had an 80% likelihood of persistent use postoperatively. Day of surgery predictors for 6-month opioid use by opioid-naive patients included greater overall body pain (P = 0.002), greater affected joint pain (knee/hip) (P = 0.034), and greater catastrophizing (P = 0.010). For both opioid-naive and opioid users on the day of surgery, decreases in overall body pain from baseline to 6 months were associated with decreased odds of being on opioids at 6 months (adjusted odds ratio aOR = 0.72, P = 0.050; aOR = 0.62, P = 0.001); however, change in affected joint pain (knee/hip) was not predictive of opioid use (aOR = 0.99, P = 0.939; aOR = 1.00, P = 0.963). In conclusion, many patients taking opioids before surgery continue to use opioids after arthroplasty and some opioid-naive patients remained on opioids; however, persistent opioid use was not associated with change in joint pain. Given the growing concerns about chronic opioid use, the reasons for persistent opioid use and perioperative prescribing of opioids deserve further study.
OBJECTIVE:To explore the clinical and financial implications of preoperative opioid use in major abdominal surgery.
BACKGROUND:Opioids are increasingly used to manage chronic pain, and chronic opioid ...users are challenging to care for perioperatively. Given the epidemic of opioid-related morbidity and mortality, it is critical to understand how preoperative opioid use impacts surgical outcomes.
METHODS:This was an analysis of nonemergent, abdominopelvic surgeries from 2008 to 2014 from a single center within the Michigan Surgical Quality Collaborative clinical registry database. Preoperative opioid use (binary exposure variable) was retrospectively queried from the home medication list of the preoperative evaluation. Our primary outcome was 90-day total hospital costs. Secondary outcomes included hospital length of stay, 30-day major complication rates, discharge destination, and 30-day hospital readmission rates. Analyses were risk-adjusted for case complexity and patient-specific risk factors such as demographics, insurance, smoking, comorbidities, and concurrent medication use.
RESULTS:In all, 2413 patients met the inclusion criteria. Among them, 502 patients (21%) used opioids preoperatively. After covariate adjustment, opioid users (compared with those who were opioid-naïve) had 9.2% higher costs 95% confidence interval (CI) 2.8%–15.6%; adjusted means $26,604 vs $24,263; P = 0.005), 12.4% longer length of stay (95% CI 2.3%–23.5%; adjusted means 5.9 vs 5.2 days; P = 0.015), more complications (odds ratio 1.36; 95% CI 1.04–1.78; adjusted rates 20% vs 16%; P = 0.023), more readmissions (odds ratio 1.57; 95% CI 1.08–2.29; adjusted rates 10% vs 6%; P = 0.018), and no difference in discharge destination (P = 0.11).
CONCLUSIONS:Opioid use is common before abdominopelvic surgery, and is independently associated with increased postoperative healthcare utilization and morbidity. Preoperative opioids represent a potentially modifiable risk factor and a novel target to improve quality and value of surgical care.
Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding ...protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here, we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues. Ctcf+/− tumors are characterized by increased aggressiveness, including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf+/− tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome wide. These findings establish CTCF as a prominent tumor-suppressor gene and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression.
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•Mice with hemizygous loss of CTCF are cancer prone•CTCF reduction destabilizes DNA methylation prior to tumor development•CTCF is frequently hemizygously deleted or mutated in human cancer•CTCF is thus a haploinsufficient tumor-suppressor gene
Deletions on chromosome 16q22.1 occur at high frequency in breast and other human cancers, implying the existence of a cancer gene or genes at this location. CTCF, a DNA-binding protein that regulates genome organization, resides at 16q22.1. Kemp et al. now demonstrate that mice lacking one copy of Ctcf have abnormal patterns of DNA methylation and are markedly predisposed to cancer. Furthermore, CTCF is one of the most frequently mutated genes in human cancers, thus establishing CTCF as a major tumor-suppressor gene.
Evidence suggests that pain patients who report lifetime abuse experience greater psychological distress, have more severe pain and other physical symptoms, and greater functional disability. The aim ...of the present study was to determine the associations between a history of lifetime abuse and affective distress, fibromyalgianess (measured using the 2011 Fibromyalgia Survey), pain severity and interference, and physical functioning. A cross-sectional analysis of 3,081 individuals presenting with chronic pain was performed using validated measures and a history of abuse was assessed via patient self-report. Multivariate logistic regression showed that individuals with a history of abuse (n = 470; 15.25%) had greater depression, greater anxiety, worse physical functioning, greater pain severity, worse pain interference, higher catastrophizing, and higher scores on the Fibromyalgia Survey criteria (P < .001 for all comparisons). Mediation models showed that the Fibromyalgia Survey score and affective distress independently mediate the relationship between abuse and pain severity and physical functioning (Ps < .001). Our mediation models support a novel biopsychosocial paradigm wherein affective distress and fibromyalgianess interact to play significant roles in the association between abuse and pain. We posit that having a centralized pain phenotype underlies the mediation of increased pain morbidity in individuals with a history of abuse.
This article examines the associations between a history of lifetime abuse and affective distress, fibromyalgianess, pain severity and interference, and physical functioning in chronic pain patients. Our findings support a novel biopsychosocial paradigm in which affective distress and fibromyalgianess interact to play roles in the association between abuse and pain.
OBJECTIVE:The aim of this study was to determine preoperative patient characteristics associated with postoperative outpatient opioid use and assess the frequency of postoperative opioid ...overprescribing.
SUMMARY BACKGROUND DATA:Although characteristics associated with inpatient opioid use have been described, data regarding patient factors associated with opioid use after discharge are lacking. This hampers the development of individualized approaches to postoperative prescribing.
METHODS:We included opioid-naïve patients undergoing hysterectomy, thoracic surgery, and total knee and hip arthroplasty in a single-center prospective observational cohort study. Preoperative phenotyping included self-report measures to assess pain severity, fibromyalgia survey criteria score, pain catastrophizing, depression, anxiety, functional status, fatigue, and sleep disturbance. Our primary outcome measure was self-reported total opioid use in oral morphine equivalents. We constructed multivariable linear-regression models predicting opioids consumed in the first month following surgery.
RESULTS:We enrolled 1181 patients; 1001 had complete primary outcome data and 913 had complete phenotype data. Younger age, non-white race, lack of a college degree, higher anxiety, greater sleep disturbance, heavy alcohol use, current tobacco use, and larger initial opioid prescription size were significantly associated with increased opioid consumption. Median total oral morphine equivalents prescribed was 600 mg (equivalent to one hundred twenty 5-mg hydrocodone pills), whereas median opioid consumption was 188 mg (38 pills).
CONCLUSIONS:In this prospective cohort of opioid-naïve patients undergoing major surgery, we found a number of characteristics associated with greater opioid use in the first month after surgery. Future studies should address the use of non-opioid medications and behavioral therapies in the perioperative period for these higher risk patients.
Polygenic risk scores (PRS) are designed to serve as single summary measures that are easy to construct, condensing information from a large number of genetic variants associated with a disease. They ...have been used for stratification and prediction of disease risk. The primary focus of this paper is to demonstrate how we can combine PRS and electronic health records data to better understand the shared and unique genetic architecture and etiology of disease subtypes that may be both related and heterogeneous. PRS construction strategies often depend on the purpose of the study, the available data/summary estimates, and the underlying genetic architecture of a disease. We consider several choices for constructing a PRS using data obtained from various publicly-available sources including the UK Biobank and evaluate their abilities to predict not just the primary phenotype but also secondary phenotypes derived from electronic health records (EHR). This study was conducted using data from 30,702 unrelated, genotyped patients of recent European descent from the Michigan Genomics Initiative (MGI), a longitudinal biorepository effort within Michigan Medicine. We examine the three most common skin cancer subtypes in the USA: basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma. Using these PRS for various skin cancer subtypes, we conduct a phenome-wide association study (PheWAS) within the MGI data to evaluate PRS associations with secondary traits. PheWAS results are then replicated using population-based UK Biobank data and compared across various PRS construction methods. We develop an accompanying visual catalog called PRSweb that provides detailed PheWAS results and allows users to directly compare different PRS construction methods.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The current study was designed to test the hypothesis that the fibromyalgia survey criteria would be directly associated with increased opioid consumption after hysterectomy even when accounting for ...other factors previously described as being predictive for acute postoperative pain.
Two hundred eight adult patients undergoing hysterectomy between October 2011 and December 2013 were phenotyped preoperatively with the use of validated self-reported questionnaires including the 2011 fibromyalgia survey criteria, measures of pain severity and descriptors, psychological measures, preoperative opioid use, and health information. The primary outcome was the total postoperative opioid consumption converted to oral morphine equivalents.
Higher fibromyalgia survey scores were significantly associated with worse preoperative pain characteristics, including higher pain severity, more neuropathic pain, greater psychological distress, and more preoperative opioid use. In a multivariate linear regression model, the fibromyalgia survey score was independently associated with increased postoperative opioid consumption, with an increase of 7-mg oral morphine equivalents for every 1-point increase on the 31-point measure (Estimate, 7.0; Standard Error, 1.7; P < 0.0001). In addition to the fibromyalgia survey score, multivariate analysis showed that more severe medical comorbidity, catastrophizing, laparotomy surgical approach, and preoperative opioid use were also predictive of increased postoperative opioid consumption.
As was previously demonstrated in a total knee and hip arthroplasty cohort, this study demonstrated that increased fibromyalgia survey scores were predictive of postoperative opioid consumption in the posthysterectomy surgical population during their hospital stay. By demonstrating the generalizability in a second surgical cohort, these data suggest that patients with fibromyalgia-like characteristics may require a tailored perioperative analgesic regimen.
We developed the Michigan Body Map (MBM) as a self-report measure to assess body areas where chronic pain is experienced and to specifically quantify the degree of widespread body pain when assessing ...for centralized pain features (eg, fibromyalgia-like presentation). A total of 402 patients completed the measure in 5 distinct studies to support the validation of the original and a revised version of the MBM. Administration is rapid 39 to 44 seconds, and errors for the original MBM were detected in only 7.2% of the possible body areas. Most errors underestimated the number of painful areas or represented confusion in determining the right vs left side. The MBM was preferred (P = 0.013) and felt to better depict pain location (P = 0.001) when compared with the Widespread Pain Index checklist of the 2011 Fibromyalgia Survey Criteria, but participants did not express any preference between the MBM and Brief Pain Inventory body map. Based on the data from the first 3 studies, a revised version of the MBM was created including a front and back body image and improved guidance on right-sidedness vs left. The revised MBM was preferred when compared with the original and was more accurate in depicting painful body areas (P = 0.004). Furthermore, the revised MBM showed convergent and discriminant validity with other self-report measures of pain, mood, and function. In conclusion, the MBM demonstrated utility, reliability, and construct validity. This new measure can be used to accurately assess the distribution of pain or widespread bodily pain as an element of the fibromyalgia survey score.
Depression may be a critical factor in the initiation and maintenance of opioids. This study investigated the association among opioid use, pain, and depression in patients evaluated at a ...university-based outpatient pain clinic. Of the 2,104 new patients included, 55.89% reported current opioid use and showed a worse phenotypic profile (eg, higher pain severity, worse physical functioning) compared with nonopioid users. In addition, more opioid users reported symptoms suggestive of depression than those not taking opioids (43.6% vs 26.8%, P < .001). In a multivariate logistic regression model, increased pain severity was associated with increased probability of taking opioids; however, this was moderated by depression (estimate = -.212, P < .001). For nondepressed patients, the predicted probabilities of opioid use increased as pain severity increased. In contrast, among patients with symptoms of depression, the probability of taking opioids did not change based on pain severity. Similarly, although increased physical function was associated with increased probability of opioid use, this was moderated by depression (estimate = .033, P = .034). Patients with symptoms of depression were more likely to be taking opioids at higher levels of functioning (Ps < .03). Perspective: This study investigated the association among opioid use, pain, and depression at a university-based outpatient pain clinic. Depression emerged as a moderator of the relationship among opioid use, pain severity, and physical functioning. These findings lend support to the hypothesis that patients may be self-medicating affective pain with opioids.
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