Multi-ancestry genome- and phenome-wide association studies of diverticular disease in electronic health records with natural language processing enriched phenotyping algorithm.

OBJECTIVE: Diverticular disease (DD) is one of the most prevalent conditions encountered by gastroenterologists, affecting ~50% of Americans before the age of 60. Our aim was to identify genetic risk variants and clinical phenotypes associated with DD, leveraging multiple electronic health record (EHR) data sources of 91,166 multi-ancestry participants with a Natural Language Processing (NLP) technique. MATERIALS AND METHODS: We developed a NLP-enriched phenotyping algorithm that incorporated colonoscopy or abdominal imaging reports to identify patients with diverticulosis and diverticulitis from multicenter EHRs. We performed genome-wide association studies (GWAS) of DD in European, African and multi-ancestry participants, followed by phenome-wide association studies (PheWAS) of the risk variants to identify their potential comorbid/pleiotropic effects in clinical phenotypes. RESULTS: Our developed algorithm showed a significant improvement in patient classification performance for DD analysis (algorithm PPVs ≥ 0.94), with up to a 3.5 fold increase in terms of the number of identified patients than the traditional method. Ancestry-stratified analyses of diverticulosis and diverticulitis of the identified subjects replicated the well-established associations between ARHGAP15 loci with DD, showing overall intensified GWAS signals in diverticulitis patients compared to diverticulosis patients. Our PheWAS analyses identified significant associations between the DD GWAS variants and circulatory system, genitourinary, and neoplastic EHR phenotypes. DISCUSSION: As the first multi-ancestry GWAS-PheWAS study, we showcased that heterogenous EHR data can be mapped through an integrative analytical pipeline and reveal significant genotype-phenotype associations with clinical interpretation. CONCLUSION: A systematic framework to process unstructured EHR data with NLP could advance a deep and scalable phenotyping for better patient identification and facilitate etiological investigation of a disease with multilayered data.

Use of Six-Minute Walk Test to Measure Functional Capacity After Liver Transplantation.

BACKGROUND: Functional impairment is common in people with chronic liver disease (CLD), and improvement is expected following liver transplantation (LT). The Six-Minute Walk Test (6MWT) is an objective measure of functional performance. OBJECTIVE: The aims of this study were: (1) to evaluate the feasibility of 6MWT performance after LT, (2) to compare post-LT 6MWT performance over time between patients with and without CLD, (3) to determine when post-LT 6MWT performance approaches expected values, and (4) to investigate predictors of poor 6MWT performance. METHODS: The 6MWT was performed by 162 consecutive ambulatory participants (50 healthy controls, 62 with CLD, 50 with LT). Sex, age, and body mass index were used to predict expected 6MWT performance. Chi-square testing, analysis of variance, and Pearson coefficients compared percentage of predicted 6-minute walk distance (%6MWD) across groups. Multivariable mixed models assessed predictors of improvement. RESULTS: The participants' mean age was 53.5 years (SD=13.0), 39.5% were female, and 39.1% were nonwhite. At 1-month post-LT, only 52% of all LT recipients met the inclusion criteria for 6MWT performance. Mean %6MWD values for female participants improved from 49.8 (SD=22.2) at 1 month post-LT to 90.6 (SD=12.8) at 1 year post-LT (P<.0001), which did not differ statistically from the CLD group (X̅=95.9, SD=15.6) or the control group (X̅=95.6, SD=18.0) (P=.58). However, at 1-year post-LT, mean %6MWD values for male participants (X̅=80.4, SD=19.5) remained worse than for both the CLD group (X̅=93.3, SD=13.7) and the control group (X̅=91.9, SD=14.3) (P=.03). Six-Minute Walk Test performance was directly correlated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical component score (r=.51, P<.01) and was inversely correlated with nonalcoholic steatohepatitis (r=-.52, P<.01) and diabetes (r=-.48, P<.05). In multivariate analysis adjusted for age and sex, hepatitis C independently predicted 6MWT improvement (estimated ß=69.8, standard error=27.6, P=.01). LIMITATIONS: A significant proportion of patients evaluated for enrollment were excluded due to level of illness early after LT (n=99, 47.4%). Thus, sampling bias occurred in this study toward patients without significant postoperative complications. CONCLUSIONS: The 6MWT is a simple test of physical functioning but may be difficult to apply in LT recipients. The 6MWT performance improved following LT but was lower than expected, suggesting a low level of fitness up to 1 year following LT.

Low incidence of acute rejection in hepatitis B virus positive liver transplant recipients and the impact of hepatitis B immunoglobulin.

Historically, hepatitis B virus (HBV) liver transplantation (LT) recipients have less acute cellular rejection (ACR) than those without HBV. We questioned whether this has persisted in an era of decreased Hepatitis B immunoglobulin use (HBIG) given its in vitro immunoregulatory effects. We compared the incidence, risk factors and outcomes of ACR among 40,593 primary LT recipients with HBV, hepatitis C, steatohepatitis, and immune liver disease (OPTN 2000-2011). We also assessed the in vitro effect of HBIG on alloimmune lymphoproliferation and regulatory T cell generation using mixed lymphocyte reactions. In multivariate analysis, HBV status remained a strong independent predictor of freedom from ACR (OR 0.58, 95% CI: 1.5-2.1). Patient (67.7% vs 72.3%) and graft (60.8% vs 69.1%) survival were significantly lower in patients with ACR versus no ACR for all causes except HBV. HBIG use had no statistical association with ACR. In vitro, HBIG at concentrations equivalent to clinical dosing did not inhibit lymphoproliferation or promote regulatory T cell development. In summary, the incidence and impact of ACR is lower now for HBV LT and does not appear to be secondary to HBIG by our in vitro and in vivo analyses. Rather, it may be due to the innate immunosuppressive properties of chronic HBV infection.

High success rate of repeat colonoscopy with standard endoscopes in patients referred for prior incomplete colonoscopy.

BACKGROUND: In patients with incomplete colonoscopy, cecal intubation is sometimes unsuccessful due to a redundant or tortuous colon. Repeat colonoscopy may be successful with the use of alternate endoscopes or careful attention to technique but limited outcomes data is available. The aim of this study was to describe the technique, success rate and outcomes of consecutive patients referred for previous incomplete colonoscopy. METHODS: We conducted a retrospective chart review of incomplete colonoscopy procedures in patients age 18-90 at an academic teaching hospital referred to an endoscopist specializing in difficult colonoscopy. RESULTS: Cecal intubation was successful in 96 of 100 repeat colonoscopies and 83 procedures were completed with a standard endoscope (adult, pediatric, or gastroscope). The adenoma detection rate was 28% for successful repeat colonoscopies; a majority of these patients had no adenomas identified on incomplete exam. In 69.4% of cases, an endoscope was used to successfully complete colonoscopy that was not used in the incomplete colonoscopy. The median insertion time was significantly less for the complete colonoscopy (10.6 min) compared to the incomplete colonoscopy (18.8 min, P = 0.004). CONCLUSIONS: Repeat colonoscopy has a high success rate and identified a significant number of new adenomas. Use of all available endoscopes should be considered prior to procedure termination in patients with a tortuous colon. Repeat colonoscopy can often be accomplished using a standard endoscope and is not attributed to increased endoscope insertion time.

Delaying cholecystectomy for complicated gallstone disease in pregnancy is associated with recurrent postpartum symptoms.

INTRODUCTION: Pregnancy is a risk factor for gallstone disease; in some patients, cholecystectomy may be delayed to the postpartum period. Our aim was to examine the effect of antepartum interventions on postpartum outcomes in complicated gallstone disease (CGD) during pregnancy. MATERIAL AND METHODS: Retrospective analysis of patients seeking medical care for CGD (cholecystitis, choledocholithiasis, or gallstone pancreatitis) during pregnancy at a single tertiary care institution over a 10-year period (2002-2012). Patients were contacted via standardized telephone survey to account for outside hospitalizations. RESULTS AND DISCUSSION: We identified 56 patients with CGD during pregnancy, 42.9 % initially presenting during the second trimester. Choledocholithiasis was the most common diagnosis (n = 30). Antepartum cholecystectomy was performed in 17.9 %. Seventeen patients did not follow up postpartum and did not complete telephone survey. Of the remaining 29 patients, 58.6 % had recurrent postpartum symptoms, 35.3 % recurred within 1 month, and 82.4 % within 3 months of delivery. Antepartum ERCP with biliary sphincterotomy decreased postpartum symptom recurrence (38.5 vs. 75.0 %, p = 0.07). CONCLUSIONS: The majority of patients with CGD who do not undergo antepartum cholecystectomy have recurrent postpartum symptoms often within 3 months postpartum. When appropriate, physicians should advocate for antepartum or early postpartum cholecystectomy to minimize symptom recurrence and unplanned hospitalizations.

Impact of an incomplete colonoscopy referral program on recommendations after incomplete colonoscopy.

BACKGROUND: There are limited data on recommendations and adherence to complete colon evaluation (CCE) after incomplete colonoscopy (IC). AIMS: Our objectives were to (1) identify recommendations and adherence to recommendations after IC, (2) determine the diagnostic yield of CCE after IC, and (3) determine the effect of an IC referral program on recommendations for CCE. METHODS: We conducted a retrospective review of IC procedures at a teaching hospital over two time periods (January 1 to May 1 2004 and July 1 to November 1 2010). A referral process for repeat colonoscopy after IC was instituted in April 2009. Outcomes included (1) recommendations (2) adherence, and (3) yield of CCE after IC. RESULTS: A total of 222 patients underwent at least one IC (overall rate of 2.5 %). In 120 patients (54.1 %), CCE was recommended within 1 year; the rate did not change from 2004 to 2010. Patients with IC due to poor preparation were more likely to have specific CCE recommendations (85.5 vs. 72.2 %, P = 0.03) and recommendations of endoscopic follow-up (76.3 vs. 10.4 %, P < 0.0001) than those with IC due to difficult anatomy. When IC was due to difficult colonoscopy, there was increase in endoscopic follow-up recommended (16.3 vs. 2.8 %, P = 0.01) in 2010 compared to 2004. Adherence to recommendations was similar regardless of modality recommended, inpatient/outpatient status, polyps on initial exam, or extent of initial exam. Polyp detection rate was greater utilizing colonoscopy than barium enema (34.3 vs. 3.6 %, P < 0.0001). CONCLUSIONS: There is a lack of consensus in management strategies for patients after IC. Implementation of a referral program has had minimal impact on provider recommendations.