Comparison of clinical note quality between an automated digital intake tool and the standard note in the emergency department.

BACKGROUND: Medical encounters require an efficient and focused history of present illness (HPI) to create differential diagnoses and guide diagnostic testing and treatment. Our aim was to compare the HPI of notes created by an automated digital intake tool versus standard medical notes created by clinicians. METHODS: Prospective trial in a quaternary academic Emergency Department (ED). Notes were compared using the 5-point Physician Documentation Quality Instrument (PDQI-9) scale and the Centers for Medicare & Medicaid Services (CMS) level of complexity index. Reviewers were board certified emergency medicine physicians blinded to note origin. Reviewers received training and calibration prior to note assessments. A difference of 1 point was considered clinically significant. Analysis included McNemar's (binary), Wilcoxon-rank (Likert), and agreement with Cohen's Kappa. RESULTS: A total of 148 ED medical encounters were charted by both digital note and standard clinical note. The ability to capture patient information was assessed through comparison of note content across paired charts (digital-standard note on the same patient), as well as scores given by the reviewers. Reviewer agreement was kappa 0.56 (CI 0.49-0.64), indicating moderate level of agreement between reviewers scoring the same patient chart. Considering all 18 questions across PDQI-9 and CMS scales, the average agreement between standard clinical note and digital note was 54.3% (IQR 44.4-66.7%). There was a moderate level of agreement between content of standard and digital notes (kappa 0.54, 95%CI 0.49-0.60). The quality of the digital note was within the 1 point clinically significant difference for all of the attributes, except for conciseness. Digital notes had a higher frequency of CMS severity elements identified. CONCLUSION: Digitally generated clinical notes had moderate agreement compared to standard clinical notes and within the one point clinically significant difference except for the conciseness attribute. Digital notes more reliably documented billing components of severity. The use of automated notes should be further explored to evaluate its utility in facilitating documentation of patient encounters.

Implementation and evaluation of sepsis surveillance and decision support in medical ICU and emergency department.

OBJECTIVE: To improve the timely diagnosis and treatment of sepsis many institutions implemented automated sepsis alerts. Poor specificity, time delays, and a lack of actionable information lead to limited adoption by bedside clinicians and no change in practice or clinical outcomes. We aimed to compare sepsis care compliance before and after a multi-year implementation of a sepsis surveillance coupled with decision support in a tertiary care center. DESIGN: Single center before and after study. SETTING: Large academic Medical Intensive Care Unit (MICU) and Emergency Department (ED). POPULATION: Patients 18 years of age or older admitted to *** Hospital MICU and ED from 09/4/2011 to 05/01/2018 with severe sepsis or septic shock. INTERVENTIONS: Electronic medical record-based sepsis surveillance system augmented by clinical decision support and completion feedback. MEASUREMENTS AND MAIN RESULTS: There were 1950 patients admitted to the MICU with the diagnosis of severe sepsis or septic shock during the study period. The baseline characteristics were similar before (N = 854) and after (N = 1096) implementation of sepsis surveillance. The performance of the alert was modest with a sensitivity of 79.9%, specificity of 76.9%, positive predictive value (PPV) 27.9%, and negative predictive value (NPV) 97.2%. There were 3424 unique alerts and 1131 confirmed sepsis patients after the sniffer implementation. During the study period average care bundle compliance was higher; however after taking into account improvements in compliance leading up to the intervention, there was no association between intervention and improved care bundle compliance (Odds ratio: 1.16; 95% CI: 0.71 to 1.89; p-value 0.554). Similarly, the intervention was not associated with improvement in hospital mortality (Odds ratio: 1.55; 95% CI: 0.95 to 2.52; p-value: 0.078). CONCLUSIONS: A sepsis surveillance system incorporating decision support or completion feedback was not associated with improved sepsis care and patient outcomes.

Patient Length of Stay Under the Two-Midnight Rule: Assessing the Accuracy of Providers' Predictions.

EXECUTIVE SUMMARY: We sought to determine emergency medicine physicians' accuracy in designating patients' disposition status as "inpatient" or "observation" at the time of hospital admission in the context of Medicare's Two-Midnight rule and to identify characteristics that may improve the providers' predictions. We conducted a 90-day observational study of emergency department (ED) admissions involving adults aged 65 years and older and assessed the accuracy of physicians' disposition decisions. Logistic regression models were fit to explore associations and predictors of disposition. A total of 2,257 patients 65 and older were admitted through the ED. The overall error rate in physician designation of observation or inpatient was 36%. Diagnoses most strongly associated with stays lasting less than two midnights included diverticulitis, syncope, and nonspecific chest pain. Diagnoses most strongly associated with stays lasting two or more midnights included orthopedic fractures, biliary tract disease, and back pain. ED physicians inaccurately predicted patient length of stay in more than one third of all patients. Under the Two-Midnight rule, these inaccurate predictions place hospitals at risk of underpayment and patients at risk of significant financial liability. Further work is needed to increase providers' awareness of the financial repercussions of their admission designations and to identify interventions that can improve prediction accuracy.

Interphysician Differences in Emergency Department Length of Stay.

BACKGROUND: Emergency physicians differ in many ways with respect to practice. One area in which interphysician practice differences are not well characterized is emergency department (ED) length of stay (LOS). OBJECTIVE: To describe how ED LOS differs among physicians. METHODS: We performed a 3-year, five-ED retrospective study of non-fast-track visits evaluated primarily by physicians. We report each provider's observed LOS, as well as each provider's ratio of observed LOS/expected LOS (LOSO/E); we determined expected LOS based on site average adjusted for the patient characteristics of age, gender, acuity, and disposition status, as well as the time characteristics of shift, day of week, season, and calendar year. RESULTS: Three hundred twenty-seven thousand, seven hundred fifty-three visits seen by 92 physicians were eligible for analysis. For the five sites, the average shortest observed LOS was 151 min (range 106-184 min), and the average longest observed LOS was 232 min (range 196-270 min); the average difference was 81 min (range 69-90 min). For LOSO/E, the average lowest LOSO/E was 0.801 (range 0.702-0.887), and the average highest LOSO/E was 1.210 (range 1.186-1.275); the average difference between the lowest LOSO/E and the highest LOSO/E was 0.409 (range 0.305-0.493). CONCLUSION: There are significant differences in ED LOS at the level of the individual physician, even after accounting for multiple confounders. We found that the LOSO/E for physicians with the lowest LOSO/E at each site averaged approximately 20% less than predicted, and that the LOSO/E for physicians with the highest LOSO/E at each site averaged approximately 20% more than predicted.

"Let's Chat!" Improving Emergency Department Staff Satisfaction with the Medication Reconciliation Process.

Introduction: Patients who stay in the emergency department (ED) for prolonged periods of time require verification of home medications, a process known as medication reconciliation. The complex nature of medication reconciliation can lead to adverse events and staff dissatisfaction. A multidisciplinary team was formed to improve accuracy, timing, and staff satisfaction with the medication reconciliation process. Methods: Between November 2021-January 2022, stakeholders were surveyed to identify gaps in the medication reconciliation process. This project implemented education on role-specific tasks, as well as a "Let's chat!" huddle, bringing together the entire care team to perform medication reconciliation. We used real-time evaluations by frontline staff to evaluate effectiveness during plan- do-study-act cycles and obtain feedback. Following the implementation period, stakeholders completed the post-intervention survey between June-July 2022, using a 4-point Likert scale (0 = very dissatisfied to 3 = very satisfied). We calculated the change in staff satisfaction from pre-intervention to post-intervention. Differences in proportions and 95% confidence intervals are reported. This study adhered to the Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0) and followed the Lean Six Sigma rapid cycle process improvement (define-measure-analyze-improve-control). Results: A total of 111 front-line ED staff (physicians, nurse practitioners, physician assistants, pharmacists, nurses) completed the pre-intervention survey (of 350 ED staff, corresponding to a 31.7% response rate), and 89 stakeholders completed the post-intervention survey (a 25.4% response rate). Subjective feedback from staff identifying causes of low satisfaction with the initial process included the following: complexity of process; unclear delineation of staff roles; time burden to completion; high patient volume; and lack of standardized communication of task completion. Overall satisfaction improved after the intervention. The greatest improvement was seen in the correct medication (difference 20.7%, confidence interval [CI] 6.3-33.9%, P < 0.01), correct dose (25.6%, CI 11.4-38.6%, P < 0.001) and time last taken (24.5%, CI 11.4-37.0%, P < 0.001). Conclusion: There is a steep learning curve to educate multidisciplinary staff on a new process and implement the associated changes. With goals to impact the safety of our patients and reduce negative outcomes, engagement and awareness of the team involved in the medication reconciliation process is critical to improve staff satisfaction.

Patiromer to Reduce Albuminuria Through Increased Renin Angiotensin Aldosterone System Inhibition in Patients With CKD-A Feasibility Trial.

Introduction: We tested the feasibility of adding a potassium binder to enable increased renin angiotensin aldosterone system inhibition (RAASi) and reduce albuminuria in patients with chronic kidney disease (CKD). In a controlled trial design, a potassium binder was introduced exclusively in patients developing hyperkalemia after intensified RAASi, thereby mirroring clinical decision-making. Methods: We planned to include 140 patients aged 18 to 80 years with estimated glomerular filtration rate (eGFR) 25 to 60 ml/min per 1.73 m2, albuminuria, and a history of hyperkalemia to an open-label, randomized trial comparing treatment with or without patiromer alongside maximally tolerated RAASi. Patients were randomized only if developing a documented P-potassium >5.5 mmol/l during run-in with intensified RAASi (losartan/spironolactone). The primary end point was change in urine albumin-creatinine ratio (UACR). Results: Screening among 800,000 individuals with available laboratory results yielded just 317 candidates meeting major selection criteria during 18⅔ months, with 75 ultimately included. Among them, only 23 developed P-potassium >5.5 mmol/l, qualifying for randomization. Consequently, only 20 participants completed the study, falling short of the planned 98, precluding a significant effect on the primary outcome. Inclusion and randomization challenges stemmed from a limited pool of eligible patients for intensified RAASi at risk of hyperkalemia, along with a lower than expected incidence of hyperkalemia during run-in. Conclusion: Despite extensive screening efforts, few eligible patients were identified, and fewer developed hyperkalemia during run-in. Hence, a trial design limited to CKD patients at high hyperkalemia risk and including a run-in phase appears unlikely to provide evidence for a potential renal benefit from additional use of potassium binders.

Age- and time-dependent increases in incident anti-glomerular basement membrane disease: a nationwide cohort study.

Background: Epidemiologic assessments of anti-glomerular basement membrane (GBM) disease have been challenging due to its rare occurrence. We examined changes in the incidence and outcomes from 1998 to 2018 using nationwide healthcare registries. Methods: All patients with incident anti-GBM disease were identified using the International Classification of Diseases, 10th Revision code DM31.0A. Controls were matched 4:1 on birthyear and sex using exposure density sampling. Log link regression adjusted for time, age and sex was applied to model survival. Results: We identified 97 patients with incident anti-GBM disease, corresponding to an incidence of 0.91 cases/million/year [standard deviation (SD) 0.6]. The incidence increased over time [1998-2004: 0.50 (SD 0.2), 2005-2011: 0.80 (SD 0.4), 2012-2018: 1.4 (SD 0.5); P = .02] and with age [0.76 (SD 0.4), 1.5 (SD 1.04) and 4.9 (SD 2.6) for patients <45, 45-75 and >75 years]. The median age was 56 years (interquartile range 46) and 51.6% were female. Dialysis was required in 58.4%, 61.9% and 62.9% of patients at day 30, 180 and 360, respectively. The 1-year kidney survival probability was 0.38 (SD 0.05) and exhibited time-dependent changes [1998-2004: 0.47 (SD 0.13), 2005-2011: 0.16 (SD 0.07), 2012-2018: 0.46 (SD 0.07); P = .035]. The 5-year mortality was 26.8% and mortality remained stable over time (P = .228). The risk of death was greater than that of the matched background population {absolute risk ratio [ARR] 5.27 [confidence interval (CI) 2.45-11.3], P < .001}, however, it was comparable to that of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) requiring renal dialysis at presentation [ARR 0.82 (CI 0.48-1.41), P = .50]. Conclusion: The incidence of anti-GBM disease increased over time, possibly related to temporal demographic changes. Mortality remained high and was comparable with an age- and sex-matched cohort of dialysis-dependent AAV patients.

Retrospective validation of acute heart failure risk stratification in the emergency department.

BACKGROUND: Heart Failure (HF) is a primary diagnosis for hospital admission from the Emergency Department (ED), although not all patients require hospitalization. The Emergency Heart Failure Mortality Risk Grade (EHMRG) estimates 7-day mortality in patients with acute HF in ED settings, but further validation is needed in the United States (US). OBJECTIVES: To validate EHMRG scores by risk-stratifying patients with acute HF in a large tertiary healthcare center in the US and analyze outcome measures to determine if EHMRG risk scores safely identify low-risk groups that may be discharged or managed in ED observation units (EDOUs). METHODS: A retrospective cohort analysis of 304 patients with acute HF presenting to an ED at a large, tertiary healthcare center was completed. EHMRG scores were calculated to stratify patients according to published thresholds. Mortality and major adverse cardiac event (MACE) rates were analyzed. RESULTS: No deaths occurred in very low and low-risk EHMRG groups at 7 days post discharge. 30-day mortality was significantly less in the lower risk groups (3.1%) when compared to all other patients (11.1%). MACE rates at 30 days in the very low risk group (15%) were significantly less when compared to all other patients (31.3%). Hospitalizations occurred in 23.4% of patients in lower risk groups. CONCLUSIONS: ED risk stratification with EHMRG differentiates high-risk patients requiring hospitalization from lower risk patients who can be safely managed in alternative settings with good outcomes. Data supports improved pathways for patients with acute HF during a time of high hospital volumes.

A groupwise association test for rare mutations using a weighted sum statistic.

Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used.

Influence of Test Specimen Geometry on Probability of Failure of Composites Based on Weibull Weakest Link Theory.

This paper presents an analytical model that quantifies the stress ratio between two test specimens for the same probability of failure based on the Weibull weakest link theory. The model takes into account the test specimen geometry, i.e., its shape and volume, and the related non-constant stress state along the specimen. The proposed model is a valuable tool for quantifying the effect of a change of specimen geometry on the probability of failure. This is essential to distinguish size scaling from the actual improvement in measured strength when specimen geometry is optimized, aiming for failure in the gauge section. For unidirectional carbon fibre composites with Weibull modulus m in the range 10-40, it can be calculated by the model that strength measured with a straight-sided specimen will be 1-2% lower than the strength measured with a specific waisted butterfly-shaped specimen solely due to the difference in test specimen shape and volume.

Comparison of emergency department throughput and process times between male and female patients: A retrospective cohort investigation by the Reducing Disparities Increasing Equity in Emergency Medicine Study Group.

Introduction: Health equity for all patients is an important characteristic of an effective healthcare system. Bias has the potential to create inequities. In this study, we examine emergency department (ED) throughput and care measures for sex-based differences, including metrics such as door-to-room (DTR) and door-to-healthcare practitioner (DTP) times to look for potential signs of systemic bias. Methods: We conducted an observational cohort study of all adult patients presenting to the ED between July 2015 and June 2017. We collected ED operational, throughput, clinical, and demographic data. Differences in the findings for male and female patients were assessed using Poisson regression and generalized estimating equations (GEEs). A priori, a clinically significant time difference was defined as 10 min. Results: A total of 106,011 adult visits to the ED were investigated. Female patients had 8-min longer median length-of-stay (LOS) than males (P < 0.01). Females had longer DTR (2-min median difference, P < 0.01), and longer DTP (5-min median difference, P < 0.01). Females had longer median door-to-over-the-counter analgesia time (84 vs. 80, P = 0.58), door-to-advanced analgesia (95 vs. 84, P < 0.01), door-to-PO (by mouth) ondansetron (70 vs. 62, P = 0.02), and door-to-intramuscular/intravenous antiemetic (76 vs. 69, P = 0.02) times compared with males. Conclusion: Numerous statistically significant differences were identified in throughput and care measures-mostly these differences favored male patients. Few of these comparisons met our criteria for clinical significance.

Prioritizing health care workers and first responders for access to the COVID19 vaccine is not unethical, but both fair and effective - an ethical analysis.

The Nordic countries have differed in their approach as to how much priority for COVID19 vaccine access should be given to health care workers. Two countries decided not to give health care workers highest priority, raising some controversy. The rationale was that those at highest risk of dying needed to come first. However, when it comes to protecting those at the highest risk of dying from COVID19, their needs and vulnerabilities need to be considered more broadly than just in terms of the individual protection that vaccination will afford them. Likewise, when considering whether to prioritize health care workers for the vaccine, their crucial role in keeping the health care system operational, and right to a safe work environment need to be factored in. Below we review several ethical arguments for why frontline health care workers and first responders should receive priority access to the COVID19 vaccine.

Experimental Method for Tensile Testing of Unidirectional Carbon Fibre Composites Using Improved Specimen Type and Data Analysis.

This paper presents an experimental method for tensile testing of unidirectional carbon fibre composites. It uses a novel combination of a new specimen geometry, protective layer, and a robust data analysis method. The experiments were designed to test and analyze unprotected (with conventional end-tabs) and protected (with continuous end-tabs) carbon fibre composite specimens with three different specimen geometries (straight-sided, butterfly, and X-butterfly). Initial stiffness and strain to failure were determined from second-order polynomial fitted stress-strain curves. A good agreement between back-calculated and measured stress-strain curves is found, on both composite and fibre level. For unprotected carbon composites, the effect of changing specimen geometry from straight-sided to X-butterfly was an increase in strain to failure from 1.31 to 1.44%. The effect of protection on X-butterfly specimens was an increase in strain to failure from 1.44 to 1.53%. For protected X-butterfly specimens, the combined effect of geometry and protection led to a significant improvement in strain to failure of 17% compared to unprotected straight-sided specimens. The observed increasing trend in the measured strain to failure, by changing specimen geometry and protection, suggests that the actual strain to failure of unidirectional carbon composites is getting closer to be realized.

Experimental evaluation of stiffness predictions of multiaxial flax fibre composites by classical laminate theory.

Despite the good mechanical properties of natural fibre composites, their use in load-bearing components is still limited, which may be due to lack of knowledge and confidence in calculating the performance of the composites by mechanical models. The present study is providing an experimental evaluation of stiffness predictions of multiaxial flax fibre composite by classical laminate theory (CLT). The experimental base is (i) multiaxial flax fibre composites fabricated with two types of biaxial non-crimp fabrics, having a nominal yarn orientation of ±45°, and (ii) uniaxial flax fibre composites fabricated with the same flax yarn as used in the fabrics. The fabricated composites are characterised by volumetric composition, yarn orientation and tensile properties. A fast and easy operational Fast Fibre Orientation (FFO) method is developed to determine the actual yarn orientation in fabrics and composites. It is demonstrated that the FFO method is a robust method, giving repeatable results for yarn orientations, and it can be used both on fabrics and composites. CLT predictions of stiffness of the multiaxial flax fibre composites are shown to be in good agreement with the measured stiffnesses of the composites in three testing directions (0°, 45°, and 90°). The use of the actual yarn orientations measured by the FFO method, instead of the nominal yarn orientations of ±45°, is shown to result in improved CLT predictions of stiffness with a mean deviation between predictions and measurements on 0.2 GPa. Altogether, it is demonstrated that stiffness of multiaxial flax fibre composites can be accurately predicted by CLT, without any fitting constants, based on independently determined stiffness parameters of the related uniaxial flax fibre composite, and based on measured yarn orientations in the flax fibre fabric.

Risk of death within 7 days of discharge from emergency departments with different organizational models.

OBJECTIVE: The aim of this study is to investigate the association between emergency department (ED) organizational models and the risk of death within 7 days of ED discharge. PATIENTS AND METHODS: We included Danish ED discharges between 1 January 2011 and 24 December 2014 that led to death within 7 days of discharge. The inclusion criterion was age older than 18 years. The exclusion criterion was further in-hospital admission. First model (Virtual): other departments employ interns who perform ED tasks. They are responsible for ED patient care and prioritize their task order between their own department and the ED. Second model (Hybrid): the ED/other departments perform tasks; interns/consultants are employed by the ED/other departments. The ED/other departments have patient care responsibility. Third model (Independent): the ED performs all tasks; employs interns/consultants; and have patient care responsibility. Sex, age, Charlson Comorbidity Index score, and primary diagnosis were used to describe patient characteristics. We calculated the risk of death within 7 days of discharge using multiple logistic regression analysis. RESULTS: In 805 out of 201 299 discharges included in the study, the patient died within 7 days. Compared with the Virtual model, the odds ratio for death within 7 days of discharge was 0.72 (95% confidence interval: 0.59-0.92) for the Independent model and 0.75 (95% confidence interval: 0.61-0.92) for the Hybrid+Virtual model. Increased risk was associated with male sex, older age, and a medium or a high Charlson Comorbidity Index score. CONCLUSION: Compared with discharges from a Virtual model, the risk of death within 7 days of discharge was lower if the ED had an Independent or a Hybrid+Virtual model.

The organization of Danish emergency departments.

INTRODUCTION: Twenty-one new Danish emergency departments (EDs) were established following a 2007 policy reform that included ED autonomy to self-organize. The aim of this study was to describe the organization of the 21 departments and their organizational challenges. PARTICIPANTS AND METHODS: We used a qualitative design based on COREQ guidelines. All 21 EDs participated, and 123 semi-structured interviews with hospital and ED leaders, physicians, nurses, and secretaries were performed between 2013 and 2015. We used the framework matrix method to investigate the ED goals, setting, structure, staff, task coordination, and incentive structure. RESULTS: We identified three generic models (virtual, hybrid, and independent). All had goals of high quality of care and high efficiency. The virtual model was staffed by junior physicians and tasks were coordinated by other departments. The hybrid model was staffed by junior physicians and senior physicians according to other departments and the ED. The ED coordinated all activities. The independent model was staffed by junior physicians and senior physicians, and activities were coordinated by the ED. Of the EDs, 19 utilized different organizational models at different times during a 24-h period and on weekdays and weekends. The main challenge of the virtual and hybrid models was high dependency on other departments. The main challenge of the independent model was establishing a high level of quality of emergency medicine. DISCUSSION AND CONCLUSION: We identified three organizational ED models (virtual, hybrid, and independent). Nineteen EDs used more than one organizational model depending on the time of day or day of the week.

Short tandem repeats in human exons: a target for disease mutations.

BACKGROUND: In recent years it has been demonstrated that structural variations, such as indels (insertions and deletions), are common throughout the genome, but the implications of structural variations are still not clearly understood. Long tandem repeats (e.g. microsatellites or simple repeats) are known to be hypermutable (indel-rich), but are rare in exons and only occasionally associated with diseases. Here we focus on short (imperfect) tandem repeats (STRs) which fall below the radar of conventional tandem repeat detection, and investigate whether STRs are targets for disease-related mutations in human exons. In particular, we test whether they share the hypermutability of the longer tandem repeats and whether disease-related genes have a higher STR content than non-disease-related genes. RESULTS: We show that validated human indels are extremely common in STR regions compared to non-STR regions. In contrast to longer tandem repeats, our definition of STRs found them to be present in exons of most known human genes (92%), 99% of all STR sequences in exons are shorter than 33 base pairs and 62% of all STR sequences are imperfect repeats. We also demonstrate that STRs are significantly overrepresented in disease-related genes in both human and mouse. These results are preserved when we limit the analysis to STRs outside known longer tandem repeats. CONCLUSION: Based on our findings we conclude that STRs represent hypermutable regions in the human genome that are linked to human disease. In addition, STRs constitute an obvious target when screening for rare mutations, because of the relatively low amount of STRs in exons (1,973,844 bp) and the limited length of STR regions.

The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population.

BACKGROUND: Mutations in the mismatch repair genes hMLH1 and hMSH2 predispose to hereditary non-polyposis colorectal cancer (HNPCC). Genetic screening of more than 350 Danish patients with colorectal cancer (CRC) has led to the identification of several new genetic variants (e.g. missense, silent and non-coding) in hMLH1 and hMSH2. The aim of the present study was to investigate the frequency of these variants in hMLH1 and hMSH2 in Danish patients with sporadic colorectal cancer and in the healthy background population. The purpose was to reveal if any of the common variants lead to increased susceptibility to colorectal cancer. METHODS: Associations between genetic variants in hMLH1 and hMSH2 and sporadic colorectal cancer were evaluated using a case-cohort design. The genotyping was performed on DNA isolated from blood from the 380 cases with sporadic colorectal cancer and a sub-cohort of 770 individuals. The DNA samples were analyzed using Single Base Extension (SBE) Tag-arrays. A Bonferroni corrected Fisher exact test was used to test for association between the genotypes of each variant and colorectal cancer. Linkage disequilibrium (LD) was investigated using HaploView (v3.31). RESULTS: Heterozygous and homozygous changes were detected in 13 of 35 analyzed variants. Two variants showed a borderline association with colorectal cancer, whereas the remaining variants demonstrated no association. Furthermore, the genomic regions covering hMLH1 and hMSH2 displayed high linkage disequilibrium in the Danish population. Twenty-two variants were neither detected in the cases with sporadic colorectal cancer nor in the sub-cohort. Some of these rare variants have been classified either as pathogenic mutations or as neutral variants in other populations and some are unclassified Danish variants. CONCLUSION: None of the variants in hMLH1 and hMSH2 analyzed in the present study were highly associated with colorectal cancer in the Danish population. High linkage disequilibrium in the genomic regions covering hMLH1 and hMSH2, indicate that common genetic variants in the two genes in general are not involved in the development of sporadic colorectal cancer. Nevertheless, some of the rare unclassified variants in hMLH1 and hMSH2 might be involved in the development of colorectal cancer in the families where they were originally identified.