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Gastrointestinal Diseases (gastrointestinal + disease)
Kinds of Gastrointestinal Diseases Selected AbstractsMassive Hiatal Hernia of Gastrointestinal Tract: A Rare Intrathoracic Gastrointestinal DiseaseJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 11 2009Wing-Keung Cheung MD No abstract is available for this article. [source] Clinical Nutrition in Gastrointestinal Disease.OBESITY REVIEWS, Issue 2 2007Edited by Alan L. Buchman. [source] Methodology and Indications of H2 -Breath Testing in Gastrointestinal Diseases: the Rome Consensus ConferenceALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2009Article first published online: 30 MAR 200 First page of article [source] Emergency case admissions at a large animal tertiary university referral hospital during a 12-month periodJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 3 2008Brett A. Dolente VMD, DACVIM Abstract Objective: To collate and describe emergency admissions to a large animal tertiary university referral hospital during a 12-month period. Design: Prospective clinical study. Setting: Large animal tertiary university referral hospital. Animals: Large animal emergency patient admissions. Interventions: None. Measurements and main results: Information obtained from the medical record included the presenting complaint, clinical problem, admission time, duration of clinical signs before presentation, diagnostic procedures performed, therapies administered, and therapeutic procedures performed during the first 24 hours following admission, and survival to discharge. The most common category listed for the presenting complaint and clinical problem categories was gastrointestinal. Most emergency cases were admitted during the evening and in late spring, summer, and early fall. Most cases had a duration of clinical signs before presentation of >2 hours and ,8 hours (27%) or >8 hours and ,24 hours (29%). The most common diagnostic procedures performed during the first 24 hours were palpation per rectum, ultrasonographic examination, radiographs, and abdominocentesis. Antimicrobials, fluids, and nonsteroidal anti-inflammatory drugs were the most common therapies administered. Approximately 25% of cases required surgery. An exploratory celiotomy was performed in approximately 15% of cases. Enterotomy, intestinal resection and anastomosis, cesarean section, or joint or sheath lavage was each performed in <5% of cases. Overall survival to discharge was 74%. Conclusions: Large animal emergency clinicians are required to have knowledge on a wide range of diseases and should be proficient at performing numerous procedures on an emergency basis. Gastrointestinal disease is the most common type of emergency and the diagnostic and therapeutic procedures performed during the first 24 hours following admission are a reflection of this type of case. Only 25% of cases required surgery. Additional research in the form of a multicenter study and surveying both private and university practitioners needs to be performed to further define the necessary skills for an ,ideal' large animal emergency clinician. [source] Halitosis among racially diverse populations: an updateINTERNATIONAL JOURNAL OF DENTAL HYGIENE, Issue 1 2008S Rayman Abstract:, The aim of this paper is to highlight the cultural perceptions of halitosis to dental professionals. Halitosis (oral malodour or bad breath) is caused mainly by tongue coating and periodontal disease. Bacterial metabolism of amino acids leads to metabolites including many compounds, such as indole, skatole and volatile sulphur compounds (VSC), hydrogen sulphide, methyl mercaptan and dimethyl sulphide. They are claimed to be the main aetiological agents for halitosis. Gastrointestinal diseases are also generally believed to cause halitosis. In general, physicians and dentists are poorly informed about the causes and treatments for halitosis. The paper reviews the prevalence and distribution of halitosis, oral malodour, its aetiology, concepts of general and oral health and diseases and their perception among racially diverse population. Eating, smoking and drinking habits and understanding of halitosis as a social norm among different people has been highlighted. The treatment options have also been presented very briefly. A brief discussion about general importance within existing healthcare services has been highlighted. Oral malodour may rank only behind dental caries and periodontal disease as the cause of patient's visits to the dentist. It is a public social health problem. The perception of halitosis is different in culturally diverse populations. So the dental professionals should be aware of the cultural perceptions of halitosis among racially and culturally diverse populations. There is a need to integrate the cultural awareness and knowledge about halitosis among the dental professional for better understanding of halitosis to treat patients with the social dilemma of halitosis to improve the quality of life and well-being of individuals with the problem. It is concluded that dental professionals (especially dental hygienists) should be prepared to practice in a culturally diverse environment in a sensitive and appropriate manner, to deliver optimal oral health and hygiene care. [source] Risk factors for faecal sand excretion in Icelandic horsesEQUINE VETERINARY JOURNAL, Issue 4 2005L. HUSTED Summary Reasons for performing study: Sandy soil is often mentioned as a risk factor in the development of sand-related gastrointestinal disease (SGID) in the horse. There are other variables, but few studies confirm any of these. Objective: To investigate soil type, pasture quality, feeding practice in the paddock, age, sex and body condition score as risk factors for sand intake in the horse. Methods: Faeces were collected from 211 Icelandic horses on 19 different studs in Denmark together with soil samples and other potential risk factors. Sand content in faeces determined by a sand sedimentation test was interpreted as evidence of sand intake. Soil types were identified by soil analysis and significance of the data was tested using logistic analysis. Results: Of horses included in the study, 56.4% showed sand in the faeces and 5.7% had more than 5 mm sand as quantified by the rectal sleeve sedimentation test. Soil type had no significant effect when tested as main effect, but there was interaction between soil type and pasture quality. Significant interactions were also found between paddock feeding practice and pasture quality. Conclusion: To evaluate the risk of sand intake it is important to consider 3 variables: soil type, pasture quality and feeding practice. Pasture quality was identified as a risk factor of both short and long grass in combination with sandy soil, while clay soil had the lowest risk in these combinations. Feeding practice in the paddock revealed feeding directly on the ground to be a risk factor when there was short (1,5 cm) or no grass. Also, no feeding outdoors increased the risk on pastures with short grass, while this had no effect in paddocks with no grass. More than 50% of all horses investigated in this study had sand in the faeces. Potential relevance: The identification of risk factors is an important step towards prevention of SGID. Further research is necessary to determine why some horses exhibit more than 5 mm sand in the sedimentation test and whether this is correlated with geophagic behaviour. [source] Prognostic value of serum angiogenic activity in colorectal cancer patientsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2007Francisco-Jesus Gonzalez Abstract Angiogenesis, resulting from an imbalance between angiogenic activator factors and inhibitors, is required for tumour growth and metastasis. The determination of the circulating concentration of all angiogenic factors (activators and inhibitors) is not feasible at present. We have evaluated diagnostic and prognostic values of the measurement of serum angiogenic activity in colorectal carcinoma (CRC) patients. Serum proliferative activity (PA) on human umbilical vein endothelial cells (HUVEC) in vitro, and serum vascular endothelial growth factor (VEGF) levels were determined by ELISA in 53 patients with primary CRC, 16 subjects with non-neoplastic gastrointestinal disease (SC) and 34 healthy individuals. Data were compared with clinical outcome of the patients. Although serum from CRC patients significantly increased the PA of HUVEC, compared to culture control (HUVEC in medium + 10% foetal bovine serum (FBS); P < 0.001); our results indicate that serum PA in CRC patients was similar to that of SC or healthy individuals. There was no correlation between serum PA and circulating VEGF concentrations. Surgery produced a decrease of PA at 8 hrs after tumour resection in CRC patients compared to pre-surgery values (186 ± 47 versus 213 ± 41, P < 0.001). However, an increase in serum VEGF values was observed after surgery (280 [176,450] versus 251 [160,357] pg/ml, P = 0.004). Patients with lower PA values after surgery showed a worse outcome that those with higher PA values. Therefore, this study does not support a diagnostic value for serum angiogenic activity measured by proliferative activity on HUVEC but suggests it could have a prognostic value in CRC patients. [source] Changing trends in gastrointestinal disease in the Asia,Pacific regionJOURNAL OF DIGESTIVE DISEASES, Issue 4 2007KL GOH The new millennium has seen distinct changes in the pattern of gastrointestinal disease in the Asia,Pacific region. These changes are important as more than half of the world's population come from the region and therefore impact significantly on the global disease burden. The highest incidence of gastric cancer (GCA) has been reported from Asia and GCA remains a very important cancer. However time-trend studies have shown a decrease in GCA incidence in several countries in Asia. A rise in cardio-esophageal cancers as seen in the West has not been reported. On the other hand, colorectal cancer has been steadily increasing in Asia with age-standardized incidence rates of some countries approaching that of the West. The pattern of acid-related diseases has also changed. Gastroesophageal reflux disease is a fast emerging disease with an increasing prevalence of reflux esophagitis and reflux symptoms. The prevalence of peptic ulcer disease has at the same time declined in step with a decrease in H. pylori infection. Many of the changes taking place mirror the Western experience of several decades ago. Astute observation of the epidemiology of emerging diseases combined with good scientific work will allow a clearer understanding of the key processes underlying these changes. With rapid modernization, lifestyle changes have been blamed for an increase in several diseases including gastroesophageal reflux disease, nonalcoholic fatty liver disease and colorectal cancer. A worrying trend has been the increase in obesity among Asians, which has been associated with an increase in metabolic diseases and various gastrointestinal cancers. Conversely, an improvement in living conditions has been closely linked to the decrease in GCA and H. pylori prevalence. [source] Toll-like receptors and their role in gastrointestinal diseaseJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 6 2009Adam G Testro Abstract The innate immune response to invading pathogens is centred upon a family of non-clonal, germline-encoded pattern recognition receptors (PRRs), the Toll-like receptors (TLRs). These provide specificity for a vast range of microbial pathogens, and offer an immediate anti-microbial response system. Thirteen mammalian TLRs have been described; 10 are expressed in humans, each responsible for the recognition of distinct, invariant microbial structures originating from bacteria, viruses, fungi and protozoa. The two most thoroughly studied are TLR4 and TLR2, the PRRs for Gram-negative and Gram-positive bacterial products, respectively. TLR4 is also the major receptor recognising endogenous ligands released from damaged or dying cells. Activation of a TLR by its relevant ligand rapidly ignites a complex intracellular signaling cascade that ultimately results in upregulation of inflammatory genes and production of proinflammatory cytokines, interferons and recruitment of myeloid cells. It also stimulates expression, upon antigen presenting cells, of co-stimulatory molecules required to induce an adaptive immune response. Whilst a robust TLR response is critical for survival and defence against invading pathogens, inappropriate signaling in response to alterations in the local microflora environment can be detrimental. Such ,unhelpful TLR responses' could form the basis for a large number of gastrointestinal and liver disorders, including inflammatory bowel disease, viral hepatitis, autoimmune liver diseases and hepatic fibrosis. As our understanding of TLRs expands, the pathogenesis of a number of gastrointestinal disorders will be further elucidated, and this offers potential for specific therapies aimed directly at TLR signaling. [source] Comparison of viral load and duration of virus shedding in symptomatic and asymptomatic neonatal rotavirus infectionsJOURNAL OF MEDICAL VIROLOGY, Issue 10 2010Sasirekha Ramani Abstract A single rotavirus strain causing asymptomatic infections as well as severe gastrointestinal disease has been described in the neonatal nurseries of the Christian Medical College, Vellore. In this study, quantitative real-time RT-PCR was used to determine the association of viral load with the presence of gastrointestinal symptoms in neonates. Viral load was estimated in terms of the crossing point [C(t) value] at which the amplicon could be detected in the real-time PCR assay. The study was carried out on 103 neonates, including 33 asymptomatic neonates and 70 neonates with different gastrointestinal symptoms. The duration of virus shedding was also compared between five symptomatic and four asymptomatic neonates using real-time RT-PCR. There was no significant difference in viral load between symptomatic and asymptomatic neonates (P,=,0.087). Among neonates with different gastrointestinal symptoms, those presenting with feed intolerance and abdominal distension had a significantly higher viral load than those with other gastrointestinal symptoms (P,=,0.02). For the study on virus shedding, nine neonates were followed up for a median duration of 53 days, with a median of 31 samples tested per child. Extended shedding of low copies of rotavirus was found, with no significant differences in pattern of shedding between symptomatic and asymptomatic neonates. The lack of correlation between viral load and gastrointestinal disease demonstrates yet another difference between neonatal rotavirus infection and infection in older children where higher viral load correlates with severe disease. J. Med. Virol. 82:1803,1807, 2010. © 2010 Wiley-Liss, Inc. [source] Mean Corpuscular Volume and ADH1C Genotype in White Patients With Alcohol-Associated DiseasesALCOHOLISM, Issue 5 2005Leimin Sun Background: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volume (MCV) has been recognized as a biomarker for alcohol abuse and heavy drinkers. Recent studies from Japan revealed that macrocytosis is related to ALDH-2/2 genotype, leading to increased acetaldehyde accumulation. It has also demonstrated that increased MCV values could also be an independent biomarker for esophageal cancer in Asians. Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage. Methods: In this study, a total of 510 alcoholic patients were enrolled with esophageal cancer (n= 98), chronic pancreatitis (n= 98), alcoholic liver cirrhosis (n= 151), and alcohol abuse without gastrointestinal disease (n= 163). ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2) controlled for the amount of drinking, smoking, and age were investigated using both univariate and multivariate analysis. Results: In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis. In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCV values. No other variables, including which alcohol-associated disease the patient had, had an independent effect. Adding ADH genotype rendered no independent significant effect on MCV value. Conclusions: In a white population, MCV values were not associated with genotype polymorphisms of ADH1C. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma are still pending. [source] Lactose intolerance in patients with chronic functional diarrhoea: the role of small intestinal bacterial overgrowthALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2010J. ZHAO Aliment Pharmacol Ther,31, 892,900 Summary Background, Many studies report a high prevalence of lactose intolerance in patients with functional, gastrointestinal disease. Aim, To evaluate the role of small intestinal bacterial overgrowth (SIBO) in condition of lactose intolerance and the mechanism by which SIBO may impact lactose tolerance in affected patients. Methods, Consecutive out-patients with chronic functional diarrhoea (CFD) and healthy controls underwent a validated 20 g lactose hydrogen breath test (HBT). Patients completed also a 10 g lactulose HBT with concurrent assessment of small bowel transit by scintigraphy. Results, Lactose malabsorption was present in 27/31 (87%) patients with CFD and 29/32 (91%) healthy controls (P = 0.708). From the patient group 14/27 (52%) had lactose intolerance and 13/27 (48%) experienced no symptoms (lactose malabsorption controls). Only 5 (17%) healthy controls reported symptoms (P < 0.01). The oro-caecal transit time was similar between patient groups with or without symptoms (P = 0.969). SIBO was present in 11 (41%) subjects and was more prevalent in lactose intolerance than in lactose malabsorption [9/14 (64%) vs. 2/13 (15%), P = 0.018]. Symptom severity was similar in lactose intolerance patients with and without SIBO (P = 0.344). Conclusions, Small intestinal bacterial overgrowth increases the likelihood of lactose intolerance in patients with CFD as a direct result of lactose fermentation in the small intestine, independent of oro-caecal transit time and visceral sensitivity. [source] Clinical and biochemical abnormalities in endurance horses eliminated from competition for medical complications and requiring emergency medical treatment: 30 cases (2005,2006)JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 5 2009C. Langdon Fielding DVM, DACVECC Abstract Objective , To describe the clinical and clinicopathologic abnormalities in endurance horses eliminated from competition and requiring emergency medical treatment. Design , Retrospective study over a 2-year period (2005,2006). Ten horses that successfully completed the ride in 2006 were included for comparison. Setting , Temporary equine emergency field hospital. Animals , All horses (n=30) that were removed from endurance competition and treated for a metabolic abnormality were studied. Interventions , Horses were treated with IV fluids and analgesics. Monitoring included lab work (PCV, total protein, and electrolytes) and serial physical examinations. Statistical analysis included descriptive statistics and parametric and nonparametric comparisons (ANOVA, Friedman's test, and Kruskal-Wallis) where appropriate. Measurements and Main Results , The clinical diagnoses identified included colic, esophageal obstruction, poor cardiovascular recovery, myopathy, and synchronous diaphragmatic flutter. As a group, these sick horses had lower plasma chloride and potassium and higher total plasma protein concentrations as compared with 10 healthy horses that successfully completed the ride (P<0.05, <0.01, and <0.05 for chloride, potassium, and total protein, respectively). Horses with colic had a lower PCV as compared with horses with poor recovery and those with synchronous diaphragmatic flutter (P<0.05). All horses, including colics, were treated medically and discharged to owners. Conclusions , Based on the results of this study, the prognosis for horses requiring emergency veterinary treatment after being removed from endurance competition (for metabolic reasons) appears to be good if horses are withdrawn from competition under the same criteria outlined in this study. Biochemical abnormalities tend to be mild and do not necessarily aid in delineating sick horses from successfully completing horses. None of the horses with gastrointestinal disease required abdominal surgery. [source] Use of serum biomarkers in a diagnostic test for irritable bowel syndromeALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2009A. J. LEMBO Summary Background Currently, no single serum biomarker can reliably differentiate irritable bowel syndrome (IBS) from other functional gastrointestinal disorders or organic diseases of the gastrointestinal tract. Aim To develop and validate a diagnostic test using serum biomarkers to detect IBS. Methods Ten serum biomarkers were selected from a potential panel of 140 for their ability to differentiate IBS from non-IBS disease in blood samples from patients with IBS, other gastrointestinal disorders and healthy volunteers. A predictive modelling tool was developed to assess patterns and relationships among the 10 serum biomarkers that best differentiated IBS patients from healthy controls and patients with non-IBS gastrointestinal disease. This model was tested in a different cohort of patients and healthy controls (n = 516) to determine the predictive accuracy of differentiating IBS from non-IBS. Results The sensitivity and specificity of the 10-biomarker algorithm for differentiating IBS from non-IBS was 50% and 88% respectively. The positive predictive value was 81%, and the negative predictive value was 64% at 50% IBS prevalence in the validation cohort. Overall accuracy was 70%. Conclusions Assessing serum biomarker patterns can differentiate IBS from non-IBS with reasonable sensitivity and specificity. Assessing serum biomarkers in an overall diagnostic strategy may allow earlier diagnosis and treatment for patients with IBS. [source] Time trends in peptic ulcer, erosive reflux oesophagitis, gastric and oesophageal cancers in a multiracial Asian populationALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2009K.-L. GOH Summary Background, Dramatic changes in the prevalence and pattern of gastrointestinal disease has taken place in Asia in recent years. Aim, To compare the prevalence of duodenal (DU) and gastric ulcers (GU), erosive oesophagitis (EO), gastric cancer (GCA) and oesophageal cancer (OCA) and Helicobacter pylori infection over a 10-year interval of time in a multiracial South-East Asian population. Methods, Endoscopy records of first time gastroscopy in the University of Malaya Medical Centre, Kuala Lumpur, Malaysia were reviewed for 1989/1990 and 1999/2000. Results, In the period of 1989,1990, 3252 records and in 1999,2000, 4615 records were analysed. Both DU (21.1,9.5%) and GU (11.9,9.4%) had decreased significantly (P < 0.001). EO had increased significantly from 2.0% to 8.4% (P < 0.001). Both GCA and OCA had declined in the 10-year interval. Helicobacter pylori prevalence had decreased from 51.7% to 30.3% (P < 0.001). The decrease in DU and GU was seen in all racial groups. The increase in EO was most marked in Indians and the decrease in GCA in Chinese. The proportion of H. pylori- associated DU and GU had also decreased with time. Conclusions, Peptic ulcers and H. pylori infection had declined over a 10-year period of time and showed an opposing time trend with EO, which had increased dramatically. Both GCA and OCA had declined in prevalence. [source] Perinuclear Antineutrophilic Cytoplasmic Antibody and Response to Treatment in Diarrheic Dogs with Food Responsive Disease or Inflammatory Bowel DiseaseJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2006Nicole Luckschander The goal of this study was to investigate the correlation between perinuclear antineutrophilic cytoplasmic antibody (pANCA) and clinical scores before and after treatment in diarrheic dogs with food-responsive disease (FRD) or inflammatory bowel disease (IBD). pANCA serology was evaluated prospectively by indirect immunofluorescence in 65 dogs with signs of gastrointestinal disease, and if positive, pANCA antibody titers were determined. Thirty-nine dogs with FRD responded to a novel diet, and 26 dogs with IBD were treated with corticosteroids. The severity of clinical signs was scored by means of a canine IBD activity index (CIBDAI). At initial examination, a significantly (P= .002) higher percentage of dogs were pANCA-positive in the FRD group (62%) compared with the IBD group (23%). pANCA titers were significantly higher (P=.003) before treatment in the FRD group (median titer 100) compared with the IBD group (median titer 1). However, there was no difference in pANCA titers between the groups after respective treatments because dogs in the IBD group had a significant increase in pANCA titer after treatment. The CIBDAI score decreased significantly (P <.001) after treatment in both groups (74% moderate to severe in FRD dogs before versus 8% after treatment; 85% moderate to severe in IBD dogs before versus 32% after treatment). There was no correlation between pANCA status in FRD or IBD dogs before treatment and scores for CIBDAI, endoscopy, or histopathology before or after treatment, except for the endoscopic duodenal score in dogs with FRD after treatment (P= .03). A positive pANCA test before therapy may aid in the diagnosis of FRD. [source] Retrospective Evaluation of Partial Parenteral Nutrition in Dogs and CatsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2002Daniel L. Chan The purpose of this retrospective study was to evaluate the use of partial parenteral nutrition (PPN) in dogs and cats. The medical records of all dogs and cats receiving PPN between 1994 and 1999 were reviewed to determine signalment, reasons for use of PPN, duration of PPN administration, duration of hospitalization, complications, and mortality. Complications were classified as metabolic, mechanical, or septic. One hundred twenty-seven animals (80 dogs and 47 cats) were included in the study, accounting for 443 patient days of PPN. The most common underlying diseases were pancreatitis (n = 41), gastrointestinal disease (n = 33), and hepatic disease (n = 23). Median time of hospitalization before initiation of PPN was 2.8 days (range, 0.2,10.7 days). Median duration of PPN administration was 3.0 days (range, 0.3,8.8 days). Median duration of hospitalization was 7 days (range, 2,20 days). In the 127 animals receiving PPN, 72 complications occurred. These included metabolic (n = 43), mechanical (n = 25), and septic (n = 4) complications. The most common metabolic complication was hyperglycemia (n = 19), followed by lipemia (n = 17) and hyperbilirubinemia (n = 6). Most complications were mild and did not require discontinuation of PPN. Ninety-three (73.2%) of the 127 patients were discharged. All 4 animals with septic complications were discharged from the hospital. The presence, type, and number of complications did not impact the duration of hospitalization or outcome. However, animals that received supplemental enteral nutrition survived more often than those receiving PPN exclusively. Although PPN seems to be a relatively safe method of providing nutritional support, future studies are warranted to determine its efficacy. [source] Review article: uncomplicated diverticular disease of the colonALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2006L. PETRUZZIELLO Summary Diverticular disease of the colon is the fifth most important gastrointestinal disease in terms of direct and indirect healthcare costs in western countries. Uncomplicated diverticular disease is defined as the presence of diverticula in the absence of complications such as perforation, fistula, obstruction and/or bleeding. The distribution of diverticula along the colon varies worldwide being almost always left-sided and directly related to age in western countries and right-sided where diet is rich in fibre. The pathophysiology of diverticular disease is complex and relates to abnormal colonic motility, changes in the colonic wall, chronic mucosal low-grade inflammation, imbalance in colonic microflora and visceral hypersensitivity. Moreover, there can be genetic factors involved in the development of colonic diverticula. The use of non-absorbable antibiotics is the mainstay of therapy in patients with mild to moderate symptoms, and the effect of fibre-supplementation alone does not appear to be significantly different from placebo, although no definite data are available. More recently, alternative treatments have been reported. Mesalazine acts as a local mucosal immunomodulator and has been shown to improve symptoms and prevent recurrence of diverticulitis. In addition, probiotics have also been shown to be beneficial by re-establishing a normal gut microflora. In this study, the current literature on uncomplicated diverticular disease of the colon is reviewed. [source] Risk of schizophrenia in people with coeliac disease, ulcerative colitis and Crohn's disease: a general population-based studyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2006J. WEST Summary Background Recently, interest has been revived in whether people with coeliac disease, in contrast to other inflammatory gastrointestinal diseases, have an increased risk of schizophrenia. Aim To compare the risk of schizophrenia in people diagnosed with coeliac disease, ulcerative colitis and Crohn's disease with the general population. Methods We used data from the UK General Practice Research Database. People with coeliac disease, Crohn's disease and ulcerative colitis were matched individually with five age-, sex- and general practice-matched controls. The prevalence of schizophrenia was calculated and compared between disease groups and their respective controls. We calculated odds ratios for schizophrenia using conditional logistic regression adjusting for smoking status. Results In people with coeliac disease, Crohn's disease and ulcerative colitis the prevalence of schizophrenia was 0.25%, 0.27% and 0.24%, respectively, compared with a general population prevalence of 0.37%. The adjusted odds ratios showed no association between schizophrenia and gastrointestinal disease (coeliac disease vs. controls 0.76, 95% CI: 0.41,1.4; Crohn's disease vs. controls 0.74, 95% CI: 0.44,1.3; ulcerative colitis 0.71, 95% CI: 0.44,1.1). Conclusions Contrary to recent findings we found no evidence of an increased risk of schizophrenia in people with coeliac disease compared with the general population. [source] Carriage, quantification, and predominance of methanogens and sulfate-reducing bacteria in faecal samplesLETTERS IN APPLIED MICROBIOLOGY, Issue 1 2006J.A. Stewart Abstract Aims:, To determine carriage rates and densities of methanogens and sulfate-reducing bacteria in adults and children using molecular methods, and to also determine if a reciprocal relationship exists between these organisms. Methods and Results:, Real-time PCR was used to detect and quantify methanogens and sulfate-reducing bacteria. Real-time PCR was more sensitive than breath methane measurements. Real-time PCR assays were applied to faecal DNA samples collected from 40 children and 12 adults. Methanogens were present in 25% of the children and 42% of the adults studied, and sulfate-reducing bacteria were detected in 15% of the children and 58% of the adults. High levels of sulfate-reducing bacteria were found in two methanogenic adults. Conclusions:, Carriage rates and densities of methanogens and sulfate-reducing bacteria are greater in adults than in children. Competition does not necessarily lead to the predominance of one group in the faecal microflora. Significance and Impact of the Study:, This study describes sensitive, molecular assays that could be used to monitor these organisms in gastrointestinal disease. Therapeutic exclusion of one group from the bowel would not necessarily lead to the expansion of the other, as there does not appear to be a reciprocal relationship between these groups. [source] Global endpoints in functional gastrointestinal disease: Authors' replyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11-12 2005B. Adam No abstract is available for this article. [source] Review article: oral ulcers and its relevance to systemic disordersALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2005S. R. Porter Summary Oral ulceration is a common problem, and is sometimes a marker of gastroenterological disease. Patients with signs or symptoms of oral ulcers are sometimes referred to gastroenterology clinics, however, in most instances the ulcers does not reflect gastrointestinal disease. Indeed, a spectrum of disorders other than those of the gut can give rise to oral mucosal ulcers ranging from minor local trauma to significant local disease such as malignancy or systemic illness. This present article reviews aspects of the aetiology, diagnosis and management of common ulcerative disorders of the oral mucosa. [source] Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trialsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2001C. J. Hawkey Background: Highly selective inhibitors of the inducible cyclooxygenase-2 enzyme (coxibs) have been associated with less gastrotoxicity than nonselective NSAIDs in clinical studies. Aim: To evaluate the influence of risk factors for NSAID-induced gastrotoxicity on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen. Methods: We analysed pooled data from two identical double-blind, randomized, 12-week endoscopy studies which compared the gastroduodenal toxicity of placebo (n=371), rofecoxib 25 mg (n=390), rofecoxib 50 mg (n=379), and ibuprofen 2400 mg daily (n=376) in patients with osteoarthritis. The potential risk factors evaluated were: age (< 65, , 65 years), sex, race (white, nonwhite), Helicobacter pylori status, presence of gastroduodenal erosions at baseline, a history of upper gastrointestinal disease, prior NSAID use within 30 days of study entry, and smoking. We also evaluated these factors for possible association with the development of clinically-evident gastrointestinal perforations, ulcers or bleeds over 12 weeks. Results: Across all treatment groups, the likelihood of detecting endoscopic ulcers, or of clinical presentation with a bleed, over 12 weeks was increased approximately 4,5-fold in patients with previous upper gastrointestinal disease (relative risk [95% confidence interval] of 4.2 [2.5, 7.1] for endoscopic ulcers; 3.8 [1.4, 10.6] for bleeds), or those with gastroduodenal erosions at baseline endoscopy (relative risk of 4.4 [2.6, 7.5] for endoscopic ulcers; 5.0 [1.9, 13.5] for bleeds). H. pylori infection did not increase the risk of endoscopic ulcers or bleeds (relative risk of 1.1 [0.8, 1.6] for endoscopic ulcers; 0.3 [0.1, 0.9] for bleeds). The risk factor sub-group effects were constant across all treatment groups, and the significantly higher incidence of ulcers with ibuprofen as compared to rofecoxib and placebo was maintained in all risk factor subgroups. Conclusions: Gastroduodenal erosions at baseline and a clinical history of upper gastrointestinal disease, but not H. pylori colonization, increased the risk for endoscopically-detected ulcers and clinical bleeds. Rofecoxib did not magnify the risk in any of the patient subgroups studied. [source] Clinical Predictors of Relapse after Treatment of Primary Gastrointestinal Cytomegalovirus Disease in Solid Organ Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010A. J. Eid Primary gastrointestinal cytomegalovirus (CMV) disease after solid organ transplantation (SOT) is difficult to treat and may relapse. Herein, we reviewed the clinical records of CMV D+/R, SOT recipients with biopsy-proven gastrointestinal CMV disease to determine predictors of relapse. The population consisted of 26 kidney (13 [50%]), liver (10 [38%]) and heart (3 [12%]) transplant recipients who developed gastrointestinal CMV disease at a median of 54 (interquartile range [IQR]: 40,70) days after stopping antiviral prophylaxis. Except for one patient, all received induction intravenous ganciclovir (mean ± SD, 33.8 ± 19.3 days) followed by valganciclovir (27.5 ± 13.3 days) in 18 patients. Ten patients further received valganciclovir maintenance therapy (41.6 ± 28.6 days). The median times to CMV PCR negativity in blood was 22.5 days (IQR: 16.5,30.7) and to normal endoscopic findings was 27.0 days (IQR: 21.0,33.5). CMV relapse, which occurred in seven (27%) patients, was significantly associated with extensive disease (p = 0.03). CMV seroconversion, viral load, treatment duration, maintenance therapy and endoscopic findings at the end of therapy were not significantly associated with CMV relapse. In conclusion, an extensive involvement of the gastrointestinal tract was significantly associated with CMV relapse. However, endoscopic evidence of resolution of gastrointestinal disease did not necessarily translate into a lower risk of CMV relapse. [source] European Mathematical Genetics Meeting, Heidelberg, Germany, 12th,13th April 2007ANNALS OF HUMAN GENETICS, Issue 4 2007Article first published online: 28 MAY 200 Saurabh Ghosh 11 Indian Statistical Institute, Kolkata, India High correlations between two quantitative traits may be either due to common genetic factors or common environmental factors or a combination of both. In this study, we develop statistical methods to extract the contribution of a common QTL to the total correlation between the components of a bivariate phenotype. Using data on bivariate phenotypes and marker genotypes for sib-pairs, we propose a test for linkage between a common QTL and a marker locus based on the conditional cross-sib trait correlations (trait 1 of sib 1 , trait 2 of sib 2 and conversely) given the identity-by-descent sharing at the marker locus. The null hypothesis cannot be rejected unless there exists a common QTL. We use Monte-Carlo simulations to evaluate the performance of the proposed test under different trait parameters and quantitative trait distributions. An application of the method is illustrated using data on two alcohol-related phenotypes from the Collaborative Study On The Genetics Of Alcoholism project. Rémi Kazma 1 , Catherine Bonaďti-Pellié 1 , Emmanuelle Génin 12 INSERM UMR-S535 and Université Paris Sud, Villejuif, 94817, France Keywords: Gene-environment interaction, sibling recurrence risk, exposure correlation Gene-environment interactions may play important roles in complex disease susceptibility but their detection is often difficult. Here we show how gene-environment interactions can be detected by investigating the degree of familial aggregation according to the exposure of the probands. In case of gene-environment interaction, the distribution of genotypes of affected individuals, and consequently the risk in relatives, depends on their exposure. We developed a test comparing the risks in sibs according to the proband exposure. To evaluate the properties of this new test, we derived the formulas for calculating the expected risks in sibs according to the exposure of probands for various values of exposure frequency, relative risk due to exposure alone, frequencies of latent susceptibility genotypes, genetic relative risks and interaction coefficients. We find that the ratio of risks when the proband is exposed and not exposed is a good indicator of the interaction effect. We evaluate the power of the test for various sample sizes of affected individuals. We conclude that this test is valuable for diseases with moderate familial aggregation, only when the role of the exposure has been clearly evidenced. Since a correlation for exposure among sibs might lead to a difference in risks among sibs in the different proband exposure strata, we also add an exposure correlation coefficient in the model. Interestingly, we find that when this correlation is correctly accounted for, the power of the test is not decreased and might even be significantly increased. Andrea Callegaro 1 , Hans J.C. Van Houwelingen 1 , Jeanine Houwing-Duistermaat 13 Dept. of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands Keywords: Survival analysis, age at onset, score test, linkage analysis Non parametric linkage (NPL) analysis compares the identical by descent (IBD) sharing in sibling pairs to the expected IBD sharing under the hypothesis of no linkage. Often information is available on the marginal cumulative hazards (for example breast cancer incidence curves). Our aim is to extend the NPL methods by taking into account the age at onset of selected sibling pairs using these known marginal hazards. Li and Zhong (2002) proposed a (retrospective) likelihood ratio test based on an additive frailty model for genetic linkage analysis. From their model we derive a score statistic for selected samples which turns out to be a weighed NPL method. The weights depend on the marginal cumulative hazards and on the frailty parameter. A second approach is based on a simple gamma shared frailty model. Here, we simply test whether the score function of the frailty parameter depends on the excess IBD. We compare the performance of these methods using simulated data. Céline Bellenguez 1 , Carole Ober 2 , Catherine Bourgain 14 INSERM U535 and University Paris Sud, Villejuif, France 5 Department of Human Genetics, The University of Chicago, USA Keywords: Linkage analysis, linkage disequilibrium, high density SNP data Compared with microsatellite markers, high density SNP maps should be more informative for linkage analyses. However, because they are much closer, SNPs present important linkage disequilibrium (LD), which biases classical nonparametric multipoint analyses. This problem is even stronger in population isolates where LD extends over larger regions with a more stochastic pattern. We investigate the issue of linkage analysis with a 500K SNP map in a large and inbred 1840-member Hutterite pedigree, phenotyped for asthma. Using an efficient pedigree breaking strategy, we first identified linked regions with a 5cM microsatellite map, on which we focused to evaluate the SNP map. The only method that models LD in the NPL analysis is limited in both the pedigree size and the number of markers (Abecasis and Wigginton, 2005) and therefore could not be used. Instead, we studied methods that identify sets of SNPs with maximum linkage information content in our pedigree and no LD-driven bias. Both algorithms that directly remove pairs of SNPs in high LD and clustering methods were evaluated. Null simulations were performed to control that Zlr calculated with the SNP sets were not falsely inflated. Preliminary results suggest that although LD is strong in such populations, linkage information content slightly better than that of microsatellite maps can be extracted from dense SNP maps, provided that a careful marker selection is conducted. In particular, we show that the specific LD pattern requires considering LD between a wide range of marker pairs rather than only in predefined blocks. Peter Van Loo 1,2,3 , Stein Aerts 1,2 , Diether Lambrechts 4,5 , Bernard Thienpont 2 , Sunit Maity 4,5 , Bert Coessens 3 , Frederik De Smet 4,5 , Leon-Charles Tranchevent 3 , Bart De Moor 2 , Koen Devriendt 3 , Peter Marynen 1,2 , Bassem Hassan 1,2 , Peter Carmeliet 4,5 , Yves Moreau 36 Department of Molecular and Developmental Genetics, VIB, Belgium 7 Department of Human Genetics, University of Leuven, Belgium 8 Bioinformatics group, Department of Electrical Engineering, University of Leuven, Belgium 9 Department of Transgene Technology and Gene Therapy, VIB, Belgium 10 Center for Transgene Technology and Gene Therapy, University of Leuven, Belgium Keywords: Bioinformatics, gene prioritization, data fusion The identification of genes involved in health and disease remains a formidable challenge. Here, we describe a novel bioinformatics method to prioritize candidate genes underlying pathways or diseases, based on their similarity to genes known to be involved in these processes. It is freely accessible as an interactive software tool, ENDEAVOUR, at http://www.esat.kuleuven.be/endeavour. Unlike previous methods, ENDEAVOUR generates distinct prioritizations from multiple heterogeneous data sources, which are then integrated, or fused, into one global ranking using order statistics. ENDEAVOUR prioritizes candidate genes in a three-step process. First, information about a disease or pathway is gathered from a set of known "training" genes by consulting multiple data sources. Next, the candidate genes are ranked based on similarity with the training properties obtained in the first step, resulting in one prioritized list for each data source. Finally, ENDEAVOUR fuses each of these rankings into a single global ranking, providing an overall prioritization of the candidate genes. Validation of ENDEAVOUR revealed it was able to efficiently prioritize 627 genes in disease data sets and 76 genes in biological pathway sets, identify candidates of 16 mono- or polygenic diseases, and discover regulatory genes of myeloid differentiation. Furthermore, the approach identified YPEL1 as a novel gene involved in craniofacial development from a 2-Mb chromosomal region, deleted in some patients with DiGeorge-like birth defects. Finally, we are currently evaluating a pipeline combining array-CGH, ENDEAVOUR and in vivo validation in zebrafish to identify novel genes involved in congenital heart defects. Mark Broom 1 , Graeme Ruxton 2 , Rebecca Kilner 311 Mathematics Dept., University of Sussex, UK 12 Division of Environmental and Evolutionary Biology, University of Glasgow, UK 13 Department of Zoology, University of Cambridge, UK Keywords: Evolutionarily stable strategy, parasitism, asymmetric game Brood parasites chicks vary in the harm that they do to their companions in the nest. In this presentation we use game-theoretic methods to model this variation. Our model considers hosts which potentially abandon single nestlings and instead choose to re-allocate their reproductive effort to future breeding, irrespective of whether the abandoned chick is the host's young or a brood parasite's. The parasite chick must decide whether or not to kill host young by balancing the benefits from reduced competition in the nest against the risk of desertion by host parents. The model predicts that three different types of evolutionarily stable strategies can exist. (1) Hosts routinely rear depleted broods, the brood parasite always kills host young and the host never then abandons the nest. (2) When adult survival after deserting single offspring is very high, hosts always abandon broods of a single nestling and the parasite never kills host offspring, effectively holding them as hostages to prevent nest desertion. (3) Intermediate strategies, in which parasites sometimes kill their nest-mates and host parents sometimes desert nests that contain only a single chick, can also be evolutionarily stable. We provide quantitative descriptions of how the values given to ecological and behavioral parameters of the host-parasite system influence the likelihood of each strategy and compare our results with real host-brood parasite associations in nature. Martin Harrison 114 Mathematics Dept, University of Sussex, UK Keywords: Brood parasitism, games, host, parasite The interaction between hosts and parasites in bird populations has been studied extensively. Game theoretical methods have been used to model this interaction previously, but this has not been studied extensively taking into account the sequential nature of this game. We consider a model allowing the host and parasite to make a number of decisions, which depend on a number of natural factors. The host lays an egg, a parasite bird will arrive at the nest with a certain probability and then chooses to destroy a number of the host eggs and lay one of it's own. With some destruction occurring, either natural or through the actions of the parasite, the host chooses to continue, eject an egg (hoping to eject the parasite) or abandon the nest. Once the eggs have hatched the game then falls to the parasite chick versus the host. The chick chooses to destroy or eject a number of eggs. The final decision is made by the host, choosing whether to raise or abandon the chicks that are in the nest. We consider various natural parameters and probabilities which influence these decisions. We then use this model to look at real-world situations of the interactions of the Reed Warbler and two different parasites, the Common Cuckoo and the Brown-Headed Cowbird. These two parasites have different methods in the way that they parasitize the nests of their hosts. The hosts in turn have a different reaction to these parasites. Arne Jochens 1 , Amke Caliebe 2 , Uwe Roesler 1 , Michael Krawczak 215 Mathematical Seminar, University of Kiel, Germany 16 Institute of Medical Informatics and Statistics, University of Kiel, Germany Keywords: Stepwise mutation model, microsatellite, recursion equation, temporal behaviour We consider the stepwise mutation model which occurs, e.g., in microsatellite loci. Let X(t,i) denote the allelic state of individual i at time t. We compute expectation, variance and covariance of X(t,i), i=1,,,N, and provide a recursion equation for P(X(t,i)=z). Because the variance of X(t,i) goes to infinity as t grows, for the description of the temporal behaviour, we regard the scaled process X(t,i)-X(t,1). The results furnish a better understanding of the behaviour of the stepwise mutation model and may in future be used to derive tests for neutrality under this model. Paul O'Reilly 1 , Ewan Birney 2 , David Balding 117 Statistical Genetics, Department of Epidemiology and Public Health, Imperial, College London, UK 18 European Bioinformatics Institute, EMBL, Cambridge, UK Keywords: Positive selection, Recombination rate, LD, Genome-wide, Natural Selection In recent years efforts to develop population genetics methods that estimate rates of recombination and levels of natural selection in the human genome have intensified. However, since the two processes have an intimately related impact on genetic variation their inference is vulnerable to confounding. Genomic regions subject to recent selection are likely to have a relatively recent common ancestor and consequently less opportunity for historical recombinations that are detectable in contemporary populations. Here we show that selection can reduce the population-based recombination rate estimate substantially. In genome-wide studies for detecting selection we observe a tendency to highlight loci that are subject to low levels of recombination. We find that the outlier approach commonly adopted in such studies may have low power unless variable recombination is accounted for. We introduce a new genome-wide method for detecting selection that exploits the sensitivity to recent selection of methods for estimating recombination rates, while accounting for variable recombination using pedigree data. Through simulations we demonstrate the high power of the Ped/Pop approach to discriminate between neutral and adaptive evolution, particularly in the context of choosing outliers from a genome-wide distribution. Although methods have been developed showing good power to detect selection ,in action', the corresponding window of opportunity is small. In contrast, the power of the Ped/Pop method is maintained for many generations after the fixation of an advantageous variant Sarah Griffiths 1 , Frank Dudbridge 120 MRC Biostatistics Unit, Cambridge, UK Keywords: Genetic association, multimarker tag, haplotype, likelihood analysis In association studies it is generally too expensive to genotype all variants in all subjects. We can exploit linkage disequilibrium between SNPs to select a subset that captures the variation in a training data set obtained either through direct resequencing or a public resource such as the HapMap. These ,tag SNPs' are then genotyped in the whole sample. Multimarker tagging is a more aggressive adaptation of pairwise tagging that allows for combinations of two or more tag SNPs to predict an untyped SNP. Here we describe a new method for directly testing the association of an untyped SNP using a multimarker tag. Previously, other investigators have suggested testing a specific tag haplotype, or performing a weighted analysis using weights derived from the training data. However these approaches do not properly account for the imperfect correlation between the tag haplotype and the untyped SNP. Here we describe a straightforward approach to testing untyped SNPs using a missing-data likelihood analysis, including the tag markers as nuisance parameters. The training data is stacked on top of the main body of genotype data so there is information on how the tag markers predict the genotype of the untyped SNP. The uncertainty in this prediction is automatically taken into account in the likelihood analysis. This approach yields more power and also a more accurate prediction of the odds ratio of the untyped SNP. Anke Schulz 1 , Christine Fischer 2 , Jenny Chang-Claude 1 , Lars Beckmann 121 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany 22 Institute of Human Genetics, University of Heidelberg, Germany Keywords: Haplotype, haplotype sharing, entropy, Mantel statistics, marker selection We previously introduced a new method to map genes involved in complex diseases, using haplotype sharing-based Mantel statistics to correlate genetic and phenotypic similarity. Although the Mantel statistic is powerful in narrowing down candidate regions, the precise localization of a gene is hampered in genomic regions where linkage disequilibrium is so high that neighboring markers are found to be significant at similar magnitude and we are not able to discriminate between them. Here, we present a new approach to localize susceptibility genes by combining haplotype sharing-based Mantel statistics with an iterative entropy-based marker selection algorithm. For each marker at which the Mantel statistic is evaluated, the algorithm selects a subset of surrounding markers. The subset is chosen to maximize multilocus linkage disequilibrium, which is measured by the normalized entropy difference introduced by Nothnagel et al. (2002). We evaluated the algorithm with respect to type I error and power. Its ability to localize the disease variant was compared to the localization (i) without marker selection and (ii) considering haplotype block structure. Case-control samples were simulated from a set of 18 haplotypes, consisting of 15 SNPs in two haplotype blocks. The new algorithm gave correct type I error and yielded similar power to detect the disease locus compared to the alternative approaches. The neighboring markers were clearly less often significant than the causal locus, and also less often significant compared to the alternative approaches. Thus the new algorithm improved the precision of the localization of susceptibility genes. Mark M. Iles 123 Section of Epidemiology and Biostatistics, LIMM, University of Leeds, UK Keywords: tSNP, tagging, association, HapMap Tagging SNPs (tSNPs) are commonly used to capture genetic diversity cost-effectively. However, it is important that the efficacy of tSNPs is correctly estimated, otherwise coverage may be insufficient. If the pilot sample from which tSNPs are chosen is too small or the initial marker map too sparse, tSNP efficacy may be overestimated. An existing estimation method based on bootstrapping goes some way to correct for insufficient sample size and overfitting, but does not completely solve the problem. We describe a novel method, based on exclusion of haplotypes, that improves on the bootstrap approach. Using simulated data, the extent of the sample size problem is investigated and the performance of the bootstrap and the novel method are compared. We incorporate an existing method adjusting for marker density by ,SNP-dropping'. We find that insufficient sample size can cause large overestimates in tSNP efficacy, even with as many as 100 individuals, and the problem worsens as the region studied increases in size. Both the bootstrap and novel method correct much of this overestimate, with our novel method consistently outperforming the bootstrap method. We conclude that a combination of insufficient sample size and overfitting may lead to overestimation of tSNP efficacy and underpowering of studies based on tSNPs. Our novel approach corrects for much of this bias and is superior to the previous method. Sample sizes larger than previously suggested may still be required for accurate estimation of tSNP efficacy. This has obvious ramifications for the selection of tSNPs from HapMap data. Claudio Verzilli 1 , Juliet Chapman 1 , Aroon Hingorani 2 , Juan Pablo-Casas 1 , Tina Shah 2 , Liam Smeeth 1 , John Whittaker 124 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK 25 Division of Medicine, University College London, UK Keywords: Meta-analysis, Genetic association studies We present a Bayesian hierarchical model for the meta-analysis of candidate gene studies with a continuous outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping markers (typically SNPs) in the same genetic region. Meta analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequlibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian hierarchical linear regression that models the observed genotype group means and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach is applied to the meta analysis of 24 studies assessing the effect of 7 variants in the C-reactive protein (CRP) gene region on plasma CRP levels, an inflammatory biomarker shown in observational studies to be positively associated with cardiovascular disease. Cathryn M. Lewis 1 , Christopher G. Mathew 1 , Theresa M. Marteau 226 Dept. of Medical and Molecular Genetics, King's College London, UK 27 Department of Psychology, King's College London, UK Keywords: Risk, genetics, CARD15, smoking, model Recently progress has been made in identifying mutations that confer susceptibility to complex diseases, with the potential to use these mutations in determining disease risk. We developed methods to estimate disease risk based on genotype relative risks (for a gene G), exposure to an environmental factor (E), and family history (with recurrence risk ,R for a relative of type R). ,R must be partitioned into the risk due to G (which is modelled independently) and the residual risk. The risk model was then applied to Crohn's disease (CD), a severe gastrointestinal disease for which smoking increases disease risk approximately 2-fold, and mutations in CARD15 confer increased risks of 2.25 (for carriers of a single mutation) and 9.3 (for carriers of two mutations). CARD15 accounts for only a small proportion of the genetic component of CD, with a gene-specific ,S, CARD15 of 1.16, from a total sibling relative risk of ,S= 27. CD risks were estimated for high-risk individuals who are siblings of a CD case, and who also smoke. The CD risk to such individuals who carry two CARD15 mutations is approximately 0.34, and for those carrying a single CARD15 mutation the risk is 0.08, compared to a population prevalence of approximately 0.001. These results imply that complex disease genes may be valuable in estimating with greater precision than has hitherto been possible disease risks in specific, easily identified subgroups of the population with a view to prevention. Yurii Aulchenko 128 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Compression, information, bzip2, genome-wide SNP data, statistical genetics With advances in molecular technology, studies accessing millions of genetic polymorphisms in thousands of study subjects will soon become common. Such studies generate large amounts of data, whose effective storage and management is a challenge to the modern statistical genetics. Standard file compression utilities, such as Zip, Gzip and Bzip2, may be helpful to minimise the storage requirements. Less obvious is the fact that the data compression techniques may be also used in the analysis of genetic data. It is known that the efficiency of a particular compression algorithm depends on the probability structure of the data. In this work, we compared different standard and customised tools using the data from human HapMap project. Secondly, we investigate the potential uses of data compression techniques for the analysis of linkage, association and linkage disequilibrium Suzanne Leal 1 , Bingshan Li 129 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA Keywords: Consanguineous pedigrees, missing genotype data Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al (2005) that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. The false-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. Which family members will aid in the reduction of false-positive evidence of linkage is highly dependent on which other family members are genotyped. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. When parental genotypes are not available, false-positive evidence for linkage can be reduced by including in the analysis genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents. Najaf Amin 1 , Yurii Aulchenko 130 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Genomic Control, pedigree structure, quantitative traits The Genomic Control (GC) method was originally developed to control for population stratification and cryptic relatedness in association studies. This method assumes that the effect of population substructure on the test statistics is essentially constant across the genome, and therefore unassociated markers can be used to estimate the effect of confounding onto the test statistic. The properties of GC method were extensively investigated for different stratification scenarios, and compared to alternative methods, such as the transmission-disequilibrium test. The potential of this method to correct not for occasional cryptic relations, but for regular pedigree structure, however, was not investigated before. In this work we investigate the potential of the GC method for pedigree-based association analysis of quantitative traits. The power and type one error of the method was compared to standard methods, such as the measured genotype (MG) approach and quantitative trait transmission-disequilibrium test. In human pedigrees, with trait heritability varying from 30 to 80%, the power of MG and GC approach was always higher than that of TDT. GC had correct type 1 error and its power was close to that of MG under moderate heritability (30%), but decreased with higher heritability. William Astle 1 , Chris Holmes 2 , David Balding 131 Department of Epidemiology and Public Health, Imperial College London, UK 32 Department of Statistics, University of Oxford, UK Keywords: Population structure, association studies, genetic epidemiology, statistical genetics In the analysis of population association studies, Genomic Control (Devlin & Roeder, 1999) (GC) adjusts the Armitage test statistic to correct the type I error for the effects of population substructure, but its power is often sub-optimal. Turbo Genomic Control (TGC) generalises GC to incorporate co-variation of relatedness and phenotype, retaining control over type I error while improving power. TGC is similar to the method of Yu et al. (2006), but we extend it to binary (case-control) in addition to quantitative phenotypes, we implement improved estimation of relatedness coefficients, and we derive an explicit statistic that generalizes the Armitage test statistic and is fast to compute. TGC also has similarities to EIGENSTRAT (Price et al., 2006) which is a new method based on principle components analysis. The problems of population structure(Clayton et al., 2005) and cryptic relatedness (Voight & Pritchard, 2005) are essentially the same: if patterns of shared ancestry differ between cases and controls, whether distant (coancestry) or recent (cryptic relatedness), false positives can arise and power can be diminished. With large numbers of widely-spaced genetic markers, coancestry can now be measured accurately for each pair of individuals via patterns of allele-sharing. Instead of modelling subpopulations, we work instead with a coancestry coefficient for each pair of individuals in the study. We explain the relationships between TGC, GC and EIGENSTRAT. We present simulation studies and real data analyses to illustrate the power advantage of TGC in a range of scenarios incorporating both substructure and cryptic relatedness. References Clayton, D. G.et al. (2005) Population structure, differential bias and genomic control in a large-scale case-control association study. Nature Genetics37(11) November 2005. Devlin, B. & Roeder, K. (1999) Genomic control for association studies. Biometics55(4) December 1999. Price, A. L.et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics38(8) (August 2006). Voight, B. J. & Pritchard, J. K. (2005) Confounding from cryptic relatedness in case-control association studies. Public Library of Science Genetics1(3) September 2005. Yu, J.et al. (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nature Genetics38(2) February 2006. Hervé Perdry 1 , Marie-Claude Babron 1 , Françoise Clerget-Darpoux 133 INSERM U535 and Univ. Paris Sud, UMR-S 535, Villejuif, France Keywords: Modifier genes, case-parents trios, ordered transmission disequilibrium test A modifying locus is a polymorphic locus, distinct from the disease locus, which leads to differences in the disease phenotype, either by modifying the penetrance of the disease allele, or by modifying the expression of the disease. The effect of such a locus is a clinical heterogeneity that can be reflected by the values of an appropriate covariate, such as the age of onset, or the severity of the disease. We designed the Ordered Transmission Disequilibrium Test (OTDT) to test for a relation between the clinical heterogeneity, expressed by the covariate, and marker genotypes of a candidate gene. The method applies to trio families with one affected child and his parents. Each family member is genotyped at a bi-allelic marker M of a candidate gene. To each of the families is associated a covariate value; the families are ordered on the values of this covariate. As the TDT (Spielman et al. 1993), the OTDT is based on the observation of the transmission rate T of a given allele at M. The OTDT aims to find a critical value of the covariate which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions. Acknowledgments H Perdry is funded by ARSEP. Pascal Croiseau 1 , Heather Cordell 2 , Emmanuelle Génin 134 INSERM U535 and University Paris Sud, UMR-S535, Villejuif, France 35 Institute of Human Genetics, Newcastle University, UK Keywords: Association, missing data, conditionnal logistic regression Missing data is an important problem in association studies. Several methods used to test for association need that individuals be genotyped at the full set of markers. Individuals with missing data need to be excluded from the analysis. This could involve an important decrease in sample size and a loss of information. If the disease susceptibility locus (DSL) is poorly typed, it is also possible that a marker in linkage disequilibrium gives a stronger association signal than the DSL. One may then falsely conclude that the marker is more likely to be the DSL. We recently developed a Multiple Imputation method to infer missing data on case-parent trios Starting from the observed data, a few number of complete data sets are generated by Markov-Chain Monte Carlo approach. These complete datasets are analysed using standard statistical package and the results are combined as described in Little & Rubin (2002). Here we report the results of simulations performed to examine, for different patterns of missing data, how often the true DSL gives the highest association score among different loci in LD. We found that multiple imputation usually correctly detect the DSL site even if the percentage of missing data is high. This is not the case for the naďve approach that consists in discarding trios with missing data. In conclusion, Multiple imputation presents the advantage of being easy to use and flexible and is therefore a promising tool in the search for DSL involved in complex diseases. Salma Kotti 1 , Heike Bickeböller 2 , Françoise Clerget-Darpoux 136 University Paris Sud, UMR-S535, Villejuif, France 37 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany Keywords: Genotype relative risk, internal controls, Family based analyses Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRRs. We will analytically derive the GRR estimators for the 1:1 and 1:3 matching and will present the results at the meeting. Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRR. We will analytically derive the GRR estimator for the 1:1 and 1:3 matching and will present the results at the meeting. Luigi Palla 1 , David Siegmund 239 Department of Mathematics,Free University Amsterdam, The Netherlands 40 Department of Statistics, Stanford University, California, USA Keywords: TDT, assortative mating, inbreeding, statistical power A substantial amount of Assortative Mating (AM) is often recorded on physical and psychological, dichotomous as well as quantitative traits that are supposed to have a multifactorial genetic component. In particular AM has the effect of increasing the genetic variance, even more than inbreeding because it acts across loci beside within loci, when the trait has a multifactorial origin. Under the assumption of a polygenic model for AM dating back to Wright (1921) and refined by Crow and Felsenstein (1968,1982), the effect of assortative mating on the power to detect genetic association in the Transmission Disequilibrium Test (TDT) is explored as parameters, such as the effective number of genes and the allelic frequency vary. The power is reflected by the non centrality parameter of the TDT and is expressed as a function of the number of trios, the relative risk of the heterozygous genotype and the allele frequency (Siegmund and Yakir, 2007). The noncentrality parameter of the relevant score statistic is updated considering the effect of AM which is expressed in terms of an ,effective' inbreeding coefficient. In particular, for dichotomous traits it is apparent that the higher the number of genes involved in the trait, the lower the loss in power due to AM. Finally an attempt is made to extend this relation to the Q-TDT (Rabinowitz, 1997), which involves considering the effect of AM also on the phenotypic variance of the trait of interest, under the assumption that AM affects only its additive genetic component. References Crow, & Felsenstein, (1968). The effect of assortative mating on the genetic composition of a population. Eugen.Quart.15, 87,97. Rabinowitz,, 1997. A Transmission Disequilibrium Test for Quantitative Trait Loci. Human Heredity47, 342,350. Siegmund, & Yakir, (2007) Statistics of gene mapping, Springer. Wright, (1921). System of mating.III. Assortative mating based on somatic resemblance. Genetics6, 144,161. Jérémie Nsengimana 1 , Ben D Brown 2 , Alistair S Hall 2 , Jenny H Barrett 141 Leeds Institute of Molecular Medicine, University of Leeds, UK 42 Leeds Institute for Genetics, Health and Therapeutics, University of Leeds, UK Keywords: Inflammatory genes, haplotype, coronary artery disease Genetic Risk of Acute Coronary Events (GRACE) is an initiative to collect cases of coronary artery disease (CAD) and their unaffected siblings in the UK and to use them to map genetic variants increasing disease risk. The aim of the present study was to test the association between CAD and 51 single nucleotide polymorphisms (SNPs) and their haplotypes from 35 inflammatory genes. Genotype data were available for 1154 persons affected before age 66 (including 48% before age 50) and their 1545 unaffected siblings (891 discordant families). Each SNP was tested for association to CAD, and haplotypes within genes or gene clusters were tested using FBAT (Rabinowitz & Laird, 2000). For the most significant results, genetic effect size was estimated using conditional logistic regression (CLR) within STATA adjusting for other risk factors. Haplotypes were assigned using HAPLORE (Zhang et al., 2005), which considers all parental mating types consistent with offspring genotypes and assigns them a probability of occurence. This probability was used in CLR to weight the haplotypes. In the single SNP analysis, several SNPs showed some evidence for association, including one SNP in the interleukin-1A gene. Analysing haplotypes in the interleukin-1 gene cluster, a common 3-SNP haplotype was found to increase the risk of CAD (P = 0.009). In an additive genetic model adjusting for covariates the odds ratio (OR) for this haplotype is 1.56 (95% CI: 1.16-2.10, p = 0.004) for early-onset CAD (before age 50). This study illustrates the utility of haplotype analysis in family-based association studies to investigate candidate genes. References Rabinowitz, D. & Laird, N. M. (2000) Hum Hered50, 211,223. Zhang, K., Sun, F. & Zhao, H. (2005) Bioinformatics21, 90,103. Andrea Foulkes 1 , Recai Yucel 1 , Xiaohong Li 143 Division of Biostatistics, University of Massachusetts, USA Keywords: Haploytpe, high-dimensional, mixed modeling The explosion of molecular level information coupled with large epidemiological studies presents an exciting opportunity to uncover the genetic underpinnings of complex diseases; however, several analytical challenges remain to be addressed. Characterizing the components to complex diseases inevitably requires consideration of synergies across multiple genetic loci and environmental and demographic factors. In addition, it is critical to capture information on allelic phase, that is whether alleles within a gene are in cis (on the same chromosome) or in trans (on different chromosomes.) In associations studies of unrelated individuals, this alignment of alleles within a chromosomal copy is generally not observed. We address the potential ambiguity in allelic phase in this high dimensional data setting using mixed effects models. Both a semi-parametric and fully likelihood-based approach to estimation are considered to account for missingness in cluster identifiers. In the first case, we apply a multiple imputation procedure coupled with a first stage expectation maximization algorithm for parameter estimation. A bootstrap approach is employed to assess sensitivity to variability induced by parameter estimation. Secondly, a fully likelihood-based approach using an expectation conditional maximization algorithm is described. Notably, these models allow for characterizing high-order gene-gene interactions while providing a flexible statistical framework to account for the confounding or mediating role of person specific covariates. The proposed method is applied to data arising from a cohort of human immunodeficiency virus type-1 (HIV-1) infected individuals at risk for therapy associated dyslipidemia. Simulation studies demonstrate reasonable power and control of family-wise type 1 error rates. Vivien Marquard 1 , Lars Beckmann 1 , Jenny Chang-Claude 144 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Genotyping errors, type I error, haplotype-based association methods It has been shown in several simulation studies that genotyping errors may have a great impact on the type I error of statistical methods used in genetic association analysis of complex diseases. Our aim was to investigate type I error rates in a case-control study, when differential and non-differential genotyping errors were introduced in realistic scenarios. We simulated case-control data sets, where individual genotypes were drawn from a haplotype distribution of 18 haplotypes with 15 markers in the APM1 gene. Genotyping errors were introduced following the unrestricted and symmetric with 0 edges error models described by Heid et al. (2006). In six scenarios, errors resulted from changes of one allele to another with predefined probabilities of 1%, 2.5% or 10%, respectively. A multiple number of errors per haplotype was possible and could vary between 0 and 15, the number of markers investigated. We examined three association methods: Mantel statistics using haplotype-sharing; a haplotype-specific score test; and Armitage trend test for single markers. The type I error rates were not influenced for any of all the three methods for a genotyping error rate of less than 1%. For higher error rates and differential errors, the type I error of the Mantel statistic was only slightly and of the Armitage trend test moderately increased. The type I error rates of the score test were highly increased. The type I error rates were correct for all three methods for non-differential errors. Further investigations will be carried out with different frequencies of differential error rates and focus on power. Arne Neumann 1 , Dörthe Malzahn 1 , Martina Müller 2 , Heike Bickeböller 145 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany 46 GSF-National Research Center for Environment and Health, Neuherberg & IBE-Institute of Epidemiology, Ludwig-Maximilians University München, Germany Keywords: Interaction, longitudinal, nonparametric Longitudinal data show the time dependent course of phenotypic traits. In this contribution, we consider longitudinal cohort studies and investigate the association between two candidate genes and a dependent quantitative longitudinal phenotype. The set-up defines a factorial design which allows us to test simultaneously for the overall gene effect of the loci as well as for possible gene-gene and gene time interaction. The latter would induce genetically based time-profile differences in the longitudinal phenotype. We adopt a non-parametric statistical test to genetic epidemiological cohort studies and investigate its performance by simulation studies. The statistical test was originally developed for longitudinal clinical studies (Brunner, Munzel, Puri, 1999 J Multivariate Anal 70:286-317). It is non-parametric in the sense that no assumptions are made about the underlying distribution of the quantitative phenotype. Longitudinal observations belonging to the same individual can be arbitrarily dependent on one another for the different time points whereas trait observations of different individuals are independent. The two loci are assumed to be statistically independent. Our simulations show that the nonparametric test is comparable with ANOVA in terms of power of detecting gene-gene and gene-time interaction in an ANOVA favourable setting. Rebecca Hein 1 , Lars Beckmann 1 , Jenny Chang-Claude 147 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Indirect association studies, interaction effects, linkage disequilibrium, marker allele frequency Association studies accounting for gene-environment interactions (GxE) may be useful for detecting genetic effects and identifying important environmental effect modifiers. Current technology facilitates very dense marker spacing in genetic association studies; however, the true disease variant(s) may not be genotyped. In this situation, an association between a gene and a phenotype may still be detectable, using genetic markers associated with the true disease variant(s) (indirect association). Zondervan and Cardon [2004] showed that the odds ratios (OR) of markers which are associated with the disease variant depend highly on the linkage disequilibrium (LD) between the variant and the markers, and whether the allele frequencies match and thereby influence the sample size needed to detect genetic association. We examined the influence of LD and allele frequencies on the sample size needed to detect GxE in indirect association studies, and provide tables for sample size estimation. For discordant allele frequencies and incomplete LD, sample sizes can be unfeasibly large. The influence of both factors is stronger for disease loci with small rather than moderate to high disease allele frequencies. A decline in D' of e.g. 5% has less impact on sample size than increasing the difference in allele frequencies by the same percentage. Assuming 80% power, large interaction effects can be detected using smaller sample sizes than those needed for the detection of main effects. The detection of interaction effects involving rare alleles may not be possible. Focussing only on marker density can be a limited strategy in indirect association studies for GxE. Cyril Dalmasso 1 , Emmanuelle Génin 2 , Catherine Bourgain 2 , Philippe Broët 148 JE 2492 , Univ. Paris-Sud, France 49 INSERM UMR-S 535 and University Paris Sud, Villejuif, France Keywords: Linkage analysis, Multiple testing, False Discovery Rate, Mixture model In the context of genome-wide linkage analyses, where a large number of statistical tests are simultaneously performed, the False Discovery Rate (FDR) that is defined as the expected proportion of false discoveries among all discoveries is nowadays widely used for taking into account the multiple testing problem. Other related criteria have been considered such as the local False Discovery Rate (lFDR) that is a variant of the FDR giving to each test its own measure of significance. The lFDR is defined as the posterior probability that a null hypothesis is true. Most of the proposed methods for estimating the lFDR or the FDR rely on distributional assumption under the null hypothesis. However, in observational studies, the empirical null distribution may be very different from the theoretical one. In this work, we propose a mixture model based approach that provides estimates of the lFDR and the FDR in the context of large-scale variance component linkage analyses. In particular, this approach allows estimating the empirical null distribution, this latter being a key quantity for any simultaneous inference procedure. The proposed method is applied on a real dataset. Arief Gusnanto 1 , Frank Dudbridge 150 MRC Biostatistics Unit, Cambridge UK Keywords: Significance, genome-wide, association, permutation, multiplicity Genome-wide association scans have introduced statistical challenges, mainly in the multiplicity of thousands of tests. The question of what constitutes a significant finding remains somewhat unresolved. Permutation testing is very time-consuming, whereas Bayesian arguments struggle to distinguish direct from indirect association. It seems attractive to summarise the multiplicity in a simple form that allows users to avoid time-consuming permutations. A standard significance level would facilitate reporting of results and reduce the need for permutation tests. This is potentially important because current scans do not have full coverage of the whole genome, and yet, the implicit multiplicity is genome-wide. We discuss some proposed summaries, with reference to the empirical null distribution of the multiple tests, approximated through a large number of random permutations. Using genome-wide data from the Wellcome Trust Case-Control Consortium, we use a sub-sampling approach with increasing density to estimate the nominal p-value to obtain family-wise significance of 5%. The results indicate that the significance level is converging to about 1e-7 as the marker spacing becomes infinitely dense. We considered the concept of an effective number of independent tests, and showed that when used in a Bonferroni correction, the number varies with the overall significance level, but is roughly constant in the region of interest. We compared several estimators of the effective number of tests, and showed that in the region of significance of interest, Patterson's eigenvalue based estimator gives approximately the right family-wise error rate. Michael Nothnagel 1 , Amke Caliebe 1 , Michael Krawczak 151 Institute of Medical Informatics and Statistics, University Clinic Schleswig-Holstein, University of Kiel, Germany Keywords: Association scans, Bayesian framework, posterior odds, genetic risk, multiplicative model Whole-genome association scans have been suggested to be a cost-efficient way to survey genetic variation and to map genetic disease factors. We used a Bayesian framework to investigate the posterior odds of a genuine association under multiplicative disease models. We demonstrate that the p value alone is not a sufficient means to evaluate the findings in association studies. We suggest that likelihood ratios should accompany p values in association reports. We argue, that, given the reported results of whole-genome scans, more associations should have been successfully replicated if the consistently made assumptions about considerable genetic risks were correct. We conclude that it is very likely that the vast majority of relative genetic risks are only of the order of 1.2 or lower. Clive Hoggart 1 , Maria De Iorio 1 , John Whittakker 2 , David Balding 152 Department of Epidemiology and Public Health, Imperial College London, UK 53 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: Genome-wide association analyses, shrinkage priors, Lasso Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants of small effect, which is a plausible scenario for many complex diseases. Moreover, many simulation studies assume a single causal variant and so more complex realities are ignored. Analysing large numbers of variants simultaneously is now becoming feasible, thanks to developments in Bayesian stochastic search methods. We pose the problem of SNP selection as variable selection in a regression model. In contrast to single SNP tests this approach simultaneously models the effect of all SNPs. SNPs are selected by a Bayesian interpretation of the lasso (Tibshirani, 1996); the maximum a posterior (MAP) estimate of the regression coefficients, which have been given independent, double exponential prior distributions. The double exponential distribution is an example of a shrinkage prior, MAP estimates with shrinkage priors can be zero, thus all SNPs with non zero regression coefficients are selected. In addition to the commonly-used double exponential (Laplace) prior, we also implement the normal exponential gamma prior distribution. We show that use of the Laplace prior improves SNP selection in comparison with single -SNP tests, and that the normal exponential gamma prior leads to a further improvement. Our method is fast and can handle very large numbers of SNPs: we demonstrate its performance using both simulated and real genome-wide data sets with 500 K SNPs, which can be analysed in 2 hours on a desktop workstation. Mickael Guedj 1,2 , Jerome Wojcik 2 , Gregory Nuel 154 Laboratoire Statistique et Génome, Université d'Evry, Evry France 55 Serono Pharmaceutical Research Institute, Plan-les-Ouates, Switzerland Keywords: Local Replication, Local Score, Association In gene-mapping, replication of initial findings has been put forwards as the approach of choice for filtering false-positives from true signals for underlying loci. In practice, such replications are however too poorly observed. Besides the statistical and technical-related factors (lack of power, multiple-testing, stratification, quality control,) inconsistent conclusions obtained from independent populations might result from real biological differences. In particular, the high degree of variation in the strength of LD among populations of different origins is a major challenge to the discovery of genes. Seeking for Local Replications (defined as the presence of a signal of association in a same genomic region among populations) instead of strict replications (same locus, same risk allele) may lead to more reliable results. Recently, a multi-markers approach based on the Local Score statistic has been proposed as a simple and efficient way to select candidate genomic regions at the first stage of genome-wide association studies. Here we propose an extension of this approach adapted to replicated association studies. Based on simulations, this method appears promising. In particular it outperforms classical simple-marker strategies to detect modest-effect genes. Additionally it constitutes, to our knowledge, a first framework dedicated to the detection of such Local Replications. Juliet Chapman 1 , Claudio Verzilli 1 , John Whittaker 156 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: FDR, Association studies, Bayesian model selection As genomewide association studies become commonplace there is debate as to how such studies might be analysed and what we might hope to gain from the data. It is clear that standard single locus approaches are limited in that they do not adjust for the effects of other loci and problematic since it is not obvious how to adjust for multiple comparisons. False discovery rates have been suggested, but it is unclear how well these will cope with highly correlated genetic data. We consider the validity of standard false discovery rates in large scale association studies. We also show that a Bayesian procedure has advantages in detecting causal loci amongst a large number of dependant SNPs and investigate properties of a Bayesian FDR. Peter Kraft 157 Harvard School of Public Health, Boston USA Keywords: Gene-environment interaction, genome-wide association scans Appropriately analyzed two-stage designs,where a subset of available subjects are genotyped on a genome-wide panel of markers at the first stage and then a much smaller subset of the most promising markers are genotyped on the remaining subjects,can have nearly as much power as a single-stage study where all subjects are genotyped on the genome-wide panel yet can be much less expensive. Typically, the "most promising" markers are selected based on evidence for a marginal association between genotypes and disease. Subsequently, the few markers found to be associated with disease at the end of the second stage are interrogated for evidence of gene-environment interaction, mainly to understand their impact on disease etiology and public health impact. However, this approach may miss variants which have a sizeable effect restricted to one exposure stratum and therefore only a modest marginal effect. We have proposed to use information on the joint effects of genes and a discrete list of environmental exposures at the initial screening stage to select promising markers for the second stage [Kraft et al Hum Hered 2007]. This approach optimizes power to detect variants that have a sizeable marginal effect and variants that have a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. As an example, I discuss a proposed genome-wide association scan for Type II diabetes susceptibility variants based in several large nested case-control studies. Beate Glaser 1 , Peter Holmans 158 Biostatistics and Bioinformatics Unit, Cardiff University, School of Medicine, Heath Park, Cardiff, UK Keywords: Combined case-control and trios analysis, Power, False-positive rate, Simulation, Association studies The statistical power of genetic association studies can be enhanced by combining the analysis of case-control with parent-offspring trio samples. Various combined analysis techniques have been recently developed; as yet, there have been no comparisons of their power. This work was performed with the aim of identifying the most powerful method among available combined techniques including test statistics developed by Kazeem and Farrall (2005), Nagelkerke and colleagues (2004) and Dudbridge (2006), as well as a simple combination of ,2-statistics from single samples. Simulation studies were performed to investigate their power under different additive, multiplicative, dominant and recessive disease models. False-positive rates were determined by studying the type I error rates under null models including models with unequal allele frequencies between the single case-control and trios samples. We identified three techniques with equivalent power and false-positive rates, which included modifications of the three main approaches: 1) the unmodified combined Odds ratio estimate by Kazeem & Farrall (2005), 2) a modified approach of the combined risk ratio estimate by Nagelkerke & colleagues (2004) and 3) a modified technique for a combined risk ratio estimate by Dudbridge (2006). Our work highlights the importance of studies investigating test performance criteria of novel methods, as they will help users to select the optimal approach within a range of available analysis techniques. David Almorza 1 , M.V. Kandus 2 , Juan Carlos Salerno 2 , Rafael Boggio 359 Facultad de Ciencias del Trabajo, University of Cádiz, Spain 60 Instituto de Genética IGEAF, Buenos Aires, Argentina 61 Universidad Nacional de La Plata, Buenos Aires, Argentina Keywords: Principal component analysis, maize, ear weight, inbred lines The objective of this work was to evaluate the relationship among different traits of the ear of maize inbred lines and to group genotypes according to its performance. Ten inbred lines developed at IGEAF (INTA Castelar) and five public inbred lines as checks were used. A field trial was carried out in Castelar, Buenos Aires (34° 36' S , 58° 39' W) using a complete randomize design with three replications. At harvest, individual weight (P.E.), diameter (D.E.), row number (N.H.) and length (L.E.) of the ear were assessed. A principal component analysis, PCA, (Infostat 2005) was used, and the variability of the data was depicted with a biplot. Principal components 1 and 2 (CP1 and CP2) explained 90% of the data variability. CP1 was correlated with P.E., L.E. and D.E., meanwhile CP2 was correlated with N.H. We found that individual weight (P.E.) was more correlated with diameter of the ear (D.E.) than with length (L.E). Five groups of inbred lines were distinguished: with high P.E. and mean N.H. (04-70, 04-73, 04-101 and MO17), with high P.E. but less N.H. (04-61 and B14), with mean P.E. and N.H. (B73, 04-123 and 04-96), with high N.H. but less P.E. (LP109, 04-8, 04-91 and 04-76) and with low P.E. and low N.H. (LP521 and 04-104). The use of PCA showed which variables had more incidence in ear weight and how is the correlation among them. Moreover, the different groups found with this analysis allow the evaluation of inbred lines by several traits simultaneously. Sven Knüppel 1 , Anja Bauerfeind 1 , Klaus Rohde 162 Department of Bioinformatics, MDC Berlin, Germany Keywords: Haplotypes, association studies, case-control, nuclear families The area of gene chip technology provides a plethora of phase-unknown SNP genotypes in order to find significant association to some genetic trait. To circumvent possibly low information content of a single SNP one groups successive SNPs and estimates haplotypes. Haplotype estimation, however, may reveal ambiguous haplotype pairs and bias the application of statistical methods. Zaykin et al. (Hum Hered, 53:79-91, 2002) proposed the construction of a design matrix to take this ambiguity into account. Here we present a set of functions written for the Statistical package R, which carries out haplotype estimation on the basis of the EM-algorithm for individuals (case-control) or nuclear families. The construction of a design matrix on basis of estimated haplotypes or haplotype pairs allows application of standard methods for association studies (linear, logistic regression), as well as statistical methods as haplotype sharing statistics and TDT-Test. Applications of these methods to genome-wide association screens will be demonstrated. Manuela Zucknick 1 , Chris Holmes 2 , Sylvia Richardson 163 Department of Epidemiology and Public Health, Imperial College London, UK 64 Department of Statistics, Oxford Center for Gene Function, University of Oxford, UK Keywords: Bayesian, variable selection, MCMC, large p, small n, structured dependence In large-scale genomic applications vast numbers of markers or genes are scanned to find a few candidates which are linked to a particular phenotype. Statistically, this is a variable selection problem in the "large p, small n" situation where many more variables than samples are available. An additional feature is the complex dependence structure which is often observed among the markers/genes due to linkage disequilibrium or their joint involvement in biological processes. Bayesian variable selection methods using indicator variables are well suited to the problem. Binary phenotypes like disease status are common and both Bayesian probit and logistic regression can be applied in this context. We argue that logistic regression models are both easier to tune and to interpret than probit models and implement the approach by Holmes & Held (2006). Because the model space is vast, MCMC methods are used as stochastic search algorithms with the aim to quickly find regions of high posterior probability. In a trade-off between fast-updating but slow-moving single-gene Metropolis-Hastings samplers and computationally expensive full Gibbs sampling, we propose to employ the dependence structure among the genes/markers to help decide which variables to update together. Also, parallel tempering methods are used to aid bold moves and help avoid getting trapped in local optima. Mixing and convergence of the resulting Markov chains are evaluated and compared to standard samplers in both a simulation study and in an application to a gene expression data set. Reference Holmes, C. C. & Held, L. (2006) Bayesian auxiliary variable models for binary and multinomial regression. Bayesian Analysis1, 145,168. Dawn Teare 165 MMGE, University of Sheffield, UK Keywords: CNP, family-based analysis, MCMC Evidence is accumulating that segmental copy number polymorphisms (CNPs) may represent a significant portion of human genetic variation. These highly polymorphic systems require handling as phenotypes rather than co-dominant markers, placing new demands on family-based analyses. We present an integrated approach to meet these challenges in the form of a graphical model, where the underlying discrete CNP phenotype is inferred from the (single or replicate) quantitative measure within the analysis, whilst assuming an allele based system segregating through the pedigree. [source] Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminaseANNALS OF NEUROLOGY, Issue 3 2008Marios Hadjivassiliou MD Objective Gluten sensitivity typically presents as celiac disease, a chronic, autoimmune-mediated, small-intestinal disorder. Neurological disorders occur with a frequency of up to 10% in these patients. However, neurological dysfunction can also be the sole presenting feature of gluten sensitivity. Development of autoimmunity directed toward different members of the transglutaminase gene family could offer an explanation for the diversity in manifestations of gluten sensitivity. We have identified a novel neuronal transglutaminase isozyme and investigated whether this enzyme is the target of the immune response in patients with neurological dysfunction. Methods Using recombinant human transglutaminases, we developed enzyme-linked immunosorbent assays and inhibition assays to analyze serum samples of patients with gluten-sensitive gastrointestinal and neurological disorders, and various control groups including unrelated inherited or immune conditions for the presence and specificity of autoantibodies. Results Whereas the development of anti-transglutaminase 2 IgA is linked with gastrointestinal disease, an anti-transglutaminase 6 IgG and IgA response is prevalent in gluten ataxia, independent of intestinal involvement. Such antibodies are absent in ataxia of defined genetic origin or in healthy individuals. Inhibition studies showed that in those patients with ataxia and enteropathy, separate antibody populations react with the two different transglutaminase isozymes. Furthermore, postmortem analysis of brain tissue showed cerebellar IgA deposits that contained transglutaminase 6. Interpretation Antibodies against transglutaminase 6 can serve as a marker in addition to human leukocyte antigen type and detection of anti-gliadin and anti-transglutaminase 2 antibodies to identify a subgroup of patients with gluten sensitivity who may be at risk for development of neurological disease. Ann Neurol 2008;64:332,343 [source] The possible significance of Clostridium spp. in blood culturesCLINICAL MICROBIOLOGY AND INFECTION, Issue 10 2006B. Benjamin Abstract The significance of Clostridium spp. in blood cultures was evaluated by two methods. In the first part of the study, a group of 80 patients with Clostridium spp. bacteraemia was compared with a group of 100 patients with Bacillus spp. in blood cultures, making the assumption that Bacillus almost invariably represents contamination (pseudobacteraemia). Significant differences were found between the two groups, suggesting that growth of Clostridium did not represent pseudobacteraemia. Patients with Clostridium bacteraemia were older, had a higher frequency of gastrointestinal disease (especially colorectal tumours), were associated more frequently with polymicrobial bacteraemia, and had a higher mortality rate. In the second part of the study, each of the 80 cases of Clostridium bacteraemia was evaluated individually for clinical relevance by an infectious diseases expert. In two-thirds of the cases, isolates of Clostridium from blood were considered to be of clinical relevance, whereas in one-third of cases, the clinical significance of this finding was doubtful. It was concluded that growth of Clostridium spp. in blood cultures, even in the absence of one of the histotoxic syndromes, is often of clinical significance, and that such findings should be properly evaluated and not ignored. [source] Interstitial cells of Cajal (ICC) in equine colic: an immunohistochemical study of horses with obstructive disorders of the small and large intestinesEQUINE VETERINARY JOURNAL, Issue 6 2004C. FINTL Summary Reasons for performing study: The gastrointestinal pacemaker cells, the interstitial cells of Cajal (ICC), have been implicated in several human gastrointestinal dysmotility syndromes. Recently, the involvement of these cells in equine gastrointestinal diseases has been investigated in cases of equine grass sickness where a significant reduction in ICC density was observed. Objective: To investigate ICC density in equine obstructive gastrointestinal disorders using immunohistochemical labelling methods. Methods: Intestinal samples were analysed from 44 horses undergoing exploratory surgery for colic and from 11 control animals subjected to euthanasia for conditions not related to the gastrointestinal tract. Immunohistochemical labelling of ICC was carried out using an anti-c-Kit antibody. Two independent observers assessed ICC density using a semiquantitative grading system. Results: There was a significant reduction in ICC density in horses with large colon disorders compared to the controls (P<0.01). Horses with strangulating lesions of the small intestine showed no difference when compared to the controls. Conclusions: There was a reduction in ICC density in horses with large intestinal disorders. Potential relevance: The reduction in ICC density may be associated with the clinical findings as well as recurrent colic episodes observed in a number of these cases. This immunohistochemical study provides a basis for future functional electrophysiological investigations to determine the precise effect of ICC reduction on equine intestinal motility. [source] Mouse models for genetic dissection of polygenic gastrointestinal diseasesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2003S. Hillebrandt Abstract Many diseases with a major public health impact are the result of complex interactions between environmental factors and multiple genes. In the past decade, methods for genome analysis, in particular quantitative trait locus (QTL) analysis in animal models, were developed to identify and localize the genes responsible for multifactorial (polygenic) diseases; QTL analysis is based on experimental crosses between inbred strains with high and low genetic susceptibility. Recently the genes underlying several QTLs could be cloned successfully. Here we describe the impact of these genomic approaches in mice on our understanding of the multifactorial genetics of three gastrointestinal diseases related to metabolism (cholesterol cholelithiasis), development (gastroschisis), and colorectal cancer. The examples demonstrate how mouse models continue to be an invaluable tool in unravelling complex pathomechanisms and unlocking our understanding of human diseases. [source] Serum tumour necrosis factor-, levels in cancer patients are discontinuous and correlate with weight lossEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2000M. Bossola Tumour necrosis factor-, (TNF) has been regarded as a potential mediator of cancer cachexia. Assessment of TNF circulating levels in cancer patients and their correlation with weight loss has led to controversial results. We measured TNF circulating levels in 28 patients with gastrointestinal cancer and 29 controls with benign gastrointestinal diseases at different times (08.00 h, 14.00 h, 20.00 h) before operation. TNF activity was not detected in any of controls at any times. In cancer patients, TNF circulating levels were detectable in 18 cases (64·3%) and appeared to be discontinuous. TNF levels above the limit of detection were present in 15 patients (53·6%) at 08.00 h, in 14 (50%) at 014.00 h and in nine (32·1%) at 20.00 h. Mean TNF levels were 14·3 ± 4 pg mL,1 at 08.00 h, 16·7 ± 4·6 pg mL,1 at 14.00 h (P = 0·05) and 18·5 ± 10·2 pg mL,1 at 20.00 h (P < 0·05 vs. 08.00 h and 14.00 h). According to Spearman's analysis, the sum of TNF concentrations at the three times significantly correlated with the severity of weight loss (Spearman's correlation coefficient =,,0·420; P = 0·026). TNF concentrations were consistently and significantly higher in patients with severe weight loss than in those with moderate or light weight loss at 08.00 h (26·3 ± 8·3, 8·9 ± 4·2, 3·8 ± 2·1, respectively; P = 0·04 at one-way anova). TNF levels were higher in anorectic than in nonanorectic patients at any hour, but the differences were not statistically significant. The present study demonstrates that TNF is intermittently or discontinuously detectable in patients with gastrointestinal cancer and that its levels correlate with the severity of weight loss. [source] | |||||||||||||||||||||||||||||||||||||