Case-control Comparison Research Articles

Body mass index at age 18\xa0years and recent body mass index in relation to risk of breast cancer overall and ER/PR/HER2-defined subtypes in white women and African-American women: a pooled analysis

BackgroundAlthough it has been well-documented that obesity is associated with decreased risk of premenopausal breast cancer and increased risk of postmenopausal breast cancer, it is unclear whether these associations differ among breast cancer subtypes defined by the tumor protein expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).MethodsWe evaluated the associations of body mass index (BMI) at age 18 years and recent BMI in relation to risk of breast cancer overall and ER/PR/HER2-defined subtypes, in 6320 women (3934 case-patient participants, 2386 control participants) aged 35–64 years, who participated in one of three population-based case-control studies. We estimated multivariable-adjusted odd ratios (ORs) and corresponding 95% confidence intervals (CIs) using polychotomous unconditional logistic regression methods for case-control comparisons in premenopausal women and postmenopausal women.ResultsBMI at age 18 years was inversely associated with risk of breast cancer, particularly among premenopausal women (≥ 25 vs. < 20 kg/m2, OR = 0.72, 95% CI = 0.53–0.96; per 5 kg/m2 increase, OR = 0.83, 95% CI = 0.73–0.95). This inverse association did not differ across ER/PR/HER2-defined subtypes or by race (white women, African-American women). Recent BMI was not associated with risk of premenopausal breast cancer after adjustment for BMI at age 18 years; nevertheless, the analysis for the joint effects of BMI at age 18 years and recent BMI showed that premenopausal women in the highest categories of the two BMI measures (≥ 25 kg/m2 at age 18 years and ≥ 30 kg/m2 for recent BMI) had 46% lower risk of breast cancer than premenopausal women in the lowest categories of the two BMI measures (< 20 kg/m2 at age 18 years and < 25 kg/m2 for recent BMI; OR = 0.54, 95% CI = 0.38–0.78). Neither measure of BMI was statistically significantly associated with risk of postmenopausal breast cancer.ConclusionOur findings indicate that high BMI near the end of adolescence decreases risk of all ER/PR/HER2-defined subtypes of premenopausal breast cancer and also suggest that this benefit could be maximized among premenopausal women who consistently have high BMI during their premenopausal years.

A Retrospective 2D Morphometric Analysis of Adult Female Chiari Type I Patients with Commonly Reported and Related Conditions.

Purpose: Researchers have sought to better understand Chiari type I malformation (CMI) through morphometric measurements beyond tonsillar position (TP). Soft tissue and bone structures within the brain and craniocervical junction have been shown to be different for CMI patients compared to healthy controls. Yet, several morphological characteristics have not been consistently associated with CMI. CMI is also associated with different prevalent conditions (PCs) such as syringomyelia, pseudotumor, Ehlers-Danlos syndrome (EDS), scoliosis, and craniocervical instability. The goal of this study was two-fold: (1) to identify unique morphological characteristics of PCs, and (2) to better explain inconsistent results from case-control comparisons of CMI.Methods: Image, demographic, and PC information was obtained through the Chiari1000, a self-report web-accessed database. Twenty-eight morphometric measurements (MMs) were performed on the cranial MR images of 236 pre-surgery adult female CMI participants and 140 female healthy control participants. Custom software was used to measure 28 structures within the posterior cranial fossa (PCF) compartment, craniocervical junction, oral cavity, and intracranial area on midsagittal MR images for each participant.Results: Morphometric analysis of adult females indicated a smaller McRae line length in CMI participants with syringomyelia compared to those without syringomyelia. TP was reduced in CMI participants with EDS than those without EDS. Basion to posterior axial line was significantly longer in CMI participants with scoliosis compared to those without scoliosis. No additional MMs were found to differ between CMI participants with and without a specific PC. Four morphometric differences were found to be consistently different between CMI participants and healthy controls regardless of PC: larger TP and a smaller clivus length, fastigium, and corpus callosum height in CMI participants.Conclusion: Syringomyelia, EDS, and scoliosis were the only PCs that showed significant morphometric differences between CMI participants. Additionally, four midsagittal MR-based MMs were found to be significantly different between healthy controls and CMI participants regardless of the presence of one or more PCs. This study suggests that the prevalence of comorbid conditions are not strongly related to CMI morphology, and that inconsistent findings in the radiographic literature cannot be explained by varying prevalence of comorbid conditions in CMI study samples.

Pulmonary valve replacement after right ventricular outflow tract reconstruction with homograft vs Contegra\xae: a case control comparison of mortality and morbidity

BackgroundRepair of congenital heart defects involving the right ventricular outflow tract may require the implantation of a right ventricle to pulmonary artery conduit. This conduit is likely to be replaced during childhood. This study compares the operative outcomes of the replacement procedure of Contegra® and homografts in pulmonary position.MethodsFrom 1999 to 2016, 82 children underwent 87 right ventricle to pulmonary artery conduit replacements (60 Contegra® and 27 homografts). Demographics, operative and clinical data were obtained through a retrospective review of the medical records. The two groups were matched for comparison using propensity score matching. All the procedures were performed by the same team of surgeons.ResultsNo statistically significant difference was observed between the two groups when considering the operative data for anesthesia, surgery, cardiopulmonary bypass and aortic clamping durations. A peroperative complication rate of 13.47% and 15.36% in Contegra® and homograft replacement groups respectively (p value = 0.758) was observed. There was no difference regarding the blood loss and fluid input. No statistically significant difference was observed between the two groups for the post-operative morbidity. We considered the Pediatric Risk of Mortality (PRISM) score, the day of extubation, the day of withdrawal of inotropic drugs, the length of the intensive care unit stay and the length of hospital stay. The overall mortality is 2.3% but there is no statistically significant difference between the two groups.ConclusionRight ventricle to pulmonary artery conduit replacement procedure can be achieved with a low surgical morbidity or mortality, not influenced by the type of conduit that is replaced. Therefore, the choice between homograft or Contegra® for right ventricle to pulmonary artery reconstruction should not be influenced by the future surgical risk during the replacement procedure.Trial registrationNCT03048071. Registered 9 February 2017 (retrospectively registered).

P199 Hidradenitis suppurativa associated with Crohn’s disease: An increased risk of permanent stoma

Hidradenitis Suppurativa (HS) is a chronic cutaneous, inflammatory disease with strong impact on quality of life. Perineal lesions in Crohn’s disease (CD) are frequently observed and may resemble to perineal HS. CD and HS both share an inadequate immune response, to commensal bacteria, in genetically predisposed subjects. The association between these two diseases is more and more described and it appears that HS could negatively influence the prognosis of CD. The aim of our study was to evaluate the impact of HS on CD outcomes. We performed a case–control with 1 on 4 ratio from a mono-centric tertiary centre where 4645 CD were seen between 2003 and 2016. Patients with both CD and HS were matched to CD patients without HS on sex, date of birth (±2.5 years), date of CD diagnosis (±2.5 years), presence of perineal lesion at the time of diagnosis and follow-up quality. HS cases were confirmed after reviewing the medical charts and by a dedicated clinical examination. Each case of HS was characterised by its location and Hurley’s classification. The prevalence of HS was 0.95% through 44 cases identified from the 4645 CD. Of these, 64% had active smoking habits. HS was severe with 80% of patients with Hurley II and III, and was mainly localised in axillary (72%) and perineal (50%) areas. HS was diagnosed after CD in 70% of cases, with a 9 years median between the two diagnosis (IQR 5.25–12.75). In the case–control comparison, HS-associated CD was more active (56% vs. 40% years with active disease, p <0.001) and required more TNF antagonists (39% vs. 23% years spent under anti-TNF, p <0.001) than CD alone. HS-associated CD was also associated with a higher risk of permanent stoma, 16.8% (IQR 7.5–33.3) vs. 2.5% (IQR 0.8–7.4) in the control group (p = 0.002). The univariate and multivariate analysis confirmed HS as an independent risk factor for permanent stoma with a Hazard Ratio of 6.29 [95% CI (2.30–38.33) p <0.001]. Our study shows that HS has a negative effect on CD outcomes with a more active disease and an increased risk of permanent stoma, despite a higher use of anti-TNF antagonists.

Cutaneous toxicities of epidermal growth factor receptor inhibitors: A prospective study in 60 Asian patients.

Several prospective studies have been conducted in epidermal growth factor receptor (EGFR) inhibitor-related cutaneous reactions in Caucasian patients, but prospective studies in Asian populations are scarce. To investigate the cutaneous side effects of EGFR inhibitors in Asian cancer patients and to assess tumor response to dermatologic manifestations. Sixty patients with lung or colorectal cancer who were receiving EGFR inhibitors were prospectively followed for at least one year by oncologists and dermatologists. Of 60 patients (33 males, 27 females), 46 lung cancer patients received erlotinib (n=29) and gefitinib (n=17). Cetuximab was prescribed in 14 colorectal cancer patients. Fifty-eight patients (58/60, 96.7%) developed cutaneous reactions. The most common reactions were xerosis (82.8%), acne (79.3%), and skin desquamation (62.1%). Most reactions were mild and well-tolerated. Of 14 patients who had severe reactions, temporary treatment interruption was necessary in 3 patients and a decreasing dose was required in another 3 patients. There were no statistically significant differences in type, severity, or number of cutaneous reactions between responders (29/58) and non-responders (29/58) to EGFR inhibitors. At median follow-up time of 11.92±1.08 months, no patient died from cutaneous toxicities. Nine patients died from cancer and 11 patients lost to follow-up. In this Asian population, almost all patients (96.7%) developed cutaneous toxicities of EGFR inhibitors. Xerosis, acne, and desquamation were common in Asian cancer patients. Most reactions were mild and well tolerated. Due to limited number of patients, this study did not show significant associations between cutaneous toxicities and tumor response.

The Rise and Fall and Rise of Linkage Analysis as a Technique for Finding and Characterizing Inherited Influences on Disease Expression.

For many years, family-based studies using linkage analysis represented the primary approach for identifying disease genes. This strategy is responsible for the identification of the greatest number of genes proven to cause human disease. However, technical advancements in next generation sequencing and high throughput genotyping, coupled with the apparent simplicity of association testing, led to the rejection of family-based studies and of linkage analysis. At present, genetic association methods, using case-control comparisons, have become the exclusive approach for detecting disease-related genes, particularly those underlying common, complex diseases. In this chapter, we present a historical overview of linkage analysis, including a description of how the approach works, as well as its strengths and weaknesses. We discuss how the transition from family-based studies to population comparison association studies led to a critical loss of information with respect to genetic etiology and inheritance, and we present historical and contemporary examples of linkage analysis "success stories" in identifying genes contributing to the development of human disease. Currently, linkage analysis is re-emerging as a useful approach for identifying disease genes, determining genetic parameters, and resolving genetic heterogeneity. We posit that the combination of linkage analysis, association testing, and high throughput sequencing provides a powerful approach for identifying disease-causing genes.

Abstract 05: Untangling the gene-epigenome networks: Timing of epigenetic regulation of gene expression in acquired cetuximab resistance gene programs

Abstract The current study performs time course RNA-seq and DNA methylation profiling to determine the complex interactions between gene expression and epigenetic changes in acquired therapeutic resistance. The genomics era provides widespread characterization of the genomic landscape of tumors and has enabled precision treatment strategies. Currently, epidermal growth factor receptor (EGFR) inhibitors are the only FDA-approved targeted therapy for clinical use in head and neck squamous cell carcinoma (HNSCC). EGFR inhibitors are only effective in a subset of each of these tumors. Moreover, patients with de novo sensitivity to EGFR inhibitors often subsequently acquire resistance and succumb to their tumors. Numerous genetic and epigenetic alterations occur in tumors with acquired resistance. However, their timing and function remain unknown. Therefore, we develop new computational techniques to find gene programs associated with the acquisition of resistance. High-throughput transcriptional profiling enables unprecedented characterization of individual genes during cancer treatment. However, identifying and targeting mechanisms of EGFR resistance from these high-throughput data requires novel systems biology techniques that can discriminate altered cellular signaling pathways in response to cancer treatment. Therefore, we developed a new bioinformatics algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS) to quantify multiplexed regulation and gene reuse in oncogenic signaling. To test this algorithm, we modified the HaCaT keratinocyte cell line model of premalignancy to simulate cancer cells with constitutive overexpression of wild-type EGFR and with activating mutations in HRAS and PIK3CA in a controlled genetic background. We apply CoGAPS to gene expression data from these models. This algorithm quantified relative changes in cellular signaling pathway activity in these data, not accessible to standard gene comparisons. Increases in CoGAPS pathway signatures from HRAS also occurred in gene expression data from the cetuximab resistant HNSCC cell line (1CC8) relative to its parental, sensitive cell line (UMSCC1). Investigation of the mechanisms of acquired resistance has previously been limited by reliance on case-control comparisons between sensitive and resistant cells, such as the UMSCC1 and 1CC8 cell lines. Since activity in cellular signaling pathways evolves during cetuximab resistance, it is essential to extend these case-control paradigms to quantify the dynamics responsible for resistance. Therefore, we developed a novel time course analysis to determine the molecular mechanisms of acquired cetuximab resistance in HNSCC. Specifically, we treated the cetuximab sensitive SCC25 HNSCC cell line over generations with both cetuximab and PBS. This long-term treatment protocol models the progression of acquired therapeutic resistance, including controls for clonal selection unrelated to treatment. Overexpression of the previous HRAS gene program also occurs in gene expression data measured during acquired cetuximab resistance in SCC25. We also measure DNA methylation during this time course to find the driver of this aberrant signaling associated with resistance. We apply CoGAPS analysis to the time course data for both DNA methylation and gene expression. This analysis distinguished early gene expression changes from cetuximab treatment from longer-term epigenetic alterations to gene expression during acquired resistance. Epigenetic regulation of FGFR1 expression emerged as the dominant mechanism of acquired therapeutic resistance in this system. Thus, our integration of time course DNA methylation and gene expression data enables unprecedented inference of the timing of targetable gene-epigenome programs responsible for acquired resistance. Citation Format: Genevieve Stein-O'Brien, Luciane T. Kagohara, Sijia Li, Manjusha Thakar, Ruchira Ranaweera, Michael Considine, Ludmila V. Danilova, Hiroyuki Ozawa, Joseph A. Califano, Daria A. Gaykalova, Michael F. Ochs, Christine H. Chung, Elana J. Fertig. Untangling the gene-epigenome networks: Timing of epigenetic regulation of gene expression in acquired cetuximab resistance gene programs [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 05.

Hormone-secreting adrenal tumours cause severe hypertension and high rates of poor pregnancy outcome; a UK Obstetric Surveillance System study with case control comparisons.

To examine the management and outcomes of adrenal tumours in pregnancy. A national observational, cohort study over 4 years using the UK Obstetric Surveillance System (UKOSS). Consultant-led obstetric units. Women with phaeochromocytoma, primary aldosteronism or Cushing's syndrome diagnosed before or during pregnancy. Clinical features of UKOSS cases were compared with those of women with adrenal tumours reported from 1985-2015. Nested case-control comparisons involving the UKOSS cases as well as those identified in the literature were performed for pregnancy outcome data using UKOSS controls with uncomplicated singleton (n = 2250) pregnancy and data from the Office of National Statistics (ONS). Incidence, management and frequency of adverse maternal and offspring outcomes of adrenal tumours in pregnancy. Fifteen pregnant women met the inclusion criteria: ten phaeochromocytoma, three primary aldosteronism and two Cushing's syndrome. All of the tumours had an incidence rate <2 per 100 000 pregnancies. Clinical symptoms were similar to those in non-pregnant women due to the hormones released. All women had severe hypertension, and in those diagnosed in pregnancy prior to conception. There was a significantly increased risk of adverse pregnancy outcomes in affected women, with increased rates of stillbirth, preterm labour and operative delivery. Adrenal tumours are associated with increased risks for pregnant women and their babies. Data on these tumours to inform practice are limited and international collaborative efforts are likely to be needed. Study of hormone-secreting adrenal tumours in pregnancy linked with high BP and high rates of fetal morbidity.

The Pierre Robin Mandible is Hypoplastic and Morphologically Abnormal.

For Pierre Robin sequence (PRS) patients, there is incomplete characterization of 3D differences and effects of mandibular distraction osteogenesis (MDO) on the mandible compared to normal controls. PRS infants who underwent MDO at 2 craniofacial referral centerals with pre- and postoperative computed tomography (CT) scans were identified. A group of age-matched control patients with CTs were identified in the PACS database. Demographic and perioperative data were recorded. Mandibular lengths, angles, and volumes were measured. Morphologic and outcomes data were analyzed in a case-control comparison. Sixty-three CT scans were analyzed. Fifteen pre-op PRS patient and 15 control CTs were well matched in terms of age and sex. Mandibular volume (78%), ramus length (87%), and body length (95%) were all decreased in the PRS patients. Anterior symphyseal angle (84%) was significantly reduced in PRS patients while mandibular angle (102%) was maintained. Eighteen post-op PRS patient and 15 control CTs were well matched in terms of age and gender. Mandibular volumes (106%) were normalized following distraction with shorter mandibular rami (88%) and longer mandibular bodies (109%). Postoperatively, mandibular angle (100%) and anterior symphyseal angle (99%) were ultimately indistinguishable from controls. The mandible in PRS is dysmorphic compared to age-matched controls. Overall, they have a smaller volume, shorter ramus, and an obtuse symphyseal angle. MDO improves mandibular volume and normalizes the symphyseal angle, but results in a longer mandibular body and shorter mandibular ramus.

Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus

ObjectivesLow copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort.MethodsWe genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupus-associated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE.ResultsHomozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR) = 5.329; p = 7.7 × 10−3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR = 3.699; p = 6.8 × 10−3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110 g/l (two copies) to 0.256 g/l (five to six copies; p = 4.9 × 10−6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR = 4.044; p = 0.040 and OR = 5.798; p = 0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p = 0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR = 2.231; p = 1.33 × 10−5).ConclusionsOur findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLA-DRB1*0301 without a proven pathophysiological mechanism.

Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.

Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43×10-9, DOCK3, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (α=8.9×10-4), the most significant associations were observed for SNPs rs10505477 (P=6.08×10-4) and rs6983267 (P=7.35×10-4) of CASC8, rs3802842 (P=8.98×10-5, COLCA1,2), and rs12953717 (P=4.64×10-4, SMAD7). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer.

Factors associated with suicide: Case-control study in South Tyrol

BackgroundAs suicide is related to many factors in addition to psychiatric illness, broad and comprehensive risk-assessment for risk of suicide is required. This study aimed to differentiate nondiagnostic risk factors among suicides versus comparable psychiatric patients without suicidal behavior. MethodsWe carried out a pilot, case-control comparison of 131 cases of suicide in South Tyrol matched for age and sex with 131 psychiatric controls, using psychological autopsy methods to evaluate differences in clinically assessed demographic, social, and clinical factors, using bivariate conditional Odds Risk comparisons followed by conditional regression modeling controlled for ethnicity. ResultsBased on multivariable conditional regression modeling, suicides were significantly more likely to have experienced risk factors, ranking as: [a] family history of suicide or attempt≥[b] recent interpersonal stressors≥[c] childhood traumatic events≥[d] lack of recent clinician contacts≥[e] previous suicide attempt≥[f] non-Italian ethnicity, but did not differ in education, marital status, living situation, or employment, nor by psychiatric or substance-abuse diagnoses. ConclusionsBoth recent and early factors were associated with suicide, including lack of recent clinical care, non-Italian cultural subgroup-membership, familial suicidal behavior, and recent interpersonal distress.

Sensorimotor performance and function in people with osteoarthritis of the hand: A case-control comparison.

To determine whether hand left/right judgements, tactile acuity, and body perception are impaired in people with hand OA. To examine the relationships between left right judgements, tactile acuity and hand pain. To explore the relationships between sensorimotor measures (left/right judgements and tactile acuity) and measures of hand function in people with hand OA. Twenty patients with symptomatic hand OA and 19 healthy pain-free controls undertook a hand left/right judgment task, a control left/right judgement task, two-point discrimination (TPD) threshold testing (assessing tactile acuity), a neglect-like symptoms questionnaire (assessing body perception) and several established measures of hand function. Neglect-like symptoms were experienced more frequently in the hand OA group (P < 0.05). People with hand OA were slower (P < 0.05) and less accurate (P < 0.05) in the hand left/right judgement task when compared to healthy controls, with no significant difference in the control task. Significant associations were found between hand left/right judgement reaction time and pain intensity (P < 0.05) and accuracy and pain intensity (P < 0.05). TPD was not different between groups, and no correlation was found between TPD and left/right judgement performance. No association was found between left/right judgement performance and measures of hand function (all P > 0.05). However, TPD (tactile acuity) was related to several measures of hand function (all P < 0.05). People with hand OA had more frequent neglect-like symptoms and were slower and less accurate compared to healthy controls at hand left/right judgments, which was indicative of disrupted working body schema. Future studies may wish to examine whether interventions targeting sensorimotor dysfunction are effective at reducing pain and improving hand function and dexterity in people with hand OA.

Persistent Pulmonary Hypertension of the Newborn in Twin-Twin Transfusion Syndrome: A Case-Control Study

Background: Persistent pulmonary hypertension of the newborn (PPHN) is associated with severe morbidity and mortality. Twin-twin transfusion syndrome (TTTS) is suggested to increase the risk of PPHN. Objectives: To describe the incidence of PPHN in TTTS twins and to identify risk factors in TTTS twins for the development of severe PPHN. Methods: Cases with severe PPHN were extracted from our monochorionic twin database (2002-2016). Severe PPHN was defined as severe hypoxaemia requiring mechanical ventilation and inhaled nitric oxide (iNO) treatment, confirmed by strict echocardiographic criteria. A case-control comparison within TTTS survivors was conducted to identify risk factors for PPHN. Results: The incidence of PPHN in TTTS twins was 4% (24/598, 95% confidence interval [CI] 2.7-5.9%) and 0.4% (2/493, 95% CI 0.1-1.5%) in uncomplicated monochorionic twins (odds ratio [OR] 10.3, 95% CI 2.4-43.9; p = 0.002). Two risk factors were independently associated with PPHN: severe prematurity (OR 3.3, 95% CI 1.0-11.4) and recipient status (OR 3.9, 95% CI 1.4-11.0). In TTTS recipients, another risk factor for PPHN is anaemia at birth (OR 7.2, 95% CI 1.8-29.6). Conclusion: Clinicians caring for neonates with TTTS should be aware of the 10-fold increased risk of PPHN compared to uncomplicated monochorionic twins. PPHN occurs more often in case of premature delivery and in recipient twins, particularly in the presence of anaemia at birth. As the development of severe PPHN is difficult to predict, we advise that all TTTS twins should be delivered in a tertiary care centre with iNO treatment options.

Decision Support for Diabetes in Scotland: Implementation and Evaluation of a Clinical Decision Support System.

Automated clinical decision support systems (CDSS) are associated with improvements in health care delivery to those with long-term conditions, including diabetes. A CDSS was introduced to two Scottish regions (combined diabetes population ~30 000) via a national diabetes electronic health record. This study aims to describe users' reactions to the CDSS and to quantify impact on clinical processes and outcomes over two improvement cycles: December 2013 to February 2014 and August 2014 to November 2014. Feedback was sought via patient questionnaires, health care professional (HCP) focus groups, and questionnaires. Multivariable regression was used to analyze HCP SCI-Diabetes usage (with respect to CDSS message presence/absence) and case-control comparison of clinical processes/outcomes. Cases were patients whose HCP received a CDSS messages during the study period. Closely matched controls were selected from regions outside the study, following similar clinical practice (without CDSS). Clinical process measures were screening rates for diabetes-related complications. Clinical outcomes included HbA1c at 1 year. The CDSS had no adverse impact on consultations. HCPs were generally positive toward CDSS and used it within normal clinical workflow. CDSS messages were generated for 5692 cases, matched to 10 667 controls. Following clinic, the probability of patients being appropriately screened for complications more than doubled for most measures. Mean HbA1c improved in cases and controls but more so in cases (-2.3 mmol/mol [-0.2%] versus -1.1 [-0.1%], P = .003). The CDSS was well received; associated with improved efficiencies in working practices; and large improvements in guideline adherence. These evidence-based, early interventions can significantly reduce costly and devastating complications.

Case-Control Comparison of Enteric Viromes in Captive Rhesus Macaques with Acute or Idiopathic Chronic Diarrhea.

Diarrhea is the major cause of non-research-associated morbidity and mortality affecting the supply of rhesus macaques and, potentially, their responses to experimental treatments. Idiopathic chronic diarrhea (ICD) in rhesus macaques also resembles ulcerative colitis, one form of human inflammatory bowel disease. To test for viral etiologies, we characterized and compared the fecal viromes from 32 healthy animals, 31 animals with acute diarrhea, and 29 animals with ICD. The overall fractions of eukaryotic viral reads were 0.063% for the healthy group, 0.131% for the acute-diarrhea group, and 0.297% for the chronic-diarrhea group. Eukaryotic viruses belonging to 6 viral families, as well as numerous circular Rep-encoding single-stranded DNA (CRESS DNA) viral genomes, were identified. The most commonly detected sequences were from picornaviruses, making up 59 to 88% of all viral reads, followed by 9 to 17% for CRESS DNA virus sequences. The remaining 5 virus families, Adenoviridae, Astroviridae, Anelloviridae, Picobirnaviridae, and Parvoviridae, collectively made up 1 to 3% of the viral reads, except for parvoviruses, which made up 23% of the viral reads in the healthy group. Detected members of the families Picornaviridae and Parvoviridae were highly diverse, consisting of multiple genera, species, and genotypes. Coinfections with members of up to six viral families were detected. Complete and partial viral genomes were assembled and used to measure the number of matching short sequence reads in feces from the 92 animals in the two clinical and the healthy control groups. Several enterovirus genotypes and CRESS DNA genomes were associated with ICD relative to healthy animals. Conversely, higher read numbers from different parvoviruses were associated with healthy animals. Our study reveals a high level of enteric coinfections with diverse viruses in a captive rhesus macaque colony and identifies several viruses positively or negatively associated with ICD.

Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma.

Although genome-wide association studies have identified several susceptibility loci for adult glioma, little is known regarding the potential contribution of genetic variation in the human leukocyte antigen (HLA) region to glioma risk. HLA associations have been reported for various malignancies, with many studies investigating selected candidate HLA polymorphisms. However, no systematic analysis has been conducted in glioma patients, and no investigation into potential non-additive effects has been described. We conducted comprehensive genetic analyses of HLA variants among 1746 adult glioma patients and 2312 controls of European-ancestry from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, and we imputed HLA alleles using a reference panel of 5225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for population stratification using ancestry-informative principal components. Because alleles in different loci across the HLA region are linked, we created multigene haplotypes consisting of the genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, inclusion of a dominance term significantly improved the model for multigene haplotype HLA-DRB1*1501-DQA1*0102-DQB1*0602 (P = 0.002). Heterozygous carriers of the haplotype had an increased risk of glioma [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.01-1.49], while homozygous carriers were at decreased risk compared with non-carriers (OR 0.64; 95% CI 0.40-1.01). Our results suggest that the DRB1*1501-DQA1*0102-DQB1*0602 haplotype may contribute to the risk of glioma in a non-additive manner, with the positive dominance effect partly explained by an epistatic interaction with HLA-DRB1*0401-DQA1*0301-DQB1*0301.

Abstract 1320: Non-additive and interaction effects of HLA class 2 polymorphism contributing to risk of glioma

Abstract Although genome-wide association studies have identified a number of susceptibility loci for adult glioma, little is still known regarding whether polymorphisms in the human leukocyte antigen (HLA) region contribute risk. HLA associations have previously been reported for a number of malignancies, with selected HLA polymorphisms investigated in a subset of glioma studies. However, no systematic analysis has been conducted to date, and no investigation into potential non-additive effects of such associations has been described. In this study, we conducted comprehensive genetic analyses of HLA variants in the major histocompatibility complex (MHC) region among 1,746 adult glioma patients and 2,312 controls from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, containing 1,822 SNP probes across the MHC region. We imputed HLA alleles using a reference panel of 5,225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Subjects were of European-ancestry, and case-control comparisons were adjusted for population stratification using ancestry-informative principal components. Because alleles in different loci across the MHC region are linked, we created multi-locus haplotypes consisting of genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, DRB1*15:01-DQA1*01:02-DQB1*06:02 showed an improvement in model fit after the inclusion of a non-additive term, which was significant after Bonferroni correction (P = 2.5x10-3). Furthermore, the interaction of DRB1*15:01-DQA1*01:02-DQB1*06:02 with haplotype DRB1*04:01-DQA1*03:01- DQB1*03:01 resulted in a 3.80-fold increase in the odds of glioma (P = 8.8x10-3). Our results indicate that the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype contributes to the risk of glioma via a dominant effect, with heterozygosity conferring greater risk of glioma than expected from homozygote disease risk in an additive model. Citation Format: Chenan Zhang, Kyle Walsh. Non-additive and interaction effects of HLA class 2 polymorphism contributing to risk of glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1320. doi:10.1158/1538-7445.AM2017-1320

COGNITIVE CORRELATES OF BLOOD PRESSURE VARIABILITY IN ALZHEIMER’S DISEASE

Vascular abnormality, especially small vessel disease, has been frequently reported in Alzheimer's disease (AD). Some studies suggest that small vessel lesions and cognitive performance are affected by the loss of a nocturnal BP dip or SBP variability. In this study, we compared and analyzed 24-hour BP values between patients with amnestic mild cognitive impairment (aMCI) and dementia of the Alzheimer type (AD). Case-control comparisons were made among outpatients that visited the Department of Neurology, The Catholic University of Korea, Bucheon St. Mary's Hospital for the evaluation of cognitive impairment between January 2015 and November 2016. Twenty-eight patients with MCI and 46 patients with Alzheimer's disease were selected according to inclusion criteria. All of the subjects received brain MRI and MR angiography, detailed neuropsychological testing, and 24-hour ambulatory BP monitoring. Frequency of non-dippers and reverse dippers were higher in patients with AD (84.4%; 7 dippers, 17 non-dippers, and 21 reverse dippers), compared to patients with MCI (71.4%; 8, 14, and 6). Demographic data including age and education, and MRI parameters such as WMHs and medial temporal atrophy were not different between non-dippers and dippers. Just 2 variables of MMSE score and BMI value were different. MMSE score of the non-dippers was lower (19.18±6.36) than that of dippers (22.43±5.03). BMI was lower in non-dippers (22.90±3.21) than dippers (24.76±2.97). We have found that AD is associated with loss of nocturnal BP dipping and SBP. variability. Loss of nocturnal dipping was significantly associated with cognitive impairment. Accordingly, the correction of these factors could be important for prevention of AD, independent of the reduction in BP.

OP 36 Home blood pressure monitoring in pregnancy – A cost analysis

Introduction Hypertensive disorders complicate 10% of pregnancies and are associated with an increased risk of maternal and fetal morbidity and mortality. Traditional monitoring requires frequent hospital visits and investigations, which are time-consuming and stressful for patients, as well as a burden on maternity services. Home blood pressure monitoring (HBPM) offers an accurate and safe means of monitoring blood pressure and could provide cost-savings. We have introduced HBPM with the adjunct of an innovative smartphone app to record results and give advice to women with hypertension in pregnancy. Patients and methods We conducted a cost analysis for a cohort of hypertensive pregnant women using HBPM with our app using 2 techniques: process modelling and a direct case-control comparison with a cohort of women on traditional monitoring. Models were derived from common scenarios and costs obtained from NICE tariffs and NHS Practice Reports. For the direct comparison, data was collected from case notes and hospital databases. Variables included number of outpatient attendances, inpatient bed days and number of investigations. Results There were 108 patients in the HBPM cohort and 58 patients on the traditional pathway. Using process modelling we estimated that by using HBPM and thereby reducing the number of DAU visits required, costs per patient per week could be reduced from £196.64-£294.96 to £49.16-£98.32. The direct comparison demonstrated average savings of £200.85 per patient, per week of monitoring using HBPM compared to the traditional pathway with savings of £286.59 in some scenarios. There was no statistical difference in adverse outcomes between the groups. Conclusion This pilot study suggests that HBPM is a cost-saving initiative which is acceptable to patients in a hypertensive pregnant population. A larger study is required to confirm these findings.