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Recent Discoveries


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Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

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Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Nat Genet. 2018 Aug 13;:

Authors: Zhou W, Nielsen JB, Fritsche LG, Dey R, Gabrielsen ME, Wolford BN, LeFaive J, VandeHaar P, Gagliano SA, Gifford A, Bastarache LA, Wei WQ, Denny JC, Lin M, Hveem K, Kang HM, Abecasis GR, Willer CJ, Lee S

Abstract
In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, the linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.

PMID: 30104761 [PubMed - as supplied by publisher]

Effect of a Behavioral Intervention for Underserved Preschool-Age Children on Change in Body Mass Index: A Randomized Clinical Trial.

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Effect of a Behavioral Intervention for Underserved Preschool-Age Children on Change in Body Mass Index: A Randomized Clinical Trial.

JAMA. 2018 Aug 07;320(5):450-460

Authors: Barkin SL, Heerman WJ, Sommer EC, Martin NC, Buchowski MS, Schlundt D, Po'e EK, Burgess LE, Escarfuller J, Pratt C, Truesdale KP, Stevens J

Abstract
Importance: Prevention of obesity during childhood is critical for children in underserved populations, for whom obesity prevalence and risk of chronic disease are highest.
Objective: To test the effect of a multicomponent behavioral intervention on child body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) growth trajectories over 36 months among preschool-age children at risk for obesity.
Design, Setting, and Participants: A randomized clinical trial assigned 610 parent-child pairs from underserved communities in Nashville, Tennessee, to a 36-month intervention targeting health behaviors or a school-readiness control. Eligible children were between ages 3 and 5 years and at risk for obesity but not yet obese. Enrollment occurred from August 2012 to May 2014; 36-month follow-up occurred from October 2015 to June 2017.
Interventions: The intervention (n = 304 pairs) was a 36-month family-based, community-centered program, consisting of 12 weekly skills-building sessions, followed by monthly coaching telephone calls for 9 months, and a 24-month sustainability phase providing cues to action. The control (n = 306 pairs) consisted of 6 school-readiness sessions delivered over the 36-month study, conducted by the Nashville Public Library.
Main Outcomes and Measures: The primary outcome was child BMI trajectory over 36 months. Seven prespecified secondary outcomes included parent-reported child dietary intake and community center use. The Benjamini-Hochberg procedure corrected for multiple comparisons.
Results: Participants were predominantly Latino (91.4%). At baseline, the mean (SD) child age was 4.3 (0.9) years; 51.9% were female. Household income was below $25 000 for 56.7% of families. Retention was 90.2%. At 36 months, the mean (SD) child BMI was 17.8 (2.2) in the intervention group and 17.8 (2.1) in the control group. No significant difference existed in the primary outcome of BMI trajectory over 36 months (P = .39). The intervention group children had a lower mean caloric intake (1227 kcal/d) compared with control group children (1323 kcal/d) (adjusted difference, -99.4 kcal [95% CI, -160.7 to -38.0]; corrected P = .003). Intervention group parents used community centers with their children more than control group parents (56.8% in intervention; 44.4% in control) (risk ratio, 1.29 [95% CI, 1.08 to 1.53]; corrected P = .006).
Conclusions and Relevance: A 36-month multicomponent behavioral intervention did not change BMI trajectory among underserved preschool-age children in Nashville, Tennessee, compared with a control program. Whether there would be effectiveness for other types of behavioral interventions or implementation in other cities would require further research.
Trial Registration: ClinicalTrials.gov Identifier: NCT01316653.

PMID: 30088008 [PubMed - in process]

Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.

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Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.

J Am Coll Cardiol. 2018 Aug 07;72(6):662-680

Authors: Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, de Ferranti SD, Defesche JC, Freiberger T, Hershberger RE, Hovingh GK, Karayan L, Kastelein JJP, Kindt I, Lane SR, Leigh SE, Linton MF, Mata P, Neal WA, Nordestgaard BG, Santos RD, Harada-Shiba M, Sijbrands EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ, Convened by the Familial Hypercholesterolemia Foundation

Abstract
Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.

PMID: 30071997 [PubMed - in process]

EGF Receptor-Dependent YAP Activation Is Important for Renal Recovery from AKI.

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EGF Receptor-Dependent YAP Activation Is Important for Renal Recovery from AKI.

J Am Soc Nephrol. 2018 Aug 02;:

Authors: Chen J, You H, Li Y, Xu Y, He Q, Harris RC

Abstract
BACKGROUND: Increasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI.
METHODS: We used immunofluorescence to examine YAP expression in kidney biopsy samples from patients with clinical AKI and controls (patients with minimal change disease). Studies of RPTC activation of YAP and TAZ used cultured human RPTCs that were exposed to hypoxia-reoxygenation as well as knockout mice (with inducible deletions of Yap, Taz, or both occurring specifically in RPTCs) that were subjected to bilateral IRI.
RESULTS: YAP was activated in RPTCs in kidneys from post-AKI patients and post-IRI mouse kidneys. Inhibition of the interaction of YAP and the TEA domain (TEAD) transcription factor complex by verteporfin or conditional deletion of YAP in RPTCs delayed renal functional and structural recovery from IRI, whereas TAZ deletion had no effect. Activation of the EGFR-PI3K-Akt pathway in response to IRI signaled YAP activation, which promoted cell cycle progression.
CONCLUSIONS: This study shows that EGFR-PI3K-Akt-dependent YAP activation plays an essential role in mediating epithelial cell regeneration during kidney recovery from AKI.

PMID: 30072422 [PubMed - as supplied by publisher]

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, from Training Through Independent Practice.

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, from Training Through Independent Practice.

Gastroenterology. 2018 Jul 26;:

Authors: Wani S, Keswani RN, Han S, Aagaard E, Hall M, Simon V, Abidi WM, Banerjee S, Baron TH, Bartel M, Bowman E, Brauer BC, Buscaglia JM, Carlin L, Chak A, Chatrath H, Choudhary A, Confer B, Coté GA, Das KK, DiMaio CJ, Dries AM, Edmundowicz SA, El Chafic AH, El Hajj I, Ellert S, Ferreira J, Gamboa A, Gan IS, Gangarosa L, Gannavarapu B, Gordon SR, Guda NM, Hammad HT, Harris C, Jalaj S, Jowell P, Kenshil S, Klapman J, Kochman ML, Komanduri S, Lang G, Lee LS, Loren DE, Lukens F, Mullady D, Muthusamy RV, Nett AS, Olyaee MS, Pakseresht K, Perera P, Pfau P, Piraka C, Poneros JM, Rastogi A, Razzak A, Riff B, Saligram S, Scheiman JM, Schuster I, Shah RJ, Sharma R, Spaete JP, Singh A, Sohail M, Sreenarasimhaiah J, Stevens T, Tabibian JH, Tzimas D, Uppal D, Urayama S, Vitterbo D, Wang AY, Wassef W, Yachimski P, Zepeda-Gomez S, Zuchelli T, Early D

Abstract
BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) result in high-quality care in independent practice. We aimed to measure quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence.
METHODS: We performed a prospective multicenter cohort study, inviting participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, the participating AETs entered data into a database pertaining to every EUS and ERCP during their first year of independent practice, anchored by key QIs.
RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS, 91.7% and ERCP, 73.9%) and cognitive competence (EUS, 91.7% and ERCP, 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median 136 EUS exams/AET and 116 ERCPs/AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses), and ERCP (94.9% overall cannulation rate).
CONCLUSIONS: In a prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. clinicaltrials.gov no: NCT02509416.

PMID: 30056094 [PubMed - as supplied by publisher]

Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103).

Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103).

J Clin Oncol. 2018 Jul 24;:JCO2018792028

Authors: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW

Abstract
Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

PMID: 30040523 [PubMed - as supplied by publisher]

Endogenous Bradykinin and BK1-5 during ACE Inhibitor-Associated Angioedema.

Endogenous Bradykinin and BK1-5 during ACE Inhibitor-Associated Angioedema.

J Allergy Clin Immunol. 2018 Jul 20;:

Authors: Hubers S, Kohm K, Wei S, Yu C, Nian H, Grabert R, Sexton DJ, Brown NJ

Abstract
Bradykinin concentrations and the ratio of bradykinin to its stable metabolite BK1-5 (RPPGF) were significantly increased in patients presenting with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema compared to ACE inhibitor-treated controls. Cleavage of high molecular weight kininogen was not increased in patients with ACE inhibitor-associated angioedema, indicating that increased bradykinin concentrations result from decreased degradation.

PMID: 30036596 [PubMed - as supplied by publisher]

VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.

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VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.

Science. 2018 Jul 20;361(6399):290-295

Authors: Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, Liu XD, Jonasch E, Xie L, Chen X, Yao X, Teh BT, Tan P, Zheng X, Li M, Lawrence C, Fan J, Geng J, Liu X, Hu L, Wang J, Liao C, Hong K, Zurlo G, Parker JS, Auman JT, Perou CM, Rathmell WK, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS, Zhang Q

Abstract
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

PMID: 30026228 [PubMed - in process]

Higher Aortic Stiffness is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults.

Higher Aortic Stiffness is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults.

Circulation. 2018 Jul 17;:

Authors: Jefferson AL, Cambronero FE, Liu D, Moore EE, Neal JE, Terry JG, Nair S, Pechman KR, Rane S, Davis LT, Gifford KA, Hohman TJ, Bell SP, Wang TJ, Beckman JA, Carr JJ

Abstract
Background -Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults. Methods -Vanderbilt Memory & Aging Project participants free of clinical dementia, stroke, and heart failure were studied, including older adults with normal cognition (NC, n=155, 72±7, 59% male) or mild cognitive impairment (MCI, n=115, 73±7, 57% male). Aortic pulse wave velocity (PWV m/sec) was quantified from cardiac magnetic resonance. Resting CBF (mL/100g/min) and CVR (CBF response to hypercapnic normoxia stimulus) were quantified from pseudo-continuous arterial spin labeling MRI. Linear regression models related aortic PWV to regional CBF, adjusting for age, race/ethnicity, education, Framingham Stroke Risk Profile (diabetes, smoking, left ventricular hypertrophy, prevalent cardiovascular disease (CVD), atrial fibrillation), hypertension, body mass index, apolipoprotein E4 (APOE4) status, and regional tissue volume. Models were repeated testing PWV x APOE4 interactions. Sensitivity analyses excluded participants with prevalent CVD and atrial fibrillation. Results -Among NC participants, higher aortic PWV related to lower frontal lobe CBF (β=-0.43, p=0.04) and higher CVR in the whole brain (β=0.11, p=0.02), frontal lobes (β=0.12, p<0.05), temporal lobes (β=0.11, p=0.02), and occipital lobes (β=0.14, p=0.01). Among NC APOE4 carriers, findings were more pronounced with higher PWV relating to lower whole brain CBF (β=-1.16, p=0.047), lower temporal lobe CBF (β=-1.81, p=0.004) and higher temporal lobe CVR (β=0.26, p=0.08), though the latter result did not meet the a priori significance threshold. Results were similar in sensitivity models. Among MCI participants, higher aortic PWV related to lower CBF in the occipital lobe (β=-0.70, p=0.02), but this finding was attenuated when excluding participants with prevalent CVD and atrial fibrillation. Among MCI APOE4 carriers, findings were more pronounced with higher PWV relating to lower temporal lobe CBF (β=-1.20, p=0.02). Conclusions -Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity.

PMID: 30018169 [PubMed - as supplied by publisher]

Updated international consensus diagnostic criteria for eosinophilic esophagitis: Proceedings of the AGREE conference.

Updated international consensus diagnostic criteria for eosinophilic esophagitis: Proceedings of the AGREE conference.

Gastroenterology. 2018 Jul 12;:

Authors: Dellon ES, Liacouras CA, Molina-Infante J, Furuta GT, Spergel JM, Zevit N, Spechler SJ, Attwood SE, Straumann A, Aceves SS, Alexander JA, Atkins D, Arva NC, Blanchard C, Bonis PA, Book WM, Capocelli KE, Chehade M, Cheng E, Collins MH, Davis CM, Dias JA, Di Lorenzo C, Dohil R, Dupont C, Falk GW, Ferreira CT, Fox A, Gonsalves NP, Gupta SK, Katzka DA, Kinoshita Y, Menard-Katcher C, Kodroff E, Metz DC, Miehlke S, Muir AB, Mukkada VA, Murch S, Nurko S, Ohtsuka Y, Orel R, Papadopoulou A, Peterson KA, Philpott H, Putnam PE, Richter JE, Rosen R, Rothenberg ME, Schoepfer A, Scott MM, Shah N, Sheikh J, Souza RF, Strobel MJ, Talley NJ, Vaezi MF, Vandenplas Y, Vieira MC, Walker MM, Wechsler JB, Wershil BK, Wen T, Yang GY, Hirano I, Bredenoord AJ

Abstract
BACKGROUND AND AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE in order to develop updated international consensus criteria for EoE diagnosis.
METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries utilized on-line communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences.
RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement.
CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or ∼60 eosinophils per mm2) on esophageal biopsy, and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.

PMID: 30009819 [PubMed - as supplied by publisher]

Hypogonadism as a Reversible Cause of Torsades de Pointes in Men.

Hypogonadism as a Reversible Cause of Torsades de Pointes in Men.

Circulation. 2018 Jul 03;138(1):110-113

Authors: Salem JE, Waintraub X, Courtillot C, Shaffer CM, Gandjbakhch E, Maupain C, Moslehi JJ, Badilini F, Haroche J, Gougis P, Fressart V, Glazer AM, Hidden-Lucet F, Touraine P, Lebrun-Vignes B, Roden DM, Bachelot A, Funck-Brentano C

PMID: 29967236 [PubMed - in process]

Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation.

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Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation.

Nat Genet. 2018 Jun 28;:

Authors: Gamazon ER, Segrè AV, van de Bunt M, Wen X, Xi HS, Hormozdiari F, Ongen H, Konkashbaev A, Derks EM, Aguet F, Quan J, GTEx Consortium, Nicolae DL, Eskin E, Kellis M, Getz G, McCarthy MI, Dermitzakis ET, Cox NJ, Ardlie KG

Abstract
We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40-80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU.

PMID: 29955180 [PubMed - as supplied by publisher]

Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.

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Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.

Lancet. 2018 Jun 23;391(10139):2525-2536

Authors: Parekh DJ, Reis IM, Castle EP, Gonzalgo ML, Woods ME, Svatek RS, Weizer AZ, Konety BR, Tollefson M, Krupski TL, Smith ND, Shabsigh A, Barocas DA, Quek ML, Dash A, Kibel AS, Shemanski L, Pruthi RS, Montgomery JS, Weight CJ, Sharp DS, Chang SS, Cookson MS, Gupta GN, Gorbonos A, Uchio EM, Skinner E, Venkatramani V, Soodana-Prakash N, Kendrick K, Smith JA, Thompson IM

Abstract
BACKGROUND: Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy.
METHODS: The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than -15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676.
FINDINGS: Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI -9·6% to 10·9%; pnon-inferiority=0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group).
INTERPRETATION: In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types.
FUNDING: National Institutes of Health National Cancer Institute.

PMID: 29976469 [PubMed - in process]

Analysis of shared heritability in common disorders of the brain.

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Analysis of shared heritability in common disorders of the brain.

Science. 2018 Jun 22;360(6395):

Authors: Brainstorm Consortium, Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, Duncan L, Escott-Price V, Falcone GJ, Gormley P, Malik R, Patsopoulos NA, Ripke S, Wei Z, Yu D, Lee PH, Turley P, Grenier-Boley B, Chouraki V, Kamatani Y, Berr C, Letenneur L, Hannequin D, Amouyel P, Boland A, Deleuze JF, Duron E, Vardarajan BN, Reitz C, Goate AM, Huentelman MJ, Kamboh MI, Larson EB, Rogaeva E, St George-Hyslop P, Hakonarson H, Kukull WA, Farrer LA, Barnes LL, Beach TG, Demirci FY, Head E, Hulette CM, Jicha GA, Kauwe JSK, Kaye JA, Leverenz JB, Levey AI, Lieberman AP, Pankratz VS, Poon WW, Quinn JF, Saykin AJ, Schneider LS, Smith AG, Sonnen JA, Stern RA, Van Deerlin VM, Van Eldik LJ, Harold D, Russo G, Rubinsztein DC, Bayer A, Tsolaki M, Proitsi P, Fox NC, Hampel H, Owen MJ, Mead S, Passmore P, Morgan K, Nöthen MM, Rossor M, Lupton MK, Hoffmann P, Kornhuber J, Lawlor B, McQuillin A, Al-Chalabi A, Bis JC, Ruiz A, Boada M, Seshadri S, Beiser A, Rice K, van der Lee SJ, De Jager PL, Geschwind DH, Riemenschneider M, Riedel-Heller S, Rotter JI, Ransmayr G, Hyman BT, Cruchaga C, Alegret M, Winsvold B, Palta P, Farh KH, Cuenca-Leon E, Furlotte N, Kurth T, Ligthart L, Terwindt GM, Freilinger T, Ran C, Gordon SD, Borck G, Adams HHH, Lehtimäki T, Wedenoja J, Buring JE, Schürks M, Hrafnsdottir M, Hottenga JJ, Penninx B, Artto V, Kaunisto M, Vepsäläinen S, Martin NG, Montgomery GW, Kurki MI, Hämäläinen E, Huang H, Huang J, Sandor C, Webber C, Muller-Myhsok B, Schreiber S, Salomaa V, Loehrer E, Göbel H, Macaya A, Pozo-Rosich P, Hansen T, Werge T, Kaprio J, Metspalu A, Kubisch C, Ferrari MD, Belin AC, van den Maagdenberg AMJM, Zwart JA, Boomsma D, Eriksson N, Olesen J, Chasman DI, Nyholt DR, Avbersek A, Baum L, Berkovic S, Bradfield J, Buono R, Catarino CB, Cossette P, De Jonghe P, Depondt C, Dlugos D, Ferraro TN, French J, Hjalgrim H, Jamnadas-Khoda J, Kälviäinen R, Kunz WS, Lerche H, Leu C, Lindhout D, Lo W, Lowenstein D, McCormack M, Møller RS, Molloy A, Ng PW, Oliver K, Privitera M, Radtke R, Ruppert AK, Sander T, Schachter S, Schankin C, Scheffer I, Schoch S, Sisodiya SM, Smith P, Sperling M, Striano P, Surges R, Thomas GN, Visscher F, Whelan CD, Zara F, Heinzen EL, Marson A, Becker F, Stroink H, Zimprich F, Gasser T, Gibbs R, Heutink P, Martinez M, Morris HR, Sharma M, Ryten M, Mok KY, Pulit S, Bevan S, Holliday E, Attia J, Battey T, Boncoraglio G, Thijs V, Chen WM, Mitchell B, Rothwell P, Sharma P, Sudlow C, Vicente A, Markus H, Kourkoulis C, Pera J, Raffeld M, Silliman S, Boraska Perica V, Thornton LM, Huckins LM, William Rayner N, Lewis CM, Gratacos M, Rybakowski F, Keski-Rahkonen A, Raevuori A, Hudson JI, Reichborn-Kjennerud T, Monteleone P, Karwautz A, Mannik K, Baker JH, O'Toole JK, Trace SE, Davis OSP, Helder SG, Ehrlich S, Herpertz-Dahlmann B, Danner UN, van Elburg AA, Clementi M, Forzan M, Docampo E, Lissowska J, Hauser J, Tortorella A, Maj M, Gonidakis F, Tziouvas K, Papezova H, Yilmaz Z, Wagner G, Cohen-Woods S, Herms S, Julià A, Rabionet R, Dick DM, Ripatti S, Andreassen OA, Espeseth T, Lundervold AJ, Steen VM, Pinto D, Scherer SW, Aschauer H, Schosser A, Alfredsson L, Padyukov L, Halmi KA, Mitchell J, Strober M, Bergen AW, Kaye W, Szatkiewicz JP, Cormand B, Ramos-Quiroga JA, Sánchez-Mora C, Ribasés M, Casas M, Hervas A, Arranz MJ, Haavik J, Zayats T, Johansson S, Williams N, Dempfle A, Rothenberger A, Kuntsi J, Oades RD, Banaschewski T, Franke B, Buitelaar JK, Arias Vasquez A, Doyle AE, Reif A, Lesch KP, Freitag C, Rivero O, Palmason H, Romanos M, Langley K, Rietschel M, Witt SH, Dalsgaard S, Børglum AD, Waldman I, Wilmot B, Molly N, Bau CHD, Crosbie J, Schachar R, Loo SK, McGough JJ, Grevet EH, Medland SE, Robinson E, Weiss LA, Bacchelli E, Bailey A, Bal V, Battaglia A, Betancur C, Bolton P, Cantor R, Celestino-Soper P, Dawson G, De Rubeis S, Duque F, Green A, Klauck SM, Leboyer M, Levitt P, Maestrini E, Mane S, De-Luca DM, Parr J, Regan R, Reichenberg A, Sandin S, Vorstman J, Wassink T, Wijsman E, Cook E, Santangelo S, Delorme R, Rogé B, Magalhaes T, Arking D, Schulze TG, Thompson RC, Strohmaier J, Matthews K, Melle I, Morris D, Blackwood D, McIntosh A, Bergen SE, Schalling M, Jamain S, Maaser A, Fischer SB, Reinbold CS, Fullerton JM, Guzman-Parra J, Mayoral F, Schofield PR, Cichon S, Mühleisen TW, Degenhardt F, Schumacher J, Bauer M, Mitchell PB, Gershon ES, Rice J, Potash JB, Zandi PP, Craddock N, Ferrier IN, Alda M, Rouleau GA, Turecki G, Ophoff R, Pato C, Anjorin A, Stahl E, Leber M, Czerski PM, Cruceanu C, Jones IR, Posthuma D, Andlauer TFM, Forstner AJ, Streit F, Baune BT, Air T, Sinnamon G, Wray NR, MacIntyre DJ, Porteous D, Homuth G, Rivera M, Grove J, Middeldorp CM, Hickie I, Pergadia M, Mehta D, Smit JH, Jansen R, de Geus E, Dunn E, Li QS, Nauck M, Schoevers RA, Beekman AT, Knowles JA, Viktorin A, Arnold P, Barr CL, Bedoya-Berrio G, Bienvenu OJ, Brentani H, Burton C, Camarena B, Cappi C, Cath D, Cavallini M, Cusi D, Darrow S, Denys D, Derks EM, Dietrich A, Fernandez T, Figee M, Freimer N, Gerber G, Grados M, Greenberg E, Hanna GL, Hartmann A, Hirschtritt ME, Hoekstra PJ, Huang A, Huyser C, Illmann C, Jenike M, Kuperman S, Leventhal B, Lochner C, Lyon GJ, Macciardi F, Madruga-Garrido M, Malaty IA, Maras A, McGrath L, Miguel EC, Mir P, Nestadt G, Nicolini H, Okun MS, Pakstis A, Paschou P, Piacentini J, Pittenger C, Plessen K, Ramensky V, Ramos EM, Reus V, Richter MA, Riddle MA, Robertson MM, Roessner V, Rosário M, Samuels JF, Sandor P, Stein DJ, Tsetsos F, Van Nieuwerburgh F, Weatherall S, Wendland JR, Wolanczyk T, Worbe Y, Zai G, Goes FS, McLaughlin N, Nestadt PS, Grabe HJ, Depienne C, Konkashbaev A, Lanzagorta N, Valencia-Duarte A, Bramon E, Buccola N, Cahn W, Cairns M, Chong SA, Cohen D, Crespo-Facorro B, Crowley J, Davidson M, DeLisi L, Dinan T, Donohoe G, Drapeau E, Duan J, Haan L, Hougaard D, Karachanak-Yankova S, Khrunin A, Klovins J, Kučinskas V, Lee Chee Keong J, Limborska S, Loughland C, Lönnqvist J, Maher B, Mattheisen M, McDonald C, Murphy KC, Nenadic I, van Os J, Pantelis C, Pato M, Petryshen T, Quested D, Roussos P, Sanders AR, Schall U, Schwab SG, Sim K, So HC, Stögmann E, Subramaniam M, Toncheva D, Waddington J, Walters J, Weiser M, Cheng W, Cloninger R, Curtis D, Gejman PV, Henskens F, Mattingsdal M, Oh SY, Scott R, Webb B, Breen G, Churchhouse C, Bulik CM, Daly M, Dichgans M, Faraone SV, Guerreiro R, Holmans P, Kendler KS, Koeleman B, Mathews CA, Price A, Scharf J, Sklar P, Williams J, Wood NW, Cotsapas C, Palotie A, Smoller JW, Sullivan P, Rosand J, Corvin A, Neale BM

Abstract
Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

PMID: 29930110 [PubMed - in process]

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

Nat Genet. 2018 Jun 18;:

Authors: Wu L, Shi W, Long J, Guo X, Michailidou K, Beesley J, Bolla MK, Shu XO, Lu Y, Cai Q, Al-Ejeh F, Rozali E, Wang Q, Dennis J, Li B, Zeng C, Feng H, Gusev A, Barfield RT, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Auer PL, Barrdahl M, Baynes C, Beckmann MW, Benitez J, Bermisheva M, Blomqvist C, Bogdanova NV, Bojesen SE, Brauch H, Brenner H, Brinton L, Broberg P, Brucker SY, Burwinkel B, Caldés T, Canzian F, Carter BD, Castelao JE, Chang-Claude J, Chen X, Cheng TD, Christiansen H, Clarke CL, NBCS Collaborators, Collée M, Cornelissen S, Couch FJ, Cox D, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Dwek M, Eccles DM, Eilber U, Eliassen AH, Engel C, Eriksson M, Fachal L, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gabrielson M, Gago-Dominguez M, Gapstur SM, García-Closas M, Gaudet MM, Ghoussaini M, Giles GG, Goldberg MS, Goldgar DE, González-Neira A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hallberg E, Hamann U, Harrington P, Hein A, Hicks B, Hillemanns P, Hollestelle A, Hoover RN, Hopper JL, Huang G, Humphreys K, Hunter DJ, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones ME, Jung A, Kaaks R, Kerin MJ, Khusnutdinova E, Kosma VM, Kristensen VN, Lambrechts D, Le Marchand L, Li J, Lindström S, Lissowska J, Lo WY, Loibl S, Lubinski J, Luccarini C, Lux MP, MacInnis RJ, Maishman T, Kostovska IM, Mannermaa A, Manson JE, Margolin S, Mavroudis D, Meijers-Heijboer H, Meindl A, Menon U, Meyer J, Mulligan AM, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Nordestgaard BG, Olopade OI, Olson JE, Olsson H, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prentice R, Presneau N, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Rudolph A, Saloustros E, Sandler DP, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Scott RJ, Scott CG, Seal S, Shah M, Shrubsole MJ, Smeets A, Southey MC, Spinelli JJ, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper W, Taylor JA, Terry MB, Tessier DC, Thomas A, Thöne K, Tollenaar RAEM, Torres D, Truong T, Untch M, Vachon C, Van Den Berg D, Vincent D, Waisfisz Q, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett WC, Winqvist R, Wolk A, Xia L, Yang XR, Ziogas A, Ziv E, kConFab/AOCS Investigators, Dunning AM, Pharoah PDP, Simard J, Milne RL, Edwards SL, Kraft P, Easton DF, Chenevix-Trench G, Zheng W

Abstract
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

PMID: 29915430 [PubMed - as supplied by publisher]

Disease Heritability Studies Harness the Healthcare System to Achieve Massive Scale.

Disease Heritability Studies Harness the Healthcare System to Achieve Massive Scale.

Cell. 2018 Jun 14;173(7):1568-1570

Authors: Denny JC, Mosley JD

Abstract
Heritability studies are essential for defining genetic influences on disease risk and trait variability. Polubriaginof et al. show how massive amounts of data contained in electronic health records can be used for heritability studies on hundreds of phenotypes. Mining emergency contact information with comparison to existing gold standards showcases the broad utility of the approach.

PMID: 29906443 [PubMed - in process]

Response by Weinberg et al to Letter Regarding Article, "Carotid Stent Fractures Are Not Associated With Adverse Events: Results From the ACT-1 Multicenter Randomized Trial (Carotid Angioplasty and Stenting Versus Endarterectomy in Asymptomatic Subjects

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Response by Weinberg et al to Letter Regarding Article, "Carotid Stent Fractures Are Not Associated With Adverse Events: Results From the ACT-1 Multicenter Randomized Trial (Carotid Angioplasty and Stenting Versus Endarterectomy in Asymptomatic Subjects Who Are at Standard Risk for Carotid Endarterectomy With Significant Extracranial Carotid Stenotic Disease)".

Circulation. 2018 Jun 12;137(24):2676-2677

Authors: Weinberg I, Beckman JA, Shu Y, Jaff MR

PMID: 29891632 [PubMed - in process]