47 research outputs found
Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies
- Author
- Aage Haugen
- AL Price
- AL Price
- Albert Rosenberger
- Alkes L. Price
- Angela Risch
- Ann W. Morgan
- Anne Barton
- Anthony G. Wilson
- Barry I. Freedman
- Benjamin Voight
- BF Voight
- Bogdan Pasaniuc
- Brian E. Henderson
- C Wallace
- Carl D. Langefeld
- Christopher Haiman
- CI Amos
- CL Kuo
- D Campa
- D Clayton
- D Cox
- D Thomas
- DA Schaumberg
- Daniel I. Chasman
- David Altshuler
- David C. Christiani
- David J. Friedman
- David J. Hunter
- David Scherf
- Debra A. Schaumberg
- DJ Hunter
- Donald W. Bowden
- DS Falconer
- Eric Tchetgen Tchetgen
- ESBD Lander
- G Genovese
- G Jin
- G Maskarinec
- Giulio Genovese
- GM Monsees
- GV Kryukov
- H Holm
- HC So
- Heike Bickeböller
- J Dong
- J Marchini
- Jane Worthington
- JK Field
- JM Neuhaus
- Joachim Heinrich
- John K. Field
- JR Perry
- JRB Perry
- Kevin M. Waters
- KL Ellis
- KM Waters
- Laurence N. Kolonel
- LD Robinson
- Leif Groop
- Loic Le Marchand
- LT Guey
- Lynne J. Hocking
- M Imielinski
- M Pirinen
- Maria Teresa Landi
- Marilyn Cornelis
- Martin Walshaw
- Michael Meister
- ML Freedman
- N Chatterjee
- N Risch
- N Zaitlen
- N Zaitlen
- Nick Patterson
- NJ Risch
- NJ Wald
- Noah Zaitlen
- NR Wray
- Olaide Y. Raji
- P Armitage
- P Kraft
- P Sulem
- Pamela J. Hicks
- Paul Wordsworth
- Peter Kraft
- Peter M. Visscher
- PM Ridker
- Robert M. Plenge
- S Kathiresan
- S Lindstrom
- S Raychaudhuri
- S Rose
- S Van Gestel
- S Zienolddiny
- Samuela Pollack
- Sara Lindström
- SH Lee
- Shanbeh Zienolddiny
- SJ Chanock
- Sophia Steer
- Steve Eyre
- T Lumley
- TH Hamza
- TJ Vanderweele
- TM Frayling
- W Thomson
- WG Hill
- WW Piegorsch
- Z Kote-Jarai
- Publication venue
- 'Public Library of Science (PLoS)'
- Publication date
- 01/01/2012
- Field of study
Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×10−9). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci
Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)
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- Publication venue
- 'American Astronomical Society'
- Publication date
- 01/01/2016
- Field of study
This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands
Multi-messenger observations of a binary neutron star merger
- Author
- Aab A
- Aartsen MG
- Abbott BP
- Abbott R
- Abbott TD
- Abbott TMC
- Abdalla H
- Abe F
- Abeysekara AU
- Abramo LR
- Abramowski A
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- Acernese F
- Acero F
- Ackermann M
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- Al Samarai I
- Albert A
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- Albuquerque IFM
- Albury JM
- Alcaniz JS
- Alexander KD
- Alfaro R
- Alighieri S Di Serego
- Allam S
- Allekotte I
- Allen B
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- Array LWA Long Wavelength
- Array MWA Murchison Widefield
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- Zimnukhov DS
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- Zucker ME
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- Zweizig J
- Zywucka N
- Publication venue
- 'American Astronomical Society'
- Publication date
- 01/01/2017
- Field of study
On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta
Localization and broadband follow-up of the gravitational-wave transient GW150914
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- Abbott BP
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- Zadrozny A
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- Publication date
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- Field of study
A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams
Association of germline variants in the <i>APOBEC3</i> region with cancer risk and enrichment with APOBEC-signature mutations in tumors
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- AM Land
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- Stephen J Chanock
- Taro Shuin
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- 'Springer Science and Business Media LLC'
- Publication date
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- Publication venue
- 'American Astronomical Society'
- Publication date
- 28/10/2022
- Field of study
On 2017 August 17 a binary neutron star coalescence candidate (later
designated GW170817) with merger time 12:41:04 UTC was observed through
gravitational waves by the Advanced LIGO and Advanced Virgo detectors.
The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray
burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to
the merger time. From the gravitational-wave signal, the source was
initially localized to a sky region of 31 deg2 at a
luminosity distance of {40}-8+8 Mpc and with
component masses consistent with neutron stars. The component masses
were later measured to be in the range 0.86 to 2.26 {M}ȯ
. An extensive observing campaign was launched across the
electromagnetic spectrum leading to the discovery of a bright optical
transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC
4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the
One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The
optical transient was independently detected by multiple teams within an
hour. Subsequent observations targeted the object and its environment.
Early ultraviolet observations revealed a blue transient that faded
within 48 hours. Optical and infrared observations showed a redward
evolution over ∼10 days. Following early non-detections, X-ray and
radio emission were discovered at the transient’s position ∼ 9
and ∼ 16 days, respectively, after the merger. Both the X-ray and
radio emission likely arise from a physical process that is distinct
from the one that generates the UV/optical/near-infrared emission. No
ultra-high-energy gamma-rays and no neutrino candidates consistent with
the source were found in follow-up searches. These observations support
the hypothesis that GW170817 was produced by the merger of two neutron
stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and
a kilonova/macronova powered by the radioactive decay of r-process
nuclei synthesized in the ejecta.</p
Localization and Broadband Follow-up of the Gravitational-wave Transient GW150914
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- Publication venue
- 'American Astronomical Society'
- Publication date
- 28/10/2022
- Field of study
A gravitational-wave (GW) transient was identified in data recorded by
the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)
detectors on 2015 September 14. The event, initially designated G184098
and later given the name GW150914, is described in detail elsewhere. By
prior arrangement, preliminary estimates of the time, significance, and
sky location of the event were shared with 63 teams of observers
covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths
with ground- and space-based facilities. In this Letter we describe the
low-latency analysis of the GW data and present the sky localization of
the first observed compact binary merger. We summarize the follow-up
observations reported by 25 teams via private Gamma-ray Coordinates
Network circulars, giving an overview of the participating facilities,
the GW sky localization coverage, the timeline, and depth of the
observations. As this event turned out to be a binary black hole merger,
there is little expectation of a detectable electromagnetic (EM)
signature. Nevertheless, this first broadband campaign to search for a
counterpart of an Advanced LIGO source represents a milestone and
highlights the broad capabilities of the transient astronomy community
and the observing strategies that have been developed to pursue neutron
star binary merger events. Detailed investigations of the EM data and
results of the EM follow-up campaign are being disseminated in papers by
the individual teams.
</p
Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.
- Author
- Ahmed Munaza
- Aitken Stuart
- Aitman Timothy
- Akawi Nadia
- Al Turki Saeed
- Alachkar Hana
- Ali Sonia
- Allen Hana Lango
- Allen Louise
- Allsup David
- Alvi Mohsan
- Ambegaonkar Gautum
- Ambridge Kirsty
- Anderson Carl
- Anderson Julie
- Anjum Uruj
- Anney Richard
- Antony Dinu
- Antrobus Richard
- Archer Hayley
- Armstrong Ruth
- Armstrong Ruth
- Arno Gavin
- Artigas Maria Soler
- Arumugakani Gururaj
- Ashford Sofie
- Astle William
- Attwood Antony
- Austin Steve
- Awada Jana
- Ayub Muhammad
- Bacchelli Chiara
- Bakchoul Tamam
- Balasubramaniam Senduran
- Balasubramanian Meena
- Banka Siddharth
- Baralle Diana
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- Barrett Jeffrey C.
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- Beales Phil
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- Bentham Jamie
- Berg Jonathan
- Bernhard Birgitta
- Bethune Claire
- Bevan A. Paul
- Bhattacharya Shoumo
- Bibi Shahnaz
- Birney Ewan
- Bitner-Glindzicz Maria
- Bitner-Glindzicz Maria
- Blackwood Douglas
- Blair Edward
- Bleda Marta
- Blyth Moira
- Bobrow Martin
- Bochukova Elena
- Boggard Harm
- Bohanna David
- Bolton Patrick
- Bolton-Maggs Paula
- Booth Claire
- Bounds Rebecca
- Bourdon Louise
- Bourn David
- Boustred Chris
- Bradley John R.
- Bradley Lisa
- Brady Angela
- Brady Angie
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- Brent Simon
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- Brown Matthew
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- Li Rui
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- Vijayarangakannan Parthiban
- Visscher Peter M.
- Vogt Julie
- Vogt Julie
- von Ziegenweldt Julie
- Vonk Noordegraaf Anton
- Wain Louise V.
- Wakeling Emma
- Wakeling Emma
- Wallwark Sarah
- Walters James T.R.
- Wang Guangbiao
- Wang Jun
- Wang Yu
- Wanjiku Ivy
- Ward Kirsten
- Warner Timothy Q.
- Wassmer Evangeline
- Wassmer Evangeline
- Waters Jonathon
- Watkins Hugh
- Weber Astrid
- Webster Andrew
- Welch Steve
- Wellesley Diana
- Westbury Sarah
- Wharton John
- Wheeler Elanor
- Whiteford Margo
- Whitehorn Deborah
- Whyte Tamieka
- Widaa Sara
- Wilcox Sarah
- Wilkins Martin
- Wilkinson Emily
- Willcocks Lisa
- Williams Denise
- Williams Hywel
- Williams Nicola
- Williamson Catherine
- Williamson Kathleen A.
- Wilson Crispian
- Wilson Louise
- Wong Kim
- Woods Geoff
- Woods Geoffrey
- Wort John
- Wragg Christopher
- Wright Caroline F.
- Wright Michael
- Xu ChangJiang
- Yang Jian
- Yates Laura
- Yau Michael
- Yeatman Nigel
- Yong Patrick
- Young Tim
- Yu Ping
- Zhang Fend
- Zhang Pingbo
- Publication venue
- AJHG
- Publication date
- 01/01/2019
- Field of study
The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)
Localization and broadband follow-up of the gravitational-wave transient GW150914
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A gravitational-wave transient was identified in data recorded by the Advanced LIGO detectors on 2015 September 14. The event candidate, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the gravitational wave data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network Circulars, giving an overview of the participating facilities, the gravitational wave sky localization coverage, the timeline and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the electromagnetic data and results of the electromagnetic follow-up campaign will be disseminated in the papers of the individual teams
Preliminary evaluation of the parasitoid wasp, <i>Collyria catoptron</i>, as a potential biological control agent against the wheat stem sawfly, <i>Cephus cinctus</i>, in North America
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<div><p>ABSTRACT</p><p>The wheat stem sawfly, <i>Cephus cinctus</i> (Hymenoptera: Cephidae) is the major pest of wheat in the northern plains of North America, with biological control providing a potentially useful management tool. Foreign exploration by the USDA-ARS identified <i>Collyria catoptron</i> (Hymenoptera: Ichneumonidae), a parasitoid wasp of <i>Cephus fumipennis</i> in northern China, as a potential biological control agent. Here we carry out a preliminary evaluation of the potential suitability of <i>C. catoptron</i>, as a candidate agent against <i>C. cinctus</i>. Specifically we: (1) Quantify the spatio-temporal variation in parasitism rates on the native host from collection sites in northern China over six years, and (2) Assess whether <i>C. catoptron</i> will oviposit and complete development in the novel targeted host. Maximum parasitism of the native host in the native range was 38%, exceeding the theoretical threshold for successful biological control. Site occupancy levels were high (83%) suggesting good colonisation abilities. <i>C. catoptron</i> clearly recognised and attacked <i>C. cinctus</i>, with parasitism levels exceeding those observed on the co-evolved host <i>C. fumipennis</i>. However, we found no evidence that <i>C. catoptron</i> can complete development in <i>C. cinctus</i>; no adults were reared from this host in either year of the study. In contrast 50–60% of the parasitoids survived to emerge as adults in <i>C. fumipennis</i>. Thus, <i>C. catoptron</i> is unlikely to be a suitable agent against <i>C. cinctus</i> due to basic host incompatibility. Future work will be directed towards developing conservation biological control approaches using native parasitoid species already present in the USA.</p></div