11 research outputs found
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar M. S.
- Abdel-Aziz M.
- Abdelrazik M.
- Abdollahi H.
- Abdullah T.
- Abecasis G. R.
- Abedalthagafi M.
- Abel L.
- Abernathy C.
- Abraheem A.
- Abul-Husn N. S.
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- Wakefield P.
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- Waldron J.
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- Woodford C.
- Woodruff M.
- Woods L.
- Woodyatt W.
- Woolley A. E.
- Worner R.
- Worsley L.
- Wray G.
- Wren L.
- Wright D.
- Wright J.
- Wright M.
- Wrobel N.
- Wu Y.
- Wulandari R.
- Wyllie D. H.
- Wynter I.
- Xavier K.
- Xue X.
- Yadav A.
- Yang J.
- Yassen A. M.
- Yates B.
- Ye C.
- Yun N.
- Zainy T.
- Zak A.
- Zaki A.
- Zamikula J.
- Zanella I.
- Zborowski A. C.
- Zeberg H.
- Zechner M.
- Zguro K.
- Zhang M.
- Zhao J. H.
- Zheng C.
- Zhou W.
- Zitter L.
- Zlatopolsky M.
- Zollner S.
- Zongo O.
- Zucchi P.
- Zyndorf M.
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Get PDFCritical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Genetic mechanisms of critical illness in COVID-19.
- Author
- A A Roger Thompson
- A Abraheem
- A Agasou
- A Ahmed
- A Ali
- A Allan
- A Altabaibeh
- A Alvaro
- A Aspinwall
- A Ayers
- A Bamford
- A Barron
- A Bashyal
- A Bellini
- A Bociek
- A Botello
- A Bowes
- A Brady
- A Brayne
- A Brown
- A Brown
- A Butler
- A Campbell
- A Carter
- A Collins
- A Cowley
- A Cowton
- A Cowton
- A Cox
- A Crew
- A Dance
- A Daniel
- A Daniels
- A Dela Rosa
- A Drummond
- A Durie
- A E Heron
- A Easthope
- A Easthope
- A Evans
- A Fofano
- A Gales
- A Ganesan
- A Gardner
- A Garg
- A Gherman
- A Gordon
- A Gratrix
- A Gulati
- A Gupta
- A Haigh
- A Haldeos
- A Harrison
- A Harvey
- A Hayes
- A Higham
- A Higham
- A Hilldrith
- A Holden
- A Hormis
- A Hutcheon
- A Javaid
- A Joseph
- A Kaliappan
- A Katary
- A Kay
- A Kayani
- A Kent
- A Kirkby
- A Knight
- A Kubisz-Pudelko
- A Kuravi
- A Lewis
- A Loveridge
- A Lyle
- A Mayer
- A McAlpine
- A McCarthy
- A McGregor
- A McGregor
- A Meikle
- A Mitchell
- A Mitra
- A Morris
- A Morrison
- A Naranjo
- A Nicholson
- A Nicholson
- A Nilsson
- A Noakes
- A Patel
- A Pickard
- A Poole
- A Price
- A Puxty
- A Quinn
- A Quinn
- A Raithatha
- A Rattray
- A Reddy
- A Reed
- A Reyes
- A Rose
- A Rose
- A Rostron
- A Roy
- A Roynon-Reed
- A S Raj
- A Salberg
- A Sanderson
- A Serrano-Ruiz
- A Solesbury
- A Sukha
- A Swain
- A Tariq
- A Thomas
- A Thomas
- A Todd
- A Tomas
- A Tridente
- A Tucci
- A Turnbull
- A Uriel
- A Ustianowski
- A Vochin
- A Vuylsteke
- A Waite
- A Walden
- A Whileman
- A Wilkinson
- A Williams
- A Williams
- A Wilson
- A Zak
- A Zaki
- Achille Iolascon
- Adam Auton
- Adam Brown
- Agnese Verzuri
- Agostino Ognibene
- Agostino Riva
- Ailsa Golightly
- Alan Maclean
- Alessandra
- Alessandra Stella
- Alessandra Vergori
- Alessia Giorli
- Alexander J Mentzer
- Alice Donati
- Alison M Meynert
- Alistair Nichol
- Ana da Silva Filipe
- Andrea Antinori
- Andrea Cossarizza
- Andrea Ganna
- Andrea Tommasi
- Andrew Rambaut
- Andrew Stenhouse
- Andy Law
- Anjali J Shastri
- Anna Canaccini
- Anna Maria Pinto
- Annarita Giliberti
- Annemarie B Docherty
- Antonella D'Arminio Monforte
- Antonia Ying Wai Ho
- Antonio Di Biagio
- Antony Symons
- Arianna Emiliozzi
- Arianna Gabrieli
- Audrey Coutts
- B Anwar
- B Attwood
- B Baines
- B Blackledge
- B Borislavova
- B Chandler
- B Charles
- B Creagh-Brown
- B David
- B Deacon
- B Deacon
- B Digby
- B Faulkner
- B Fuller
- B Gumbrill
- B Gurung
- B Hadebe
- B Hairsine
- B Hopkins
- B Johnston
- B Lenagh
- B Masunda
- B Ogg
- B Patel
- B Player
- B Purewal
- B Scholefield
- B Shelley
- B Sloan
- B Thomas
- B Wadams
- B Welsh
- B Wilkinson
- B Winter-Goodwin
- B Yates
- Baillie J Kenneth
- Barbara Rossetti
- Beale Rupert
- Beatrice Alex
- Benjamin Bach
- Bretherick Andrew D
- Bruno Frediani
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- C Dennis
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- C Stuart
- C Summers
- C Swan
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- C Wrey Brown
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- Carmen Marciano
- Caroline Abernathy
- Carrol Gamble
- Caterina Lo Rizzo
- Catherine A Shaw
- Catherine H Weldon
- Caulfield Mark
- Ceilia Boz
- Cesira Nencioni
- Chelsea Ye
- Chiara Fallerini
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- Chiara Spertilli
- Chloe Donohue
- Chris Ponting
- Christoper A Green
- Cinthia E Jannes
- Clare Jackson
- Clohisey Sara
- Cristina Mussini
- D Antcliffe
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- D Martin
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- D Tetla
- D Thornton
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- D Vedage
- D Walker
- D Warren
- D Williams
- D Wood
- D Wright
- Daniela Francisci
- Daniella Coker
- Danilo Tacconi
- David A van Heel
- David Bennet
- David L Robertson
- David Stuart
- Dawn Law
- Debby Bogaert
- Derek Murphy
- Domenico A Coviello
- E Abaleke
- E Allan
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- E Andrews
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- E B Jude
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- E Beranova
- E Bevan
- E Black
- E Brinkworth
- E Collins
- E Combes
- E Davies
- E Dobson
- E Dooks
- E Fisher
- E Gendall
- E Goff
- E Goodwin
- E Gordon
- E Heeney
- E Horsley
- E Hughes
- E Johnson
- E Knights
- E Lee
- E London
- E Maccacari
- E Massey
- E McKenna
- E Meadows
- E Moncur
- E Morino
- E Mwaura
- E Peasgood
- E Perkins
- E Radford
- E Raith
- E Raith
- E Salciute
- E Smith
- E Smithson
- E Stoddard
- E Stones
- E Thomas
- E Tilney
- E Timlick
- E Treus Gude
- E Virgilio
- E Watson
- E Wilby
- Edoardo Conticini
- Egle Saviciute
- Elena Bargagli
- Elena Desanctis
- Elisa Benetti
- Elisa Frullanti
- Elisabetta Menatti
- Elisabetta Schiaroli
- Ellie Mcmaster
- Emma C Thomson
- Emmanuelle Marques
- Enrico Martinelli
- Esther Duncan
- Esther Merlini
- Ewen M Harrison
- F Anderson
- F Auld
- F Bibi
- F Davies
- F Farquhar
- F Fisher
- F Hurford
- F Kibutu
- F McNeela
- F Moore
- F Nasir
- F Trim
- F Wakinshaw
- F Williams
- Fabio Lena
- Fawkes Angie
- Federico Anedda
- Federico Franchi
- Ferdinando Giannattasio
- Filip Taneski
- Filippo Aucella
- Filippo Biscarini
- Floriana Valentino
- Fourman Max Head
- Francesca Andretta
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- Furniss James
- G Andrew
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- G Bell
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- G Sera Howe
- G Sloane
- G Subramanian
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- G Turner
- G Watson
- G Wray
- Gabriella Coiro
- Gabriella Doddato
- Gail Carson
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- Gary Leeming
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- Giancarlo Bosio
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- Graham S Cooke
- Griffiths Fiona
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- H Reschreiter
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- H Sainsbury
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- H Tench
- H Tiveran
- H Turner
- H Whittle
- H Willis
- H Wood
- Haley Chris
- Hanning Mal
- Harrison David
- Hayley Hardwick
- Hayward Caroline
- Helen Szoor-McElhinney
- Hinds Charles
- Ho Antonia
- Horby Peter
- I Ali Mohamed Ali
- I Balagosa
- I Birkinshaw
- I Burn
- I Chadbourn
- I D Clement
- I Edmond
- I Frost
- I Hass
- I Hussain
- I Lancoma-Malcolm
- I Leadbitter
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- I Otahal
- I Turner-Bone
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- I White
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- Ilaria Meloni
- Immacolata Andolfo
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- J Allan
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- J Biddle
- J Birch
- J Birch
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- J Brown
- J Bryant
- J Butler
- J Camsooksai
- J Carter
- J Caterson
- J Cebrian Suarez
- J Cockerill-Taylor
- J Cole
- J Colley
- J Cooper
- J Cupitt
- J Cuttler
- J Daglish
- J Dasgin
- J Dawson
- J Dearden
- J Deery
- J Donnachie
- J Dykes
- J Easton
- J Egan
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- J Finn
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- J Gregory
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- J Jones
- J Jones
- J K Baillie
- J Kassam
- J Kenneth Baillie
- J Kenneth Baillie
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- McAuley Danny
- Meera Chand
- Meynert Alison
- Michelle Girvan
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- Trevor Paterson
- Tullio Trotta
- Turtle Lance
- U Poultney
- V Amin
- V Anumakonda
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- Valentina Anemoli
- Vanessa Sancho-Shimizu
- Victoria Shaw
- Vitart Veronique
- W Harrison
- W Khaliq
- W Khaliq
- W McCormick
- W Woodyatt
- Walker Susan
- Walsh Timothy
- Wang Bo
- Wei Shen Lim
- Wendy S Barclay
- William A Paxton
- William Greenhalf
- Wilson James F
- Wrobel Nicola
- Wu Yang
- X Qiu
- Y Baird
- Y Choudhury
- Y Hussain
- Y Jackson
- Y Thirlwall
- Yang Jian
- Yang Zhijian
- Z Alldis
- Z Belagodu
- Z Bradshaw
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- Z Daly
- Z Farzad
- Z Fernandez
- Z Garland
- Z Maqsood
- Z Omar
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- Z Scott
- Zechner Marie
- Zhai Ranran
- Zheng Chenqing
- Publication venue
- Nature
- Publication date
- 01/01/2020
- Field of study
Get PDFHost-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
Whole-genome sequencing reveals host factors underlying critical COVID-19
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- Abd Elghafar M.S.
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- Abdelrazik M.
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- Zöllner S.
- Åsvold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
Get PDFCritical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Thigh-length compression stockings and DVT after stroke
- Author
- Abbas M
- Abbasi S
- Abbasi S
- Abdelaziz A
- Abdelfattah M
- Abdul B
- Abdulmumeen A
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- Abdusamad K
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- Adeyeye E
- Adnan A
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- Agwada-Akeru J
- Agyapong K Ansu
- Ah-Chuen J
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- Ahmed S Haris
- Ail D
- Ainsley A
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- Akindolie O
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- Publication venue
- 'Elsevier BV'
- Publication date
- 01/07/1994
- Field of study
Get PDFControversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease
Mapping the human genetic architecture of COVID-19
- Author
- Abdelrazik M.
- Abdullah T.
- Abe R.
- Abe S.
- Abecasis G. R.
- Abel L.
- Abernathy C.
- Abraheem A.
- Abul-Husn N. S.
- Acosta-Herrera M.
- Acquilini D.
- Adachi T.
- Adachi Y.
- Adams C.
- Adams K.
- Adanini O.
- Adeleye O.
- Adeniji K.
- Adra D.
- Afifi N.
- Afilalo J.
- Afilalo M.
- Afolabi D.
- Afrasiabi Z.
- Afset J. E.
- Agasou A.
- Aghemo A.
- Agranoff D.
- Agrawal S.
- Aguirre L. A.
- Agwuh K.
- Ahmad H. F.
- Ahmad N.
- Ahmed A.
- Ahmed C.
- Ahmed K. A.
- Ai M.
- Ail D.
- Akeroyd L.
- Akhtar M. N.
- Akhtar S.
- Akinkugbe O.
- Aksentijevich A.
- Al Thani A.
- Al-Muftah W.
- Al-Sarraj Y.
- Alarcon C.
- Alarcon-Riquelme M. E.
- Alasdair F.
- Alaverdian D.
- Alavere H.
- Albertos R.
- Albillos A.
- Albrecht W.
- Albrich W.
- Albrich W. C.
- Aldera E. L.
- Aldridge J.
- Alegria A.
- Alex B.
- Alexander P.
- Alfonso J.
- Algera A. G.
- Ali A.
- Ali I. A. M.
- Ali S.
- Aliberti S.
- Allan A.
- Allan E.
- Allan J.
- Alldis Z.
- Allen L.
- Allen S.
- Allibone S.
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- Wu Y.
- Wulandari R.
- Wyllie D. H.
- Wynter I.
- Xavier K.
- Xue X.
- Yadav A.
- Yagi K.
- Yamada M.
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- Yamagata K.
- Yamasaki M.
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- Yasui Y.
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- Yengo L.
- Yermakovich D.
- Yi X.
- Yonekawa A.
- Yoon H.
- Yoon K. J.
- Yoshida K.
- Yoshida S.
- Yoshida S.
- Yoshida T.
- Yoshihara T.
- Yoshiya K.
- Yoshiyama T.
- Youlton N.
- Young P.
- Yun N.
- Zak A.
- Zaki A.
- Zambon M.
- Zamikula J.
- Zanella A.
- Zanella I.
- Zanelli G.
- Zara F.
- Zarate R.
- Zborowski A. C.
- Zeberg H.
- Zechner M.
- Zguro K.
- Zhai R.
- Zhang M.
- Zhao J. H.
- Zhen J.
- Zheng C.
- Zheng T.
- Zhou W.
- Zhu W.
- Zitter L.
- Zlatopolsky M.
- Zoller H.
- Zollner S.
- Zongo O.
- Zucchi P.
- Zyndorf M.
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2021
- Field of study
Get PDFThe genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease
A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study
- Author
- Abdullah-Koolmees H.
- Aguilar-Jaldo M. D. P.
- Aigner C.
- Alcantara-Espadafor S.
- Algera M.
- Ambagts T.
- Angelini F.
- Anguita-Romero M.
- Antolinos-Perez M. J.
- Antunez-Rodriguez A.
- Anyfantis G.
- Aomar-Millan I.
- Arrebola A.
- Assimakopoulos K.
- Baas G.
- Baena-Garzon F.
- Baldew G.
- Barba E.
- Bartoletti M.
- Bartsakoulia M.
- Bautista-Paves A. B. P.
- Beetstra B.
- Bergs I.
- Berretta M.
- Bignucolo A.
- Blagec K.
- Blagus T.
- Blancas-Lopez-Navajas R.
- Bohringer S.
- Bolzonello S.
- Bosch R.
- Bukovec L.
- Buonadonna A.
- Burillo-Gomez F.
- Buunk A.
- Caballero-Borrego J.
- Cambon-Thomsen A.
- Campos-Velazquez S.
- Cano-Herrera R.
- Canterero-Hinojosa J.
- Carazo J. J.
- Carnerero-Cordoba L.
- Castillo-Perez I.
- Ceballos-Torres A.
- Cecchin E.
- Chacon-McWeeny V.
- Chalikiopoulou K.
- Cheung K. -C.
- Comello F.
- Corsetti S.
- Cruz-Valero I.
- D'Andrea M.
- Da Ros L.
- Dal Cin L.
- Dames-Ludwig M.
- Davila Fajardo C. L.
- Davila-Fajardo C. L.
- De Hoog-Schouten L.
- De Waal Z.
- Delgado-Urena M. T.
- Dello Russo C. (ORCID:0000-0002-2538-3832)
- Den Hollander I.
- Deneer V. H.
- Di Nardo P.
- Diaz-Villamarin X.
- Dikken J.
- Diraimo T.
- Dolzan V.
- Douzenis A.
- Dubero D.
- Dupui M.
- Emmanouil G.
- Faro-Miguez N.
- Favaretto A.
- Ferentinos P.
- Fernandez-Gonzalez A. E.
- Foltran L.
- Fontana V.
- French S.
- Freschi A.
- Gallardo-Sanchez I.
- Garcia-Navas P.
- Garcia-Orta B.
- Georgila E.
- Gerasimou H.
- Giannopoulos P.
- Gil-Jimenez
- Gonzalez-Astorga C. J.
- Goossens H.
- Gourzis F.
- Grasic Kuhar C.
- Guardascione M.
- Guardia-Mancilla P.
- Guchelaar H. -J.
- Guerrero-Jimenez M.
- Guillen-Zafra L.
- Guirao-Arrabal E.
- Gumustekin M.
- Hampson J.
- Hampson L.
- Hanson A.
- Heijn A.
- Herrera T.
- Herrera-Gomez N.
- Hoogenboom S.
- Hornby R.
- Houben T.
- Ingelman-Sundberg M.
- Innocente R.
- Ivantsik O.
- Jeras K.
- Joefield-Roka C.
- Johansson I.
- Jonsson S.
- Just K. S.
- Jutersek M.
- Kanellakis F.
- Kanis T.
- Karaivazoglou A.
- Karamperis K.
- Karlsson M. O.
- Katsila T.
- Klen J.
- Kolliopoulou A.
- Konta L.
- Koopmann R.
- Kordou Z.
- Kotar T.
- Kouwen-Lubbers K.
- Kriek M.
- Lauschke V.
- Legeren-Alvarez M.
- Lehr T.
- Lewis D.
- Leyva-Ferrer R. N.
- Liopetas I.
- Little M.
- Lopez-Fernandez S.
- Lopez-Perez I.
- Manson L. E.
- Marjetic Ulcakar A.
- Martin-de la Higuera A. J.
- Martinez-Gonzalez L. J.
- Martinez-Huertas S.
- Matos E.
- Mazej Poredos B.
- Meijs V.
- Mencinger M.
- Mendrinou E.
- Mezzalira S.
- Miklavcic P.
- Minichmayr I.
- Mitropoulos K.
- Mitropoulou C.
- Mlinsek G.
- Monteforte R.
- Moreno Aguilar M. R.
- Moreno-Escobar E.
- Musaafir S.
- Nanah A.
- Navarria F.
- Nelemans L.
- Nielsen E.
- Nijenhuis M.
- Nordling A.
- Oblak I.
- Ongaro E.
- Ontiveros-Ortega M. C.
- Overmars W.
- Palazzari E.
- Patrinos G. P.
- Perez-Gutierrez E. M.
- Pertejo-Manzano L.
- Petek Ster M.
- Pirmohamed M.
- Plaza-Carrera J.
- Plemenitas Iljes A.
- Poplas Susic T.
- Praznik M.
- Prince C.
- Puglisi F.
- Radovanovic M.
- Rajasingam A.
- Rajter B.
- Rial-Sebbag E.
- Rigas G.
- Rivera R.
- Rodriguez-Gonzalez F. J.
- Rollinson V.
- Roncato R.
- Ruiz-Carazo M.
- Saje M.
- Samiou G. -C.
- Samwald M.
- Sanchez-Cano D.
- Sanchez-Garcia M. J.
- Sanchez-Ramos J. G.
- Schaeffeler E.
- Schmidt A.
- Schuil-Vlassak E.
- Schwab M.
- Sengoelge G.
- Sequero-Lopez S.
- Siamoglou S.
- Skokou M.
- Skoporc J.
- Skrinjar A.
- Slager M.
- Slapsak U.
- Spazzapan S.
- Spina M.
- Stamopoulou T.
- Stathoulias A.
- Steeman S.
- Steffens M.
- Stegne Ignjatvic T.
- Steinberger D.
- Steinhauser C.
- Stingl J. C.
- Stratopoulos A.
- Strazisar B.
- Strbac D.
- Sunder-Plassmann G.
- Sunder-Plassmann R.
- Swen J. J.
- Terzic T.
- Thomas- J.
- Tjong C.
- Toffoli G.
- Toledo-Frias P.
- Ton C.
- Tremmel R.
- Trivino-Juarez J. M.
- Tsermpini E.
- Tsermpini E. E.
- Tsikrika A.
- Turner R. M.
- Van der Plas M.
- van der Wouden C. H.
- Van Doremalen J.
- Van Leeuwen M.
- van Rhenen M. H.
- Vasileios F.
- Velasco-Fuentes S.
- Villegas-Rodriguez I.
- Vivod Pecnik Z.
- Voncina B.
- Voukelatou G.
- Vrbnjak M.
- Westhead R.
- Winnicki W.
- Yanez-Sanchez M. I.
- Yelamos-Vargas M.
- Zhou Y.
- Zidansek A.
- Zou Y.
- Zvezdana Dernovsk M.
- Publication venue
- 'Elsevier BV'
- Publication date
- 01/01/2023
- Field of study
No full textBackground: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug–gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. Findings: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54–0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61–0·79]; p <0·0001). Interpretation: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. Funding: European Union Horizon 2020
Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
- Author
- Abbas M
- Abbasi S
- Abbasi S
- Abdelaziz A
- Abdelfattah M
- Abdul B
- Abdulmumeen A
- Abdulshukkoor N
- Abdusamad K
- Aboaba A
- Abouibrahim M
- Abraham M
- Abraham T
- Abrams J
- Abung A
- Acharya D
- Acharya D
- Acheson J
- Acosta A
- Acosta A
- Acton C
- Adam M
- Adams C
- Adams K
- Adamus M
- Adegoke K
- Adenwalla S
- Adeyeye E
- Adnan A
- Agbo C
- Aggarwal S
- Agwada-Akeru J
- Agyapong K Ansu
- Ah-Chuen J
- Ahmad M
- Ahmed I
- Ahmed I
- Ahmed L
- Ahmed L
- Ahmed M
- Ahmed M Cecilia
- Ahmed N
- Ahmed N
- Ahmed R
- Ahmed RA
- Ahmed S
- Ahmed S Haris
- Ail D
- Ainsley A
- Ainsworth M
- Aitken L
- Ajibode A
- Ajmi A
- Ajmi A
- Akhtar N
- Akili S
- Akindolie O
- Al Balushi A
- Al-Asadi A
- Al-Hakim B
- Al-Jibury M
- Al-Rabahi A
- Al-Ramadhani B
- Al-Shamkhani W
- Al-Sheklly B
- Alam S
- Aldana A
- Aldouri R
- Aldridge N
- Alegria A
- Alexander A
- Alexander J
- Alexander PDG
- Ali F Runa
- Ali M
- Ali O
- Ali S
- Ali S
- Ali S
- Alkhusheh M
- Alkhusheh M
- Allanson A
- Allen L
- Allen R
- Allen S
- Allison K
- Allsop L
- Alomari L
- Alzetani M
- Ambler S
- Ambrogetti R
- Ambrose C
- Amezaga M
- Amin A
- Amosun V
- Amosun V
- Amsha K
- Anand A
- Anderson J
- Anderson L
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- Anderson R
- Andreou P
- Andrews A
- Andrews J
- Aneke K
- Ang A
- Angel T
- Antill P
- Antonina Z
- Anu V
- Appleby S
- Appleyard D
- Archer A
- Ardley C
- Arimoto R
- Arkley C
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- Armstrong C
- Armstrong S
- Armtrong P
- Arnison-Newgass C
- Arora D
- Arter A
- Arter A
- Asghar A
- Ashbrook-Raby C
- Ashish A
- Ashish A
- Ashraf S
- Ashton D
- Asrar A
- Assaf O
- Astin-Chamberlain R
- Athorne D
- Atkinson J
- Atkinson V
- Aubrey P
- Aung K Thu
- Aung N
- Aung Z Myo
- Austin E
- Avery M
- Avram C
- Awadzi G
- Aya A
- Ayaz E
- Azam J
- Aziz G
- Azzopardi G
- Babatunde F
- Babi M
- Babi M
- Babingto G
- Babs-Osibodu A Obaloluwa
- Bacon G
- Bacon J
- Bacon J
- Bagley G
- Bahadori K
- Baijiu G
- Bailey K
- Bailey K
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- Baillie H
- Baillie JK
- Baillie JK
- Baillie K
- Baird D
- Bajandouh A
- Baker E
- Baker-Moffatt M
- Bakoulas P
- Balachandran N
- Balachandran N
- Balan A
- Balaskas T
- Balasubramaniam M
- Balcombe A
- Baldwin A
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- Baldwin L
- Balfour J
- Ball C
- Bamfo S Danso
- Bamford A
- Bamford A
- Bamford P
- Bamgboye A
- Bancroft H
- Banda J
- Bandi S
- Bandi S
- Bandla N
- Bandyopadhyam S
- Bandyopadhyam S
- Banerjee R
- Banerjee S
- Banks H
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- Bannister O
- Baptist M
- Baqai T
- Barclay A
- Bari S
- Barker D
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- Barker-Williams K
- Barla J
- Barla J
- Barlow G
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- Publication venue
- 'Elsevier BV'
- Publication date
- 01/02/2021
- Field of study
Get PDFBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research
Mapping the human genetic architecture of COVID-19
- Author
- Abdelrazik M
- Abdullah T
- Abe R
- Abe S
- Abecasis GR
- Abel L
- Abernathy C
- Abraheem A
- Abul-Husn NS
- Acosta-Herrera M
- Acquilini D
- Acquilini D
- Adachi T
- Adachi Y
- Adams C
- Adams K
- Adanini O
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- zu Bentrup FM
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- Zwinderman AHK
- Zyndorf M
- Publication venue
- Publication date
- 01/01/2021
- Field of study
Get PDFThe genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease
A second update on mapping the human genetic architecture of COVID-19
- Author
- Abd Elghafar MS
- Abdel-Aziz M
- Abdelrazik M
- Abdullah MS
- Abe R
- Abe S
- Abel L
- Abel L
- Abernathy C
- Abraham R
- Abraheem A
- Abu Alragheb BO
- Abulail JA
- Acklery A
- Acosta-Herrera M
- Adachi T
- Adachi Y
- Adam R
- Adams C
- Adams K
- Adams N
- Adanini O
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- Álvarez BG
- Ávila-Arcos MA
- Ávila-Arcos MC
- Özer O
- Überla K
- Þorsteinsdóttir U
- Publication venue
- Nature Research
- Publication date
- 21/06/2023
- Field of study
Get PDFCommon, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
- Author
- Abaleke E.
- Abdelrazik M.
- Abedalthagafi M.
- Abel L.
- Abernathy C.
- Abraheem A.
- Adamek A.
- Adams C.
- Adanini O.
- Agasou A.
- Agrawal S.
- Ahmad N.
- Ahmed A.
- Ahmed C.
- Akeroyd L.
- Akinkugbe O.
- Al-Moasseb M.
- Al-Muftah W.
- Al-Sarraj Y.
- Alaamery M.
- Alaverdian D.
- AlBardis H.
- Alexander P.
- Ali A.
- Ali Mohamed Ali I.
- Aljawini N.
- Allan A.
- Allan E.
- Allan J.
- Alldis Z.
- Allen L.
- Allen S.
- Allibone S.
- Almaden-Boyle C.
- Almalki F.
- Alsuwailm M.
- Altabaibeh A.
- Alvaro A.
- Amin V.
- Amitrano S.
- Anastasescu E.
- Anderberg S. B.
- Anderson F.
- Anderson P.
- Anderson S.
- Anderson T.
- Andolfo I.
- Andretta F.
- Andreucci E.
- Andrew G.
- Andrews E.
- Anedda F.
- Anemoli V.
- Antcliffe D.
- Antinori A.
- Antoni M. D.
- Anumakonda V.
- Anwar B.
- Apetri E.
- Arbane G.
- Archer K.
- Archer S.
- Arden T.
- Ariani F.
- Armstrong L.
- Armstrong R.
- Artuso R.
- Ashbrook-Raby C.
- Aspinwall A.
- Astin-Chamberlain R.
- Attala L.
- Attwood B.
- Aucella F.
- Auld F.
- Austin K.
- Austin P.
- Ayers A.
- Azzadin A.
- Bachetti T.
- Badji R.
- Baillie J. K.
- Baines B.
- Baines K.
- Baird T.
- Baird Y.
- Bakthavatsalam D.
- Balagosa I.
- Balasubramaniam M.
- Baldassarri M.
- Bals R.
- Bamford A.
- Bamford P.
- Banach D.
- Bancroft H.
- Bandini M.
- Bandla N.
- Bano S.
- Baptista D.
- Baratti S.
- Barber R.
- Barbieri C.
- Barclay L.
- Bargagli E.
- Barker J.
- Baroni S.
- Barron A.
- Barry P.
- Baruah R.
- Bashyal A.
- Basikolo C.
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
No full textThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management
