Asia-Pacific Extra-Corporeal Life Support Organisation (AP ELSO)

GenOMICC set-up is now under way in the Asia-Pacific ELSO network

AP ELSO GenOMICC Team

Study Overview

GenOMICC (Genetics of Mortality in Critical Care) is a community-led, open-source research study that aims to discover genetic associations with susceptibility to, and outcome from, critical illness. The ultimate aim is to find new therapeutic targets to promote survival.1 To maximise the genetic effect sizes we see, and minimise the effect of random noise caused by comorbid illness, GenOMICC is restricted to people who were in good health (i.e. free from functionally-limiting comorbid illness, and age <= 70y) before developing the presenting acute problem.

GenOMICC ECMO

Inclusion criteria

In AP ELSO ECMO centres, we propose to recruit all previously-well patients who require veno-venous ECMO for respiratory failure of any aetiology. This corresponds to group 3 in the GenOMICC protocol entry criteria.

Susceptibility

We anticipate that the case mix of patients requiring ECMO includes a large proportion of disease processes for which there is evidence of genetic predisposition, including ARDS,2 influenza,3 and other infections.4 Therefore we will recruit any previously-well patient requiring ECMO, and stratify the analysis by disease process. Cases will be compared with population controls, which can be obtained from existing studies in many populations.

Genetic effect sizes for susceptibility to infection are often large,5 so associations can be detected with relatively small numbers of carefully-selected patients.3

Mortality

In order to change a patient’s outcome, we need to alter the biological processes that are active after presentation to healthcare. Hence the genetic effects of the greatest interest are those that alter the probablity of mortality from critical illness. These are inevitably smaller genetic effects;6 detecting these will require large numbers of patients, and optimal use of existing data.7

Recruitment

Recruitment to GenOMICC requires:

Case report form

A minimal case report form should be completed using an secure online interface (RedCap) to enter data about each patient into the study database. This will record only essential information relating to the study, including:

Quality control

At regular intervals an external quality check of data entered into the study should be performed.

References

1.Baillie, J.K. Targeting the host immune response to fight infection. Science 344, 807–808(2014).

2.Hinz, J., Büttner, B., Kriesel, F., Steinau, M., Popov, A.F., Ghadimi, M., Beissbarth, T., Tzvetkov, M., Bergmann, I. & Mansur, A. The FER rs4957796 TT genotype is associated with unfavorable 90-day survival in Caucasian patients with severe ARDS due to pneumonia. Scientific Reports 7, 9887(2017).

3.Everitt, A.R., Clare, S., Pertel, T., John, S.P., Wash, R.S., Smith, S.E., Chin, C.R., Feeley, E.M., Sims, J.S., Anttila, V., Baillie, J.K., Walsh, T.S., Hume, D.A., Semple, M.G., Nguyen-Van-Tam, J.S., Smyth, R.L., Openshaw, P.J., Dougan, G., Brass, A.L., Kellam, P., Colonna, V., Tyler-Smith, C., Dunning, J., Gordon, S.B., Everingham, K., Dawson, H., Hope, D., Ramsay, P., Walsh, T.S., Campbell, A., Kerr, S., Harrison, D., Rowan, K., Addison, J., Donald, N., Galt, S., Noble, D., Taylor, J., Webster, N., Taylor, I., Aldridge, J., Dornan, R., Richard, C., Gilmour, D., Simmons, R., White, R., Jardine, C., Williams, D., Booth, M., Quasim, T., Watson, V., Henry, P., Munro, F., Bell, L., Ruddy, J., Cole, S., Southward, J., Allcoat, P., Gray, S., McDougall, M., Matheson, J., Whiteside, J., Alcorn, D., Rooney, K., Sundaram, R., Imrie, G., Bruce, J., McGuigan, K., Moultrie, S., Cairns, C., Grant, J., Hughes, M., Murdoch, C., Davidson, A., Harris, G., Paterson, R., Wallis, C., Binning, S., Pollock, M., Antonelli, J., Duncan, A., Gibson, J., McCulloch, C., Murphy, L., Haley, C., Faulkner, G., Freeman, T., Hume, D.A., Baillie, J.K., Chaussabel, D., Adamson, W.E., Carman, W.F., Thompson, C., Zambon, M.C., Aylin, P., Ashby, D., Barclay, W.S., Brett, S.J., Cookson, W.O., Drumright, L.N., Dunning, J., Elderfield, R.A., Garcia-Alvarez, L., Gazzard, B.G., Griffiths, M.J., Habibi, M.S., Hansel, T.T., Herberg, J.A., Holmes, A.H., Hussell, T., Johnston, S.L., Kon, O.M., Levin, M., Moffatt, M.F., Nadel, S., Openshaw, P.J., Warner, J.O., Aston, S.J., Gordon, S.B., Hay, A., McCauley, J., O’Garra, A., Banchereau, J., Hayward, A., Kellam, P., Baillie, J.K., Hume, D.A., Simmonds, P., McNamara, P.S., Semple, M.G., Smyth, R.L., Nguyen-Van-Tam, J.S., Ho, L.-P., McMichael, A.J., Kellam, P., Smyth, R.L., Openshaw, P.J., Dougan, G., Brass, A.L. & Kellam, P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519–23(2012).

4.Sorensen, T., Nielsen, G., Andersen, P. & Teasdale, T. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 318, 727–732(1988).

5.Hill, A.V.S. Evolution, Revolution and Heresy in the Genetics of Infectious Disease Susceptibility. Philosophical Transactions of the Royal Society B: Biological Sciences 367, 840–849(2012).

6.Davenport, E.E., Burnham, K.L., Radhakrishnan, J., Humburg, P., Hutton, P., Mills, T.C., Rautanen, A., Gordon, A.C., Garrard, C., Hill, A.V.S., Hinds, C.J. & Knight, J.C. Genomic landscape of the individual host response and outcomes in sepsis: A prospective cohort study. The Lancet Respiratory Medicine 4, 259–271(2016).

7.Forrest, A. R. R., Kawaji, H., Rehli, M., Baillie, J.K., et al A promoter-level mammalian expression atlas. Nature 507, 462–470(2014).

8.Baillie, J.K., Bretherick, A., Haley, C.S., Clohisey, S., Gray, A., Neyton, L.P.A., Barrett, J., Stahl, E.A., Tenesa, A., Andersson, R., Brown, J.B., Faulkner, G.J., Lizio, M., Schaefer, U., Daub, C., Itoh, M., Kondo, N., Lassmann, T., Kawai, J., Consortium, I., Mole, D., Bajic, V.B., Heutink, P., Rehli, M., Kawaji, H., Sandelin, A., Suzuki, H., Satsangi, J., Wells, C.A., Hacohen, N., Freeman, T.C., Hayashizaki, Y., Carninci, P., Forrest, A.R.R. & Hume, D.A. Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease. PLOS Computational Biology 14, e1005934(2018).


Funding

The GenOMICC study is supported by Sepsis Research (FEAT), the Intensive Care Society, the Wellcome Trust, and the Medical Research Council.


Contact us: genomicc@roslin.ed.ac.uk