Search Strategy Employed in the Electronic Search for Papers

1

Clark & BaudouinQuality in association studies ESM

Search strategy employed in the electronic search for papers

1.Restriction fragment length polymorphism/ or genetic polymorphism/ or amplified fragment length polymorphism/ or single nucleotide polymorphism/ or polymorphism$.mp. or DNA polymorphism/

2. Genetic association$.mp. or Genetic Association/

3. Single Nucleotide Polymorphism/ or SNP$.mp.

4. Newborn sepsis/ or sepsis.mp. or gram negative sepsis/ or sepsis/

5. Bacterial Infection/ or severe infection$.mp.

6. 1 or 2 or 3

7. 4 or 5

8. 6 and 7

9. Limit 8 to (Human and English language)

Glossary

Allele

One or more alternate forms of a DNA sequence

Genotype

The genetic identity of an individual that does not show as outward characteristics

Hardy-Weinberg equilibrium.

The stable frequency distribution of genotypes, AA, Aa, and aa, in the proportions p2, 2pq, and q2 respectively (where p and q are the frequencies of the alleles, A and a) that is a consequence of random mating in the absence of mutation, migration, natural selection, or random drift. Control groups should be in Hardy-Weinberg equilibrium.

Heterozygous

Two different alleles at a given locus

Homozygous

Two identical alleles at a given locus

ESM Table 1

A table of the 48 assessed case controlled association studies, demonstrating risk of disease or sepsis development, study size, and quality.

ESM Table 2.

A table of the 72 assessed cohort association studies demonstrating mortality or sepsis risk, study size and quality

ESM additional Figure 1

The average score of genetic association studies in sepsis, expressed as a percentage of total possible scores from 0 to 1, with one standard error of the mean. Studies were divided into year of publication. There was no evidence of a trend towards improvement over time.

Complete References

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28.O'Keefe GE, Hybki DL, Munford RS (2002) The G-->A single nucleotide polymorphism at the -308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after trauma. J Trauma 52:817-825; discussion 825-816

29.Barber RC, O'Keefe GE (2003) Characterization of a single nucleotide polymorphism in the lipopolysaccharide binding protein and its association with sepsis. Am J Respir Crit Care Med 167:1316-1320

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31.Westendorp RG, Hottenga JJ, Slagboom PE (1999) Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 354:561-563

32.Kremer Hovinga JA, Franco RF, Zago MA, Ten Cate H, Westendorp RG, Reitsma PH (2004) A functional single nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) gene associates with outcome of meningococcal disease. J Thromb Haemost 2:54-57

33.Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306-309

34.Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002) A comprehensive review of genetic association studies. Genet Med 4:45-61

35.Cardon LR, Bell JI (2001) Association study designs for complex diseases. Nat Rev Genet 2:91-99

36.Buckland PR (2001) Genetic association studies of alcoholism--problems with the candidate gene approach. Alcohol Alcohol 36:99-103

37.Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, Millo JL, Welsh KI, Holloway P, Hitman GA, Piper RD, Garrard CS, Hinds CJ (2004) TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun 5:631-640

38.Peters DL, Barber RC, Flood EM, Garner HR, O'Keefe GE (2003) Methodologic quality and genotyping reproducibility in studies of tumor necrosis factor -308 G-->A single nucleotide polymorphism and bacterial sepsis: implications for studies of complex traits. Crit Care Med 31:1691-1696

39.Arnalich F, Lopez-Maderuelo D, Codoceo R, Lopez J, Solis-Garrido LM, Capiscol C, Fernandez-Capitan C, Madero R, Montiel C (2002) Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol 127:331-336

40.Read RC, Cannings C, Naylor SC, Timms JM, Maheswaran R, Borrow R, Kaczmarski EB, Duff GW (2003) Variation within genes encoding interleukin-1 and the interleukin-1 receptor antagonist influence the severity of meningococcal disease. Ann Intern Med 138:534-541

41.Ma P, Chen D, Pan J, Du B (2002) Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients. Crit Care Med 30:1046-1050

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52.Rauchschwalbe SK, Maseizik T, Mittelkotter U, Schluter B, Patzig C, Thiede A, Reith HB (2004) Effect of the LT-alpha (+250 G/A) polymorphism on markers of inflammation and clinical outcome in critically ill patients. J Trauma 56:815-822

53.Yan SB, Nelson DR (2004) Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Crit Care Med 32:S239-246

54.Kerlin BA, Yan SB, Isermann BH, Brandt JT, Sood R, Basson BR, Joyce DE, Weiler H, Dhainaut JF (2003) Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 102:3085-3092

55.Kondaveeti S, Hibberd ML, Booy R, Nadel S, Levin M (1999) Effect of the Factor V Leiden mutation on the severity of meningococcal disease. Pediatr Infect Dis J 18:893-896

56.Haralambous E, Hibberd ML, Hermans PW, Ninis N, Nadel S, Levin M (2003) Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children. Crit Care Med 31:2788-2793

57.Hermans PW, Hibberd ML, Booy R, Daramola O, Hazelzet JA, de Groot R, Levin M (1999) 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 354:556-560

58.Menges T, Hermans PW, Little SG, Langefeld T, Boning O, Engel J, Sluijter M, de Groot R, Hempelmann G (2001) Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 357:1096-1097

59.Heesen M, Bloemeke B, Schade U, Obertacke U, Majetschak M (2002) The -260 C-->T promoter polymorphism of the lipopolysaccharide receptor CD14 and severe sepsis in trauma patients. Intensive Care Med 28:1161-1163

60.Read RC, Pullin J, Gregory S, Borrow R, Kaczmarski EB, di Giovine FS, Dower SK, Cannings C, Wilson AG (2001) A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis 184:640-642