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.

Author / Polymorphisms assessed type and total / Control group size / Case group size / Number of patients with Sepsis / Risk of developing sepsis or disease from any single polymorphism. Polymorphism combinations not included. / Effect size / p value / Score
Arnalich[39] / IL-1RN / 130 / 78 / 78 / No effect from polymorphism / NS / 6
Read[40] / IL-1RN, IL-1β / 893 / 1106 / 1106 / No effect from polymorphisms / NS / 6
Fang[20] / IL-1RN, IL-1β,TNF-β / 261 / 93 / 93 / IL1-RN2/2 increase sepsis / RR=2.1 p<0.01 / 5
Ma[41] / IL-1RN, IL-1β,IL-1α / 60 / 60 / 60 / IL1-RN2 allele and homozygous increase risk sepsis / <0.05 / 4
Watanabe[42] / IL-1,IL-6,TNF-α / 150 / 150 / 150 / No effect from polymorphisms on sepsis / NS / 6
Gallagher[9] / IL-6,IL-10,TNF-α / 90 / 93 / 74 / IL-10 G allele increased risk of SIRS
No effects from other polymorphisms / p=0.02 / 2
Schluter[43] / IL-6 / 207 / 326 / 50 / No effect from polymorphisms / NS / 7
Shu[44] / IL-10 / 141 / 116 / 116 / IL-10-1082 allele 1 increase sepsis / OR=1.4 CI=1-3.0 p<0.05 / 4
Schaaf[45] / IL-10,TNF-α,TNF-β / 60 / 69 / 69 / No effect from polymorphisms / NS / 5
Lowe[46] / IL-10 / 132 / 67 / 31 / No effect from polymorphisms / NS / 3
Van der Pol[47] / IL-10,FcγRIIa, FcγRIIIa, FcγRIIIb / 422 / 50 / 50 / No effect from polymorphisms / NS / 6
Westendorp[22] / TNF-α / Not stated / 190 /0 (relatives of meningitis patients) / No effect from polymorphism / NS / 3
Zhang[48] / TNF-α / 116 / 72 / 72 / No effect from polymorphism / NS / 4
Mira [25] / TNF-α 6 poly / 87 / 89 / 89 / TNF-α2 allele increased septic shock / 39% vs 18% / p=0.002 / 5
Nadel[49] / TNF-α / 98 / 98 / No effect from polymorphism / NS / 4
Tang[50] / TNF-α / Not stated / 112/112 / TNF2 allele increased risk sepsis / p<0.01 / 4
Gordon[37] / TNF,TNFRSF / 354 / 213 / No effect from polymorphism / NS / 8
Stuber[24] / TNF-α, TNF-β / 153 / 80 / No effect from this polymorphism / NS / 5
Stuber[51] / TNF-β / 40 / 40 / No effect on sepsis development / NS / 5
Rauchswalbe[52] / TNF-β / Multiple groups / 85/85 / No effect from polymorphism, authors present data but draw no conclusions / NS / 4
Weitkamp[15] / TNF-β / 131+262 / 23 / No effect from polymorphism / NS / 5
Yan[53] / Factor V Lieden / Not stated / 150 / 150 / Factor V heterozygote decreases sepsis / p=0.05 / 7
Kerlin[54] / Factor V Lieden / Not stated / 1690 / 1690 / No effect from polymorphism / NS / 6
Kondaveeti[55] / Factor V Lieden / 80 / 184/184
75/75
79 parents/0 / No effect from polymorphism / NS / 3
Haralambous[56] / 4G/5G PAI / 155 / 510 / 510
210 / 0 (relatives) / No effect from polymorphism / NS / 8
Westendorp[31] / 4G/5G PAI / 131+183 / 50 / 50 / Increase risk septic shock / OR=5.9 CI=1.9-18 / 5
Hermans[57] / 4G/5G PAI / 226 / 175 / 175 / No effect from polymorphism / NS / 2
Menges[58] / 4G/5G PAI / 32 / 61 / 29 / No effect from polymorphism / NS / 4
Hubacek[16] / LBP, BPIP / 250 / 204 / 204 / No effect from polymorphisms / NS / 7
Gibot[27] / CD-14 / 122 / 90 / 90 / T/T genotype and allele increase sepsis / p=0.03 T, p=0.008T/T / 6
Heesen[59] / CD-14 / NS / 58/14 / No effect from polymorphism / NS / 4
Hubacek[30] / CD-14 / 247 / 204 / 204 / No effect from polymorphism / NS / 6
Agnese[23] / CD-14, TLR-4 / 39 / 77 / 38 / TLR4 variant allele increased gram –ve sepsis / p=0.004 / 5
Read[60] / TLR-4 / 879 / 1047 / 1047 / No effect from polymorphism / NS / 6
Lorenz[19] / TLR-2 / 73 / 91 / 91 / Increased incidence of staphylococcal infections? / Not given / 4
Roy[61] / MBL 52,54,57,-221 / 353 First study
679 Confirm study / 229 / 229
108 / 108 / MBL variant homozygote increase invasive pneumococcal disease
MBL variant homozygote increase invasive pneumococcal disease / OR=2.59 CI=1.4-4.4 p=0.002
OR=2.37, CI=1.5-3.7 p=0.0001 / 8
Hibberd[62] / MBL / 272
110 / 194
72 / MBL variant heterozygote and homozygote increase sepsis
MBL variant heterozygote and homozygote increase sepsis / RR=1.7 CI=1.1-2.6 p=0.02
RR=6.5 CI=2-27.2 p=0.0006
RR=2.2 CI=1.1-4.3 p=0.02
RR=4.5 CI=0.9-29.1 p=0.06 / 7
Kronborg[63] / MBL 52,54,57,-221 / 250 / 141 / 141 / No effect of polymorphism / NS / 4
Garred[64] / MBL / 250 / 272 / 197 / MBL variant heterozygote increase sepsis
MBL variant homozygote increase sepsis / RR=1.4 CI=1.1-1.5
RR=1.6 CI=1.4-1.9 / 5
Platonov[65] / Immunoglobulin-γ / 107 / 98 / 98 / No effect from polymorphism / NS / 4
Domingo[66] / Immunoglobulin-γ / 260 / 130 / 130 / FcγRIIA-R/R131increase risk sepsis / RR=3 CI=1.4-7.8 p<0.03 / 6
Yuan[67] / Immunoglobulin-γ / 57+20 / 63 / 63 / FcγRIIA-R/R131 increase risk sepsis in one control group only (N=57) / 50% vs 28% p<0.05 / 4
Yee[68] / Immunoglobulin-γ / 164 / 42 / 42 / FcγRIIA-R/R131 increase risk sepsis / p<0.05 / 6
Saleh[17] / Caspase / 120 / 38 / 38 / 125C allele increases sepsis risk
C/C genotype increases sepsis risk / p=0.002
p=0.005 / 5
Schroeder[69] / HSP, TNF-β / 110 / 87 / 87 / No effect from polymorphism / NS / 4
Harding[70] / ACE / 841 / 113 / 113 / No effect from polymorphism / NS / 6
Kremer Hovinga[32] / TAFI 1040 + 505 / 212 / 50 /50
176 relatives / No effect from polymorphism
TAFI 1040T/T increased risk childs death / NS
5 (19.2%) vs 21 (7.1%) OR=3.1 CI=1.0-9.5 p=0.03 / 5
Spolarics[71] / G6PD / 43 / 44/22 / A- Increased sepsis / 50% vs 6.25% p<0.05 / 4

ESM Table 2.

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

Author / Polymorphisms assessed type and total / Cohort size / Number of Patients in cohort with Sepsis / Mortality or sepsis risk disease from any single polymorphism. Polymorphism combinations not included. / Effect size / p value / Score
Arnalich[39] / IL-1RN / 130 / 78 / IL-1RN2/2 increased risk death / RR=6.47 CI=1-41.5 p=0.04 / 5
Bessler[72] / IL-1RN / 95 / 34 / No effect from polymorphism (sepsis) / NS / 4
Read[40] / IL-1RN, IL-1β / 1106 / 1106 / IL-1β 1allele decreased mortality / OR=2.05 CI=1.1-3.8 p=0.023 / 6
Ma[41] / IL-1RN, IL-1β,IL-1α / 60 / 60 / IL-1αA2/2,IL-1β1/2,IL-1RN2/2 and IL-1β and IL-1RN alleles increases mortality / p<0.01 for all / 3
Fang[20] / IL-1RN, IL-1β,TNF-β / 93 / 93 / TNF-β2 allele increased mortality / RR=3.47, p=0.0001 / 4
Read[21] / IL-1RN, IL-1β,IL-1α,TNFα / 276 / 276 / IL-1β1/1 or 2/2 increase mortality / IL-1β1/1 OR=3.4 CI=1.4-8.3
IL-1β2/2 OR=7.4 CI=2.5-21.5 / 6
Watanabe[42] / IL-1,IL-6,Il-1RN,TNF-α / 150 / 150 / No effect from polymorphisms on sepsis / NS / 5
Schluter[43] / IL-6 / 326 / 50 / Decreased death if IL-6GG / OR=0.11 CI=0.02-0.57) / 6
Gallagher[9] / IL-6,IL-10,TNF-α / 93 / 74 / IL-10 G allele increased mortality
No effects from other polymorphisms / OR=4.3 CI=1.39-13.2 p=0.01 / 2
Treszl[73] / IL-1β,IL-4,IL-6,IL-10,TNF-α / 103 / 33 / No effect from polymorphism sepsis / 3
Barber[74] / IL-1β,IL-6,TNF-α,CD-14,TLR-4 / 159 / 105 sepsis
36 severe sepsis / TLR4 G allele increase sepsis
TNF-α A Allele increase sepsis / TLR 4G OR=6.4 CI=1.8-23.2
TNF-α OR=4.5 CI=1.7-12 / 4
Ahrens[75] / IL-6,CD-14, TLR-4, MBL,NOD2 / 356 / 50 / IL-6 G/G increase sepsis
NOD2-3020insC increase sepsis / IL-6 OR=1.9 CI=1-3.6 p=0.039
Nod2 OR=3.2 CI=1-10.4 p=0.052 / 5
Van der Pol[47] / IL-10,FcγRIIa, FcγRIIIa, FcγRIIIb / 50 / 50 / No effect from polymorphisms / NS / 5
Lowe[46] / IL-10 / 67 / 31 / IL-10 A allele increased mortality / p=0.04 / 3
Shu[44] / IL-10 / 116 / 116 / No effect from polymorphism / NS / 3
Jaber[76] / IL-10,TNF-α / 61 / 39 / Polymorphisms did not alter sepsis risk / NS / 3
Schaaf[45] / IL-10,TNF-α,TNF-β / 69 / 69 / IL-10GG increase risk septic shock / OR=6.1 CI=1.4-27.2 p=0.024 / 5
Stassen[77] / IL-18 / 66 / 36 / No effect from single polymorphismson sepsis / NS / 3
Waterer[78] / TNF-α,TNF-β / 280 / 31 (septic shock) / TNF-β AA genotype increase septic shock
No effect mortality / RR=2.48 CI=1.3-4.8 p=0.01 / 4
Majetschak[79] / TNF-α,TNF-β / 70 / 14 / TNF-β 1/1 or 2/2 increased sepsis / β1/1 OR=13 CI=1.8-95.5 p=0.014
β2/2 OR=11 CI=1.7-66.7 p=0.01 / 3
Calvano[80] / TNF-α,TNF-β / 44 / 24 / No effect from polymorphism / NS / 4
Stuber[24] / TNF-α, TNF-β / 80 / 80 / Improved survival if TNFB1/2 vs 1/1 and 2/2 combined / 22/37 vs 17/43 survived p=0.007 / 4
O’Keefe[28] / TNF-α / 152 / 97 / TNF-α308A allele increases severe sepsis / OR=2.5 CI=1.5-4.3 / 5
Mira[25] / TNF-α / 89 / 89 / TNF-α308A allele increased mortality / 71% vs 42% death rate p=0.008 / 5
Tang[50] / TNF-α / 112 / 112 / TNF-α308AA increased mortality in subset population with septic shock n=42 / 92% vs 62% death rate p<0.05 / 4
Hedberg[81] / TNF-α / 173 / 85 / TNF-α308A allele increases mortality
No effect sepsis risk / 10% vs 3% death rate p=0.038 / 3
Nadel[49] / TNF-α / 98 / 98 / TNF-α308A allele increased mortality / RR=2.5 CI=1.1-5.7 / p=0.03 / 4
Appoloni[82] / TNF-α / 37 / 37 / TNF-β2 genotype increased mortality / OR=12 / p=0.02 / 2
Zhang[48] / TNF-α / 72 / 72 / TNF-α308A allele increased risk severe sepsis / 29 vs 46%, p=0.02 / 4
Westendorp[22] / TNF-α / 190 / 0 (relatives of meningitis patients) / No effect from polymorphism / NS / 4
Gordon[37] / TNF-α, TNFRSF / 213 / 213 / No effect from polymorphisms / NS / 8
Majetschak[83] / TNF-β / 110 / 53 / TNF-β2/2 genotype increases sepsis risk / OR=3.07 CI=1.42-6.63 p=0.004 / 4
Riese[84] / TNF-β / 172 / 18 / TNF-β2/2 genotype increase sepsis risk / p<0.02 / 4
Weitkamp[15] / TNF-β / 23 / 23 / No effect from polymorphism / NS / 4
Flach[18] / TNF-β / 40 / 10 / TNF-β2/2 increase sepsis risk / 90% of sepsis patients β2/2 p=? / 3
Stuber[51] / TNF-β / 40 / 40 / TNF-β2 allele increased mortality / p<0.005 / 5
Kahlke[85] / TNF-β / 160 / 16 / TNF-β2/2 increases sepsis mortality / p<0.05 / 5
Rauchschwalbe[52] / TNF-β / 85 / 85 / No effect from polymorphism / NS / 4
McArthur[86] / TNF-β / 34 / 34 / TNF-β2/2 genotype increased mortality / P<0.001 / 4
Schroder[87] / TNF-β / 201 / 201 / TNF-β2/2 genotype increased mortality / P<0.05 / 4
Yan[53] / Factor V Lieden / Not stated / 150 / 150 / VL +/- decrease mortality / RR=0.5 CI=0.27-0.92 / 7
Kerlin[54] / Factor V Lieden / 1690 / 1690 / VL +/- decrease mortality / OR survival 2.8 CI=1.3-5.8 p=0.006 / 6
Kondaveeti[55] / Factor V Lieden / 184
75
79parent / 184
75
0 / Increased purpura fulminans if VL+/- / 5/24 vs 14/209 p<0.03 / 3
Davis[88] / Interferon-γ D6S471 / 38 / 24 / AA genotype increased major infections / p=0.004 / 4
Stassen[89] / Interferon-γ / 61 / 30 / D allele increase sepsis risk / RR=2.09 CI=1.02-4.3 p=0.06 / 4
Haralambous[56] / 4G/5G PAI / 510 / 510 / 4G/4G increased mortality / RR=1.9 CI=1.2-3.0 p=0.005 / 8
Hermans[57] / 4G/5G PAI / 175 / 175 / 4G/4G increased mortality / RR=2 CI=1-3.8 / 2
Westendorp[31] / 4G/5G PAI / 50 / 50 / No effect on mortality / NS / 5
Hubacek[16] / LBP, BPIP / 204 / 204 / No effect from polymorphisms / NS / 6
Barber[29] / LBP / 151 / 96 / No effect from polymorphism on sepsis / NS / 6
Gibot[27] / CD-14 / 90 / 90 / T allele or T/T increase mortality / RR=5.3 CI=1.2-22.5 p=0.02 T/T / 5
Hubacek[30] / CD-14 / 204 / 204 / No effect from polymorphism / NS / 5
Sutherland[90] / CD-14, MBL, TLR2 / 252 / 252 (SIRS) / TLR-2 T16933AA genotype risk sepsis / RR=1.2 p<0.03 / 5
Heesen[59] / CD-14 / 58 / 14 / No effect from polymorphism / NS / 4
Agnese[23] / CD-14, TLR-4 / 77 / 38 / No effect from polymorphism / NS / 5
Lorenz[26] / TLR-4 / 91 / 91 / No effect on mortality / NS / 5
Read[60] / TLR-4 / 1047 / 1047 / No effect from polymorphism / NS / 6
Lorenz[19] / TLR-2 / 91 / 91 / Increased incidence of staphylococcal infections? / Not given / 4
Fidler[91] / MBL 52,54,57,X/Y / 100 / 59 / MBL variant increased sepsis / shock risk / p=0.0007 / 5
Garred[64] / MBL / 272 / 197 / MBL variant homozygotes increase risk death / RR=2.3 CI=1.2-4.5 / 5
Roy[61] / MBL 52,54,57,-221 / 229 First study
108 Confirm study / 229 invasive pneumococcus
108 invasive pneumococcus / No effect from polymorphism on mortality / NS / 7
Hibberd[62] / MBL / 194 / 194 / No increase mortality / NS / 6
Neth[92] / MBL / 100 / 90 / Increased febrile neutropenic episodes / 20.5 vs 10 days p=0.004 / 5
Kronborg[63] / MBL / 141 / 141 / No effect on mortality / NS / 4
Domingo[66] / Immunoglobulin-γ / 130 / 130 / No effect mortality / NS / 5
Platonov[65] / Immunoglobulin-γ / 98 / 98 / No mortality effect from polymorphism
Increased severity meningitis if FcγRIIaR+ / NS
P=0.02 OR=4.7 / 3
Saleh[17] / Caspase / 38 / 38 / T125C allele increases mortality / Not stated / 4
Schroeder[69] / HSP, TNF-β / 87 / 87 / TNFβ2/2 increased mortality risk / P<0.01 / 3
Waterer[93] / HSP, TNF-β / 343 / 30 septic shock / No effect on mortality (septic shock)
Incresed risk septic shock HSP70-2AA / NS
P=0.005 / 5
Harding[70] / ACE / 113 / 113 / Increased risk death in PICU patients if DD / P=0.013 / 5
Baier[94] / ACE / 295 / >145 but <150 / No effect from polymorphism / NS / 4
Kremer Hovinga[32] / TAFI 1040 + 505 / 50 / 50 / No effect from polymorphism / NS / 4

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.

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