Quantitative systematic review of the associations between ......2015/05/01  · 1 Quantitative...

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Quantitativesystematicreviewoftheassociationsbetweenshort‐termexposure

tonitrogendioxideandmortalityandhospitaladmissions

ICMills1,RWAtkinson2,SKang2,HWalton3,4,HRAnderson2,3

1‐PublicHealthEngland,CentreforRadiation,ChemicalandEnvironmentalHazards,UK

2‐PopulationHealthResearchInstituteandMRC‐PHECentreforEnvironmentandHealth,St

George’s,UniversityofLondon,London,UK

3‐MRC‐PHECentreforEnvironmentandHealth,King’sCollegeLondon,UK

4‐NIHRBiomedicalResearchCentreatGuy’sandStThomas’NHSFoundationTrustand

King’sCollegeLondon,London,UKandNIHRHealthProtectionResearchUniton

EnvironmentalHazardsatKing’sCollegeLondoninpartnershipwithPublicHealthEngland

SupplementaryMaterial

Contentslist1. MethodsLiteraturesearchcriteriaProtocolforselectingestimatesformeta‐analysis2. ListofcountriesbyWHORegionandmortalitystrata

3. ListofTablesTableS1:Randomeffectsestimatesforthepercentageincreaseincausespecificmortalityinallagesper

10µg/m3increaseinNO2

TableS2:Randomeffectsestimatesforthepercentageincreaseinrespiratoryhospitaladmissionsper10µg/m3increaseinNO2

TableS3:Randomeffectsestimatesforthepercentageincreaseincardiovascularhospitaladmissionsper10µg/m3increaseinNO2

4. ListofFiguresFigureS1:Forestplotofstudiesandestimatesselectedformeta‐analysisforall‐causemortality,allages,

24houraverageNO2.FigureS2:Forestplotofstudiesandestimatesselectedformeta‐analysisforall‐causemortality,allages,

1houraverageNO2.FigureS3:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascular

mortality,allages,24houraverageNO2.

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FigureS4:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascular

mortality,allages,1houraverageNO2.FigureS5:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratorymortality,all

ages,24houraverageNO2.

FigureS6:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratorymortality,allages,1houraverageNO2.

FigureS7:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiacmortality,allages,24houraverageNO2.

FigureS8:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseasemortality,allages,24houraverageNO2.

FigureS9:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokemortality,allages,24houraverageNO2

FigureS10:Forestplotofstudiesandestimatesselectedformeta‐analysisforCOPDincludingasthmamortality,allages,24houraverageNO2

FigureS11:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,allages,24houraverageNO2

FigureS12:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,allages,1houraverageNO2

FigureS13:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,elderly,24houraverageNO2

FigureS14:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,elderly,1houraverageNO2

FigureS15:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,children,24houraverageNO2

FigureS16:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,children,1houraverageNO2

FigureS17:Forestplotofstudiesandestimatesselectedformeta‐analysisforasthmahospitaladmissions,children,24houraverageNO2

FigureS18:Forestplotofstudiesandestimatesselectedformeta‐analysisforasthmahospitaladmissions,children,1houraverageNO2

FigureS19:Forestplotofstudiesandestimatesselectedformeta‐analysisforCOPDincludingasthmahospitaladmissions,elderly,24houraverageNO2

FigureS20:Forestplotofstudiesandestimatesselectedformeta‐analysisforCOPDhospitaladmissions,allages,24houraverageNO2

FigureS21:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,allages,24houraverageNO2

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FigureS22:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,allages,1houraverageNO2

FigureS23:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,elderly,24houraverageNO2

FigureS24:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,elderly,1houraverageNO2

FigureS25:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,allages,24houraverageNO2

FigureS26:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,allages,1houraverageNO2

FigureS27:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,elderly,24houraverageNO2

FigureS28:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,elderly,1houraverageNO2

FigureS29:Forestplotofstudiesandestimatesselectedformeta‐analysisforheartfailurehospitaladmissions,allages,24houraverageNO2

FigureS30:Forestplotofstudiesandestimatesselectedformeta‐analysisforheartfailurehospitaladmissions,elderly,24houraverageNO2

FigureS31:Forestplotofstudiesandestimatesselectedformeta‐analysisforheartfailurehospitaladmissions,elderly,1houraverageNO2

FigureS32:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseasehospitaladmissions,allages,24houraverageNO2

FigureS33:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseaseadmissions,elderly,24houraverageNO2

FigureS34:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseaseadmissions,elderly,1houraverageNO2

FigureS35:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokeadmissions,allages,24houraverageNO2

FigureS36:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokeadmissions,elderly,24houraverageNO2

FigureS37:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokeadmissions,elderly,1houraverageNO2

FigureS38:Forestplotofstudiesandestimatesselectedformeta‐analysisfordysrhythmiahospitaladmissions,allages,24houraverageNO2

FigureS39:Forestplotofstudiesandestimatesselectedformeta‐analysisfordysrhythmiahospitaladmissions,elderly,24houraverageNO2

5. Listofreferencesincludedinthereview

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METHODSLiteraturesearchcriteriaBibliographicdatabasesweresearchedtoidentifypeer‐reviewedtime‐series(andcasecrossover)papersofdailyconcentrationsofNO2anddailymortalityandhospitaladmissions.Bibliographicdatabasessearched:PubMed,EMBASEorWebofScience(whichincludestheScienceCitationIndex)Thesearchstringused:

(airpollutionORpollutionORnitricoxide*ORnitrogendioxide?)AND(timeseriesORtimeseriesORtime‐seriesORdailyORcase‐crossover)AND(mortalityORdeath*ORdyingORhospitaladmission*ORadmission*ORemergencyroomORvisit*ORattendance*OR‘a&e’OR‘aande’ORaccidentandemergencyORgeneralpract*ORphysician*ORconsultation*ORemergencydepartment*)

Norestrictiononlanguagewasapplied.Thedatabasesweresearchedforpeer‐reviewedpaperspublisheduptoMay2011.Inaddition,theliteraturesearchwassupplementedwithpapersidentifiedbytheUSEPA4–thiswasthemostcomprehensivenarrativeassessmentoftheNO2evidenceavailableatthetimeofthisreview.Protocolforselectingestimatesformeta‐analysisWeappliedanaprioriprotocolfortheselectionofestimatesformeta‐analysistoavoidselectionbiasandduplicationofstudiesfromthesamepopulation.Wegaveprioritytoestimatesfrommulti‐citystudiesoverestimatesfromsingle‐citystudiesandtheresultsfromanyonecityappearedonlyonceinameta‐analysis.Ifresultsfrommorethanonemulti‐citystudywithinaWHOregionwereavailableweselected,inorderofpriority,themulti‐cityestimatefromthestudy:

(i) withthemostcities/greatestgeographicalcoverage(ii) themostrecentlypublished(iii) themostrecentstudytimeperiod.

Ifamulti‐citystudydidnotreportasummaryestimateacrossthecitiesexamined,foranalysis,wetreatedestimatesfromthesestudiesinthesamemannerasestimatesfromsingle‐citystudies.Weselectedestimatesfromsingle‐citystudiesonlyiftheydidnotappearinmulti‐citystudies.Forcitiesnotincludedinamulti‐citystudysummaryresult,weselected,inorderofpriority:

(i) themostrecentlypublished(ii) themostrecentstudytimeperiod.

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ListofcountriesbyWHORegionandmortalitystrataReproducedfromTheWorldHealthReport2002(http://www.who.int/whr/2002/en/,accessed7thFebruary2015)

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TableS1:Randomeffectsestimatesforthepercentageincreaseincausespecificmortality*inallagesassociatedwitha10µg/m3increaseinNO2WHOregion

NO224hour NO21hour

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

Cardiacmortality,allages

Overalle 12/4 4/2 1.00(0.36,1.66) 79.1 2/1 1/1 0.19(0.00,0.39) 0AMRA 3/0 3/0 0.73(0.50,0.97) ‐ ‐ EURA 4/4 2/2 1.23(‐0.66,3.15) 1/1 0/1 0.20(0.00,0.40)WPRA 1/0 1/0 ‐0.80(‐2.81,1.25) 1/0 1/0 ‐0.02(‐1.04,1.01)WPRB 4/0 3/0 1.76(1.22,2.31) ‐ ‐ Ischaemicheartdisease,allages

Overalle 5/0 3/0 1.61(0.24,2.99) 0 Noestimates EURA 2/0 2/0 2.38(‐1.39,6.30) SEARB 1/0 1/0 1.50(‐0.70,3.75) WPRB 2/0 2/0 1.49(‐0.46,3.47) Strokemortality,allages

Overalle 16/1 4/1 1.35(0.74,1.97) 50.5

Noestimates EURA 2/1 2/1 2.47(0.66,4.31) SEARB 1/0 1/0 2.80(0.70,4.94) WPRA 1/0 1/0 0.78(0.16,1.41) WPRB 12/0 6/0 1.34(0.80,1.89) COPDincludingasthmamortality,allagesf

Overalle 12/0 4/0 1.11(0.72,1.50) 0

Noestimates AMRA 3/0 3/0 1.07(0.59,1.55) EURA 3/0 2/0 4.19(‐3.44,12.42) SEARB 1/0 1/0 ‐1.40(‐5.00,2.34) WPRB 5/0 2/0 1.25(0.56,1.94)

*Insufficientestimatesformeta‐analysisofmortalitycombinationsforheartfailureanddysrhythmiaa‐Numbersofsingle‐city(SC)/multi‐city(MC)estimatesavailablefromallstudiesb‐Numbersofsingle‐city(SC)/multicity(MC)estimatesselectedformeta‐analysisc‐Randomeffectssummaryestimate(95%confidenceinterval)per10μg/m3increaseinNO2d‐I2statisticforheterogeneitybetweenWHOregionse‐Estimatenumbersfor‘Overall’referto:(i)thenumberofsingle‐city(SC)/multi‐city(MC)estimatesavailablefromallstudies;(ii)forselectedestimates,itisthenumberofpooled(fromsingle‐cityestimates)andmulti‐cityestimatesusedtocalculatetheoverallsummaryestimateacrossWHOregionsf–noestimatesforCOPDmortalityinallagesareavailableformeta‐analysisAMR,RegionoftheAmericas;EUR,EuropeanRegion;SEAR,SouthEastAsianRegion;WPR,WesternPacificRegion.

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TableS2:Randomeffectsestimatesforthepercentageincreaseinrespiratoryhospitaladmissionsper10µg/m3increaseinNO2WHOregion NO224hour NO21hour

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

Allrespiratory,allages

Overalle 19/3 5/2 0.57(0.33,0.82) 0 6/0 3/0 0.34(‐0.02,0.70) 76AMRA 1/1 1/1 0.61(0.13,1.09) ‐ ‐ ‐EURA 8/2 4/1 0.52(0.09,0.95) 3/0 3/0 0.21(0.07,0.36)SEARD 1/0 1/0 0.40(‐0.80,1.61) ‐ ‐ ‐WPRA 1/0 1/0 0.96(‐0.41,2.34) 2/0 2/0 ‐0.13(‐0.99,0.74)WPRB 8/0 6/0 0.58(0.16,1.01) 1/0 1/0 0.63(0.37,0.89)Allrespiratory,elderly

Overalle 16/1 4/1 0.69(0.17,1.21) 53.8 6/2 2/2 0.63(‐0.01,1.27) 82.7AMRA 3/0 2/0 1.43(0.45,2.42) ‐ ‐ ‐EURA 7/1 2/1 0.17(‐0.43,0.78) 4/1 1/1 0.15(‐0.25,0.56)WPRA 2/0 2/0 ‐1.12(‐8.86,7.28) 1/1 0/1 1.42(0.79,2.06)WPRB 4/0 2/0 0.93(0.61,1.24) 1/0 1/0 0.89(0.00,1.79)Allrespiratory,children

Overalle 14/4 4/2 1.20(0.35,2.05) 86.1 7/3 3/1 1.16(0.28,2.04) 94.6AMRA 1/0 1/0 4.69(1.88,7.57) ‐ ‐ ‐AMRB 5/0 1/0 0.79(0.41,1.18) 1/0 1/0 0.19(0.00,0.39)EURA 5/1 1/1 0.18(‐0.12,0.48) 2/0 2/0 0.33(0.03,0.62)WPRA 0/3 0/1 5.95(1.74,10.33) 2/3 0/1 2.70(0.93,4.51)WPRB 3/0 2/0 2.91(1.14,4.71) 2/0 1/0 2.37(1.79,2.96)Asthma,childrenf

Overalle 17/4 4/3 1.27(0.28,2.27) 86.5

8/3 1/2 0.37(‐0.08,0.82) 0AMRB 1/0 1/0 ‐0.40(‐1.00,0.20) ‐ ‐ ‐EURA 7/2 2/2 1.72(‐0.36,3.83) 5/1 2/1 0.38(‐0.18,0.94)WPRA 3/2 1/1 5.87(2.23,9.65) 3/2 0/1 1.50(‐1.28,4.37)WPRB 6/0 2/0 1.33(0.52,2.15) ‐ ‐ ‐COPDincludingasthma,elderlyg

Overalle 8/0 3/0 1.42(1.07,1.76) 30.8 1/1 1/1 0.63(0.18,1.07) 14.8AMRA 4/0 4/0 1.28(0.99,1.58) ‐ ‐ ‐EURA 3/0 2/0 3.14(0.76,5.58) 1/0 1/0 0.51(0.09,0.92)WPRA ‐ ‐ ‐ 0/1 0/1 1.05(0.16,1.95)WPRB 1/0 1/0 1.52(1.09,1.95) ‐ ‐ ‐COPD,allagesh

Overalle 6/2 2/2 1.24(‐0.01,2.50) 93.4 3/1 0/1 0.26(0.06,0.46) ‐AMRA 1/0 1/0 0.45(‐0.38,1.29) ‐ ‐ ‐EURA 4/2 0/2 0.81(0.03,1.59) 3/1 0/1 0.26(0.06,0.46)WPRB 1/0 1/0 2.60(2.20,3.00) ‐ ‐ ‐

a‐Numbersofsingle‐city(SC)/multi‐city(MC)estimatesavailablefromallstudiesb‐Numbersofsingle‐city(SC)/multicity(MC)estimatesselectedformeta‐analysisc‐Randomeffectssummaryestimate(95%confidenceinterval)per10μg/m3increaseinNO2d‐I2statisticforheterogeneitybetweenWHOregionse‐Estimatenumbersfor‘Overall’referto:thenumberofsingle‐city(SC)/multi‐city(MC)estimatesavailablefromallstudies;(ii)forselectedestimates,itisthenumberofpooled(fromsingle‐cityestimates)andmulti‐cityestimatesusedtocalculatetheoverallsummaryestimateacrossWHOregionsf–insufficientestimatesformeta‐analysisofasthmahospitalisationinadultsandelderly.g–insufficientestimatesformeta‐analysisofCOPD(includingasthma)hospitalisationinallagesfor24hourNO2andnonefor1hourNO2h‐insufficientestimatesformeta‐analysisofCOPDhospitalisationintheelderly.AMR,RegionoftheAmericas;EUR,EuropeanRegion;SEAR,SouthEastAsianRegion;WPR,WesternPacificRegion.

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TableS3:Randomeffectsestimatesforthepercentageincreaseincardiovascularhospitaladmissionsper10µg/m3increaseinNO2

WHOregion

NO224hour NO21hour

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

Allcardiovascular,allages

Overalle 6/3 3/2 0.66(0.32,1.01) 87.8 6/0 3/0 0.36(‐0.16,0.89) 43.9EURA 1/3 1/2 0.42(0.23,0.62) 3/0 3/0 0.19(0.04,0.33)WPRA 1/0 1/0 1.96(0.65,3.30) 2/0 2/0 0.01(‐1.33,1.36)WPRB 4/0 3/0 1.00(0.75,1.24) 1/0 1/0 1.00(0.16,1.84)Allcardiovascular,elderly

Overalle 5/3 2/2 1.54(0.75,2.35) 86.9 5/0 3/0 0.49(‐0.25,1.24) 0EURA 1/2 1/1 1.02(0.08,1.97) 2/0 2/0 1.19(‐0.73,3.15)WPRA 1/1 0/1 3.08(2.15,4.01) 2/0 2/0 0.17(‐1.19,1.55)WPRB 3/0 2/0 1.18(0.88,1.48) 1/0 1/0 0.47(‐0.52,1.47)Cardiac,allages

Overalle 6/5 4/3 1.10(0.76,1.43) 84.3 3/2 ½ 0.98(0.43,1.54) 79.4AMRA 1/0 1/0 0.73(0.53,0.94) 0/1 0/1 1.34(0.89,1.79)EURA 3/5 2/3 0.93(0.66,1.20) 2/0 2/0 0.36(‐0.14,0.86)WPRA 1/0 1/0 2.26(1.57,2.94) 1/1 0/1 1.21(0.84,1.58)WPRB 1/0 1/0 1.20(0.70,1.70) ‐ ‐ ‐Cardiac,elderly

Overalle 8/3 2/2 1.65(1.02,2.29) 74.3 3/1 2/1 1.44(0.71,2.18) 64.2AMRA 4/0 4/0 1.31(1.04,1.57) 1/0 1/0 0.29(‐0.89,1.49)EURA 3/2 2/1 1.54(0.97,2.10) 1/0 1/0 2.02(1.22,2.82)WPRA 1/1 0/1 3.49(1.95,5.05) 1/1 0/1 1.58(1.16,2.00)Heartfailure,allages

Overalle 4/1 3/1 1.41(‐0.01,2.86) 84.7 Noestimates AMRA 2/0 2/0 1.20(‐0.13,2.55) EURA 1/1 1/1 0.41(‐0.64,1.47) WPRB 1/0 1/0 4.40(2.50,6.34) Heartfailure,elderly

Overalle 2/2 1/2 1.99(0.54,3.46) 79.8 8/1 1/1 0.51(0.13,0.89) ‐AMRA 2/1 2/1 1.56(0.80,2.32) 8/1 7/1 0.51(0.13,0.89)WPRA 0/1 0/1 7.08(2.26,12.13) ‐ ‐ ‐Ischemicheartdisease,allages

Overalle 16/4 4/2 0.86(0.52,1.20) 0 1/1 1/1 1.06(0.58,1.54) 0AMRA 3/0 2/0 1.34(0.17,2.52) ‐ ‐ ‐EMRB 1/0 1/0 0.62(0.26,0.98) ‐ ‐ ‐EURA 7/4 2/2 0.96(0.25,1.68) 1/0 1/0 1.11(‐0.04,2.27)WPRA ‐ ‐ ‐ 0/1 0/1 1.05(0.52,1.58)WPRB 5/0 3/0 0.90(‐0.08,1.89) ‐ ‐ ‐Ischemicheartdisease,elderly

Overalle 7/4 3/2 2.42(1.71,3.13) 0 3/1 2/1 0.70(0.17,1.22) 57.8AMRA 2/0 2/0 2.18(‐0.63,5.08) ‐ ‐ ‐AMRB ‐ ‐ ‐ 1/0 1/0 0.51(‐0.69,1.71)EURA 4/2 2/1 2.28(1.34,3.22) 2/0 2/0 0.44(0.15,0.73)WPRA 0/2 0/1 2.56(1.03,4.12) 0/1 0/1 1.16(0.58,1.74)WPRB 1/0 1/0 2.79(1.06,4.55) ‐ ‐ ‐Stroke,allages

Overalle 10/3 3/2 0.30(0.02,0.57) 0 Noestimates AMRA 3/0 2/0 0.27(‐0.06,0.61) EURA 4/3 4/2 0.28(‐0.51,1.07) WPRB 3/0 2/0 0.66(‐0.32,1.65) Stroke,elderly

Overalle 2/1 2/1 0.26(‐0.48,1.01) 0 1/2 1/2 0.50(‐0.54,1.56) 58.3AMRA 1/0 1/0 ‐0.11(‐1.45,1.24) 0/2 0/2 0.91(‐0.12,1.94)EURA 1/1 1/1 0.43(‐0.46,1.33) 1/0 1/0 ‐0.16(‐1.05,0.72)

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TableS3(continued):Randomeffectsestimatesforthepercentageincreaseincardiovascularhospitaladmissionsper10µg/m3increaseinNO2

WHOregion

NO224hour NO21hour

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

AllSC/MCa

SelectedSC/MCb

RandomEffects(95%CI)c

I2(%)d

Dysrhythmia,allages

Overalle 3/1 2/1 0.50(0.15,0.86) 0 Noestimates AMRA 2/0 2/0 0.49(‐0.14,1.12) EURA 1/1 1/1 0.51(0.08,0.94) Dysrhythmia,elderly

Overalle 2/1 2/1 1.73(0.16,3.33) 26.9 Noestimates AMRA 1/0 1/0 1.82(‐0.05,3.74) EURA 1/0 1/0 3.65(0.56,6.84) WPRA 0/1 0/1 0.41(‐1.84,2.72)

a‐Numbersofsingle‐city(SC)/multi‐city(MC)estimatesavailablefromallstudiesb‐Numbersofsingle‐city(SC)/multicity(MC)estimatesselectedformeta‐analysisc‐Randomeffectssummaryestimate(95%confidenceinterval)per10μg/m3increaseinNO2d‐I2statisticforheterogeneitybetweenWHOregionse‐Estimatenumbersfor‘Overall’referto:(i)thenumberofsingle‐city(SC)/multi‐city(MC)estimatesavailablefromallstudies;(ii)forselectedestimates,itisthenumberofpooled(fromsingle‐cityestimates)andmulti‐cityestimatesusedtocalculatetheoverallsummaryestimateacrossWHOregionsAMR,RegionoftheAmericas;EUR,EuropeanRegion;SEAR,SouthEastAsianRegion;WPR,WesternPacificRegion.

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FigureS1:Forestplotofstudiesandestimatesselectedformeta‐analysisforall‐causemortality,allages,24houraverageNO2.1

                                                            1RMIDreferstotheReferenceIDforeachstudyinourReferenceManagerdatabase.AccessIDreferstoanIDgiventoeachestimateextractedfromastudyandenteredinourMicrosoftAccessdatabase.TheestimatefromRMID1494inFigureS1wassourcedfromTable1(page7‐33)oftheTechnicalSupportDocumentbytheCaliforniaEnvironmentalProtectionAgency(2007)becausetheestimatewasonlypresentedgraphicallyinRMID1494.

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FigureS2:Forestplotofstudiesandestimatesselectedformeta‐analysisforall‐causemortality,allages,1houraverageNO2.

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FigureS3:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularmortality,allages,24houraverageNO2.

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FigureS4:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularmortality,allages,1houraverageNO2.

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FigureS5:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratorymortality,allages,24houraverageNO2.

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FigureS6:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratorymortality,allages,1houraverageNO2.

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FigureS7:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiacmortality,allages,24houraverageNO2.

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FigureS8:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseasemortality,allages,24houraverageNO2.

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FigureS9:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokemortality,allages,24houraverageNO2

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FigureS10:Forestplotofstudiesandestimatesselectedformeta‐analysisforCOPDincludingasthmamortality,allages,24houraverageNO2

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FigureS11:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,allages,24houraverageNO2

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FigureS12:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,allages,1houraverageNO2

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FigureS13:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,elderly,24houraverageNO2

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FigureS14:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,elderly,1houraverageNO2

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FigureS15:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,children,24houraverageNO2

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FigureS16:Forestplotofstudiesandestimatesselectedformeta‐analysisforallrespiratoryhospitaladmissions,children,1houraverageNO2

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FigureS17:Forestplotofstudiesandestimatesselectedformeta‐analysisforasthmahospitaladmissions,children,24houraverageNO2

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FigureS18:Forestplotofstudiesandestimatesselectedformeta‐analysisforasthmahospitaladmissions,children,1houraverageNO2

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FigureS19:Forestplotofstudiesandestimatesselectedformeta‐analysisforCOPDincludingasthmahospitaladmissions,elderly,24houraverageNO2

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FigureS20:Forestplotofstudiesandestimatesselectedformeta‐analysisforCOPDhospitaladmissions,allages,24houraverageNO2

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FigureS21:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,allages,24houraverageNO2

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FigureS22:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,allages,1houraverageNO2

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FigureS23:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,elderly,24hoursaverageNO2

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FigureS24:Forestplotofstudiesandestimatesselectedformeta‐analysisforallcardiovascularhospitaladmissions,elderly,1houraverageNO2

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FigureS25:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,allages,24houraverageNO2

36  

FigureS26:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,allages,1houraverageNO2

37  

FigureS27:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,elderly,24houraverageNO2

38  

FigureS28:Forestplotofstudiesandestimatesselectedformeta‐analysisforcardiachospitaladmissions,elderly,1houraverageNO2

39  

FigureS29:Forestplotofstudiesandestimatesselectedformeta‐analysisforheartfailurehospitaladmissions,allages,24houraverageNO2

40  

FigureS30:Forestplotofstudiesandestimatesselectedformeta‐analysisforheartfailurehospitaladmissions,elderly,24houraverageNO2

41  

FigureS31:Forestplotofstudiesandestimatesselectedformeta‐analysisforheartfailurehospitaladmissions,elderly,1houraverageNO2

42  

FigureS32:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseasehospitaladmissions,allages,24houraverageNO2

43  

FigureS33:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseaseadmissions,elderly,24houraverageNO2

44  

FigureS34:Forestplotofstudiesandestimatesselectedformeta‐analysisforischaemicheartdiseaseadmissions,elderly,1houraverageNO2

45  

FigureS35:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokeadmissions,allages,24houraverageNO2

46  

FigureS36:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokeadmissions,elderly,24houraverageNO2

47  

FigureS37:Forestplotofstudiesandestimatesselectedformeta‐analysisforstrokeadmissions,elderly,1houraverageNO2

EstimatesfromRMID1929inFigureS37relatetotwotypesofstroke(hemorrhagicandischemic)

48  

FigureS38:Forestplotofstudiesandestimatesselectedformeta‐analysisfordysrhythmiahospitaladmissions,allages,24houraverageNO2

49  

FigureS39:Forestplotofstudiesandestimatesselectedformeta‐analysisfordysrhythmiahospitaladmissions,elderly,24houraverageNO2

50  

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