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Does Long-term Exposure to Traffic-Related Particulate Matter Air Pollution Increase the Risk of Coronary… Adibi, Mohammad Amin 2016-12-13

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	SPPH	502:	Epidemiology	Methods	I	Major	Written	Assignment	Does	Long-term	Exposure	to	Traffic-Related	Particulate	Matter	Air	Pollution	Increase	the	Risk	of	Coronary	Artery	Disease?	Adibi,	Mohammad	Amin		December	13,	2016	*Final	Word	Count:	3360	(Excludes	cover	page	and	references)Adibi,	Mohammad	Amin		 2	Introduction:	Traffic-related	 air	 pollution	 levels	 have	 consistently	 been	 associated	 with	 increased	 overall	mortality	and	morbidity	 (1).	Effects	of	exposure	to	particulate	matter	 (PM)	on	the	heart	have	been	 of	 particular	 interest,	 as	 the	 elevation	 of	 fine	 particulates	 (PM2.5)	 has	 shown	 strongest	association	with	 increased	risk	of	myocardial	 infarction	 (2),	as	well	as	 ischemic	cardiovascular	disease	(1),	possibly	via	accelerated	atherosclerosis	(3).	The	 objective	 of	 this	 paper	 is	 to	 gather	 currently	 available	 evidence	 on	 whether	 long-term	exposure	 to	 elevated	 traffic-related	 PM2.5	 increases	 the	 risk	 of	 developing	 coronary	 artery	diseases,	as	measured	through	indicators	of	atherosclerosis.	The	population	of	interest	is	urban	adults	who	are	not	diagnosed	with	cardiovascular	disease.	Since	the	entire	urban	population	is	exposed	to	at	least	some	level	of	PM2.5,	comparisons	were	made	between	individuals	who	were	exposed	to	different	levels	of	PM2.5	on	a	continuous	scale.		Methods	Literature	Search	Strategy	A	 search	 of	 three	 databases	 (MEDLINE	 through	 PubMed,	 Embase	 and	 Google	 Scholar)	 was	performed	 using	 multiple	 combinations	 of	 keywords	 “air	 pollutants,”	 “particulate	 matter,”	“coronary	 artery	 disease,”	 and	 “atherosclerosis”.	 In	 PubMed,	 the	 following	MeSH	 query	was	used:	(Air	Pollutants	OR	Particulate	Matter)	AND	(Coronary	Artery	Disease	OR	Atherosclerosis).	Results	were	limited	to	full-text	human	studies	published	in	English.	Due	to	recent	advances	in	pollution	measurement	techniques,	publications	older	than	five	years	were	excluded.	Selection	Criteria	for	Three	Studies	to	Appraise	in	Full	Based	on	previously	established	PICO	criteria,	reviewed	studies	were	further	limited	to	those	that	included	PM2.5	as	an	exposure	and	at	the	very	least	reported	carotid	intima-media	thickness	or	coronary	artery	calcification	as	clinical	outcomes.	Preference	was	given	to	studies	that	reported	more	 clinical	 outcomes,	 included	 larger	 sample	 sizes,	 and	 were	 published	 in	 higher	 impact	journals.	The	Inclusion	of	diverse	pollution	exposure	data,	representative	of	both	developing	and	industrial	countries	was	also	a	major	consideration.		Adibi,	Mohammad	Amin		 3	Assessment	of	Selected	Studies	Full-texts	of	selected	studies	were	evaluated	individually	and	assessed	based	on	a	multitude	of	factors,	 including	 study	 design,	 the	 population,	 exposures	 and	 how	 exposures	 were	measured/estimated,	outcomes,	results,	and	limitations.	In	doing	that,	The	Public	health	critical	appraisal	checklist	previously	by	Heller	et	al.	(4)	was	used	as	a	guideline.			Results	Synthesis	of	the	Literature	Search	and	Summary	of	Evidence	Initially,	 a	 total	 of	 53	 studies	 were	 identified	 and	 further	 analyzed	 in	 Excel.	 Abstracts	 were	screened	and	articles	related	to	other	conditions	(11/53,	21%),	effects	of	smoking	(9/53,	17%),	acute	effects	(n=2/53,	4%),	and	non-clinical	studies	(4/53,	8%),	as	well	as	review	articles	(4/53,	8%)	and	commentaries	(4/53,	8%)	were	excluded.	Abstracts	of	the	remaining	18	articles	were	further	reviewed	to	select	three	papers	to	appraise	in	full.			Abstracts	of	included	studies	(n=18)	were	examined	further	and	studies	focused	on	exposures	other	than	PM2.5	(n=4),	biomarker	outcomes	(n=3),	racial	and	socioeconomic	differences	(n=2),	and	measurement	methods	 (n=2)	were	excluded.	 Table	1	 shows	 the	 list	of	 studies	 that	were	excluded	after	an	examination	of	abstracts	and	reasons	for	exclusion	of	each.		included	 abstracts	 are	 presented	 in	 Table	 2.	 Overall,	 the	 abstracts	 suggest	 an	 association	between	exposure	to	traffic-related	pollution,	as	measured	through	proximity	to	roadways	or	levels	 of	 PM2.5,	 PM10,	 or	 NOx,	 and	 progression	 of	 subclinical	 coronary	 artery	 disease	 as	demonstrated	through	elevated	biomarker	levels	or	progression	of	atherosclerosis	indicators.	Selected	Studies	Based	on	the	criteria	outlined	in	the	Methods	section,	the	cross-sectional	study	by	Su	et	al.	(5),	and	 the	 prospective	 cohorts	 by	 Adar	 et	 al.	 (6),	 and	 Kaufman	 et	 al.	 (7)	were	 selected	 for	 full	appraisal.	The	first	study	is	cross-sectional,	and	provides	evidence	in	high	pollution	context	of	an	Asian	metropolitan	area.	The	studies	by	Adar	et	al.,	and	Kaufman	et	al.,	are	both	prospective	cohorts	with	large	and	ethnically-diverse	population	samples.	All	studies	have	been	published	in	high	impact	journals	and	met	exposure	and	outcome	specifications	set	in	the	Methods	section.	Specifications	of	these	three	studies	have	been	outlined	in	Table	3.		 4		Table	1 Excluded	abstracts	and	reasons	for	exclusion	Study	 Journal	 IF	 Design	 Reason	for	Exclusion	Ghosh	et	al.	(2016)	 Environ	Health	Perspect.	 8.4	 Modelling	 Outcome:	The	burden	of	near	roadway	air	pollution	using	mathematical	modelling.		Jones	et	al.	(2015)	 J	Epidemiol	Community	Health.			 3.2	 Cross-Sectional	(n=6347)	 Focused	on	the	effect	of	race.	Wu	et	al.	(2015)	 Chemosphere	 3.1	 Prospective	Cohort	(n=40)	 Outcome:	Biomarkers	of	oxidative	stress.		Hajat	et	al.	(2015)	 Epidemiology	 6.1	 Prospective	Cohort	(n=6814)	 Outcome:	Biomarkers.		Leary	et	al.	(2014)	 Am	J	Respir	Crit	Care	Med.			 13.1	 Prospective	Cohort	(n=3896)	 Exposure:	NO2.		Outcome:	right	ventricle	function.		Kälsch	et	al.	(2014)	 Eur	Heart	J.	 15.2	 Retrospective	Cohort	(n=4238)	 Outcome:	thoracic	aortic	calcification.	Hajat	et	al.	(2013)	 Environ	Health	Perspect.			 8.4	 Prospective	Cohort	(n=6140)	 Focused	on	the	effect	of	socioeconomic	status.	Rivera	et	al.	(2013)	 Environ	Health	Perspect.			 8.4	 Cross-Sectional	(n=2780)	 Exposure:	NO2.	Kaufman	et	al.	(2012)	 Am.	J.	Epidemiol.	 5.5	 Methods	Paper	 Methods	Paper.	Allen	et	al.	(2012)	 Environ	Health	Perspect.			 8.4	 Methods	Paper	 Methods	Paper.	Tonne	et	al.	(2012)	 Epidemiology	 6.1	 Retrospective	Cohort	(n=2348) Exposure:	PM10.		Table	2	Final	included	abstracts	Study	 Journal	 IF	 Design	 Exposures	 Outcomes	 Notes	Kaufman	et	al.	(2016)		 Lancet	 45.2	 Prospective	Cohort	(n=6795)	 PM2.5,	NOX,	Black	Carbon	 CAC,	CIMT	 US	Data:	MESA	Air	McGuinn	et	al.	(2016)	 Environ	Res.			 3.1	 Retrospective	Cohort	(n=5679)	 PM2.5	 CAD	Index	 US	Data:	Duke	Univ.	Su	et	al.	(2015)	 Environ	Health	Perspect.	 8.4	 Cross-Sectional	(n=689)	 PM2.5,	PM10,	NOX	 CIMT	 Taiwan	Data	Kim	et	al.	(2014)	 Am.	J.	Epidemiol.	 5.5	 Cross-Sectional	(n=5488)	 PM2.5	Chemistries	 CIMT	 US	Data:	MESA		Sun	et	al.	(2013)	 Environ.	Health.	 2.7	 Cross-Sectional	(n=6256)	 PM2.5	 CAC,	CIMT	 US	Data:	MESA	Adar	et	al.	(2013)	 PLoS	Med.	 13.6	 Prospective	Cohort	(n=5276)	 PM2.5	 CIMT	 US	Data:	MESA	Krishnan	et	al.	(2012)	 J	Am	Coll	Cardiol.	 17.8	 Prospective	Cohort	(n=3040)	 PM2.5	 FMD,	BAD	 US	Data:	MESA	IF:	Impact	Factor.	CAC:	Coronary	Artery	Calcium.	CIMT:	Carotid	Intima-Media	Thickness.	CAD:	Coronary	Artery	Disease.	FMD:	Flow-Mediated	Dilation.	BAD:	Baseline	Arterial	Diameter.	MESA:	The	Multi-Ethnic	Study	of	Atherosclerosis	and	Air	Pollution.	Adibi,	Mohammad	Amin		 5	Table	3	Characteristics	of	the	Three	Selected	Studies		 Su	et	al.	(2015)(5)	 Adar	et	al.	(2013)(6)	 Kaufman	et	al.	(2016)(7)	Study	Design		 Cross-Sectional	 Prospective	Cohort		 Prospective	Cohort	(10	years)	(n=6795)	Primary	Objective	 To	evaluate	association	between	CIMT	and	one-year	average	exposure	to	traffic-related	pollution		To	examine	associations	between	long-term	PM2.5	concentrations	and	the	progression	of	atherosclerosis		To	assess	association	between	long-term	exposure	to	ambient	air	pollution	and	progression	of	coronary	artery	calcium	and	CIMT.		Population	 35–65	years	old	adults	without	diagnosis	of	coronary	heart	disease,	cerebrovascular	disease,	and	heart	failure,	who	had	volunteered	for	a	case-control	cardiovascular	study	(n=689).	MESA	participants	with	CIMT	measurements	in	the	first	three	clinical	visits	(n=5276).	MESA	study	composed	of	5660	adults	aged	45–84	without	clinical	cardiovascular	disease,	from	four	ethnic	groups	(Hispanic,	black,	white,	and	Chinese)	recruited	from	six	locations	across	US.		MESA	participants	plus	257	additional	recruitment	from	three	new	locations	to	add	heterogeneity	in	pollution	exposures.		Exposure	 PM2.5,	PM2.5sbs,	PM10,	NO2,	and	NOX,	as	estimated	using	regression	models	developed	by	the	European	Study	of	Cohorts	for	Air	Pollution	Effects	(ESCAPE)(8)	PM2.5	as	measured	for	each	participant	using	regressions	based	on	monitoring	stations	data	and	study-specific	air	samples	collected	outside	the	homes	and	in	the	communities	of	participants	PM2.5,	NOX,	and	Black	Carbon,	measured	using	regressions	based	on	27	long-term	sites,	771	community	snapshot	locations,	and	outside	697	participants’	homes	in	addition	to	EPA	monitors.	Outcome	 Carotid	Intima-Media	Thickness	 Carotid	Intima-Media	Thickness	 Coronary	Artery	Calcium	and	Carotid	Intima-Media	Thickness	Main	Results	 Average	percentage	increased	in	maximum	left	CIMT	was	4.23%	(95%	CI:	0.32,	8.13)	per	10-µg	/m3	increase	in	PM2.5abs;	3.72%	(95%	CI:	0.32,	7.11)	per	10-µg/m3	increase	in	PM10;	2.81%	(95%	CI:	0.32,	5.31)	per	20-µg/m3	increase	in	NO2;	and	0.74%	(95%	CI:	0.08,	1.41)	per	10-µg/m3	increase	in	NOx.	The	associations	were	not	evident	for	right	CIMT,	and	black	carbon	was	not	associated	with	the	outcomes.	Higher	average	levels	of	residential	PM2.5	were	associated	with	increased	CIMT	progression	among	people	living	in	the	same	metropolitan	area	after	adjusting	for	smoking	and	age.	Each	2.5	mg/m3	increase	in	PM2.5	levels,	was	associated	with	5.0	mm/year	greater	CIMT	progression	when	compared	to	people	living	in	less	polluted	regions	of	the	same	metropolitan	area.	Pollutant	exposures	were	associated	with	coronary	calcium,	but	not	intima-media	thickness	change.	For	each	5	µg	PM2.5/m³	increase,	coronary	calcium	progressed	by	4.1	(95%	CI	1·4–6·8)	Agatston	units	per	year.	The	estimate	for	the	effect	of	a	5	µg/m³	higher	long-term	exposure	to	PM2.5	in	intima-media	thickness	was	–0.9	µm	(95%	CI	–3.0	to	1.3)	per	year			EPA:	Environmental	Protection	Agency.		CIMT:	Carotid	Intima-Media	Thickness.	 6	Individual	Study	Assessments	The	following	sections	discuss	individual	study	assessments.	Although	some	of	the	studies	included	several	exposures,	discussions	here	will	be	limited	to	exposure	of	interest,	PM2.5,	and	its	black	carbon	component.		Study	1:	Su	et	al.	(2015)	The	2015	study	by	Su	and	colleagues	(5)	reported	the	cross-sectional	association	between	long-term	exposure	to	PM2.5	and	carotid	intima-media	thickness.	The	study	used	previously	developed	land-use	regression	models	(8)	to	estimate	one-year	average	exposure	for	individuals.	A	separate	measure	for	PM2.5	exposure	called	PM2.5abs	–	defined	as	absorbance	level	of	PM2.5	and	measured	through	an	evaluation	of	the	blackness	of	the	PM2.5	filter	–	was	also	measured.	The	study	found	no	 association	 between	 intima-media	 thickness	 and	 PM2.5	 levels	 but	 reported	 an	 average	increase	of	4.23%	(95%	CI:	0.32-8.13)	in	the	measurement	of	maximum	left	carotid	intima-media	thickness,	with	every	1x10-5/m	increase	in	PM2.5abs.	A	similar	significant	association,	however,	was	not	observed	for	right	carotid	artery	measurement.		The	 strength	 of	 the	 study	 is	 that	 it	 explores	 the	 relationship	 between	 pollution	 and	atherosclerosis	in	an	Asian	metropolitan	setting,	where	pollution	levels	are	consistently	higher	than	Western	European	or	North	American	cities.	Su	and	colleagues	report	an	estimated	average	annual	PM2.5	exposure	of	27.34	µg/m³,	which	 is	 almost	 three	 times	 recommended	air	quality	threshold	set	by	World	Health	Organization	(5).		The	study,	however,	suffers	 from	several	serious	biases.	The	enrollment	strategy	of	the	study	which	relied	on	volunteers	responding	to	an	advertisement	has	a	resulted	in	a	volunteer	bias,	evident	in	the	fact	that	72%	of	participants	are	men.	This	puts	the	external	validity	of	the	study	in	 question,	 as	 the	 sample	 does	 not	 seem	 to	 be	 representative	 of	 the	 general	 population	 in	Taiwan.	Another	limitation	is	the	lack	of	reporting	on	the	proportion	of	employed	participants,	especially	those	in	certain	occupations	that	are	associated	with	significantly	increased	exposure	to	pollution.		The	 analysis	 also	 seems	 to	 suffer	 from	 the	 Multiple	 Testing	 Problem.	 Instead	 of	 fitting	 the	regression	model	based	on	a	single	carotid	intima-media	thickness	score,	maximum,	mean,	and	Adibi,	Mohammad	Amin		 7	combined	scores	from	both	right	and	left	common	carotid	arteries	have	been	tested	individually.	While	every	single	one	of	these	measures	seems	to	be	a	reasonable	outcome,	multiple	testing	of	all	of	them	with	no	a	priori	physiological	justification	is	inappropriate,	and	could	result	in	finding	associations	by	chance.				Study	2:	Adar	et	al.	(2013)	In	2013,	Adar	and	colleagues	reported	early	results	from	MESA	Air,	a	prospective	cohort	study	of	PM2.5	 exposure	 and	 surrogate	 indicators	 of	 atherosclerosis	 in	 adults	 without	 pre-existing	cardiovascular	conditions(6).	In	their	analysis,	the	authors	used	mixed	models	to	show	that	a	2.5	µg/m³	 increase	 in	 PM2.5	 exposure	 was	 associated	 with	 5	 µm/y	 (95%	 CI:	 2.6-7.4)	 greater	progression	in	carotid	intima-media	thickness	among	participants	in	the	same	metropolitan	area.	The	model	adjusted	for	age,	gender,	ethnicity,	smoking	status	and	socio-economic	indicators	as	confounders.	No	significant	association	was	found	without	adjustment	for	the	metropolitan	area.		Strengths	of	the	study	include	prospective	cohort	design	that	allows	for	establishing	a	temporal	relationship	 between	 exposure	 and	 outcome,	 large	 sample	 size	 (n=5660),	 and	 estimation	 of	exposure	using	sophisticated	hierarchical	spatiotemporal	models.	The	authors	also	report	results	of	their	mixed	model	at	three	different	stages	of	development,	each	of	which	accounts	for	an	increasing	number	of	confounders.	The	transparency	in	systematic	reporting	of	results	from	all	stages	of	the	model	is	re-assuring,	as	it	shows	that	confounders	were	not	selectively	adjusted	for,	to	 produce	 the	 desired	 outcome.	 Further	 sensitivity	 analyses	 showed	 that	 the	 findings	were	robust	to	an	increasing	degree	of	control	for	an	extended	list	of	potential	confounders.	Likewise,	stratified	 analysis	 of	 subgroups	 (See	 Figure	 2	 in	 Adar	 et	 al.	 (6))	 showed	 no	 evidence	 of	confounding.		The	fact	that	each	site	used	a	different	recruitment	strategy	makes	a	systematic	enrollment	bias	less	 likely	 in	this	study,	although	 it	could	 introduce	bias	 in	centre-to-centre	comparisons.	One	shortcoming	 in	 the	 paper	 is	 that	 recruitment	 strategies	 are	 not	 spelled	 out	 in	 detail,	 which	prevents	the	proper	assessment	of	a	potential	selection	bias.		Adibi,	Mohammad	Amin		 8	Approximately	 94%	 of	 participants	 reached	 follow-up.	 Although	 the	 authors	 state	 that	 the	probability	of	being	lost	to	follow-up	was	unrelated	to	baseline	outcome	measures,	it	is	unclear	whether	this	has	been	checked	or	whether	it	is	just	being	assumed.		Study	3:	Kaufman	et	al.	(2016)	Results	of	the	MESA	Air	study	were	published	in	Lancet	in	early	2016(7).	In	the	largest	and	longest	study	 of	 its	 kind	 to	 date,	 6795	 subjects	 aged	 45-84	 years	 old	 were	 followed	 in	 a	 10-year	prospective	cohort.	Pollution	exposures	were	measured	at	27	long-term	monitoring	sites,	771	snapshot	 locations	within	communities,	and	outside	697	participants’	residences.	 	 Individually	resolved	 exposures	 were	 then	 estimated	 using	 community-specific	 spatiotemporal	 models.	Lifestyle	questionnaires,	together	with	meteorology	and	outdoor	particulate	tracers	were	used	to	 calculate	 PM2.5iwa,	 a	 separate	 exposure	 variable	 for	 each	 participant	 that	 adjusted	 for	 the	proportion	of	time	spent	indoors.	Throughout	the	course	of	the	study,	coronary	artery	calcium	and	right	common	carotid	artery	intima-media	thickness	were	repeatedly	measured	in	subjects	using	 CT	 and	 ultrasound,	 respectively.	 Association	 between	 progression	 of	 these	 surrogate	atherosclerosis	markers	and	long-term	PM2.5	and	black	carbon	exposures	were	assessed	using	complex	regression	models	adjusting	for	baseline	age,	gender,	ethnicity,	socio-economic	status,	cardiovascular	risk	factors,	clinical	site	and	CT	scanner	technology.		The	study	reported	a	positive	correlation	between	an	increase	in	PM2.5	exposure	and	increased	rate	of	coronary	artery	calcium	progression.	A	5	µg/m³	increase	in	exposure	was	associated	with	4.1	 Agatston	 units	 per	 year	 (95%	 CI	 1.4–6.8)	 increased	 rate	 of	 coronary	 artery	 calcium	progression.	PM2.5	exposure,	however,	was	not	associated	with	increased	progression	of	carotid	intima-media	thickness,	as	a	5	µg/m³	increase	in	exposure	was	associated	with	a	–0.9	µm	per	year	(95%	CI	–3.0	to	1.3)	change	in	carotid	intima-media	thickness.	No	significant	association	was	found	 for	 either	 black	 carbon	 or	 PM2.5iwa,	 although	 the	 latter	may	 be	 due	 to	 limitations	 and	inaccuracies	in	estimating	PM2.5iwa.	Sensitivity	analyses	showed	results	to	be	robust	to	changes	in	stages	of	control	for	potential	confounder	variables.		The	MESA	Air	study	is	a	significant	addition	to	the	previous	body	of	evidence	on	the	association	of	 particulate	 matter	 pollution	 and	 atherosclerosis,	 which	 previously	 comprised	 of	 cross-Adibi,	Mohammad	Amin		 9	sectional	 and	 short-term	 cohort	 studies.	 The	 ten-year	 follow-up	 period	 of	 MESA	 Air	 and	 its	ethnically-representative	 population	 sample,	 as	 well	 as	 using	 sophisticated	 exposure	models	which	enabled	resolving	within-city	exposure	contrasts	at	unprecedented	levels,	are	amongst	its	main	strengths.		Developed	exposure	prediction	models	explained	an	 impressive	79%	of	 the	variation	of	PM2.5	exposure	 in	selected	participants’	homes	(model	 fit	R2=0.79,	with	95%	CI:	0.54-0.85).	Further,	geographical	distribution	of	participants’	homes	and	the	respective	predicted	pollutants	levels	are	visualized	efficiently	using	color	coded	city	maps	(See	Figure	2	in	Kaufman	et	al.	(7)).		Similar	 to	Study	2,	 the	study	was	carried	out	 in	six	different	centres	across	 the	US,	with	each	centre	 recruiting	participants	according	 to	community-specific	 logistics	and	experience.	While	using	centre-specific	enrollment	strategies	reduces	chances	of	facing	a	study-wide	selection	bias,	one	 must	 be	 careful	 in	 interpreting	 city	 to	 city	 differences,	 as	 they	 may	 be	 attributable	 to	differences	in	selection	strategies.			An	significant	limitation	of	the	study	is	lost	to	follow-up	and	potential	biases	caused	by	that.	As	the	 authors	 mention	 in	 the	 paper,	 carotid	 intima-media	 thickness	 analysis	 was	 limited	 to	participants	who	returned	for	ultrasound	scans;	a	population	that	was	found	to	be,	on	average,	two	years	younger,	more	educated	and	less	likely	to	be	diabetic	when	compared	with	those	who	were	included	in	coronary	calcium	analysis.	While	the	authors	mention	this	potential	source	of	bias	as	a	limitation,	they	fall	short	of	addressing	it.	Since	“age”	was	found	to	be	a	confounder	(See	Figure	4	in	Kaufman	et	al.	(7)),	it	is	possible	that	the	effect	of	exposure	on	intima-media	thickness	has	been	hampered	by	the	younger	age	of	participants.		Another	major	limitation	is	that	the	study	does	not	discuss	patients	who	have	been	lost	to	follow-up	due	to	incidents	of	cardiovascular	disease,	or	cardiovascular-related	death.	The	relatively	long	duration	 of	 study	 can	 potentially	 include	 transitions	 from	 subclinical	 to	 symptomatic	atherosclerosis	in	a	subset	of	the	participants	which	needs	to	be	accounted	for.	However,	this	type	of	bias	would	skew	results	towards	the	null	hypothesis	of	no	association.	Concluded	positive	associations	are	thereby	unaffected.		Adibi,	Mohammad	Amin		 10	Discussion	Synthesis	and	Summary	of	Evidence	The	three	appraised	studies	analyze	the	association	between	long-term	exposure	to	PM2.5	and	subclinical	atherosclerosis.	The	method	used	for	estimating	exposure	is	in	principle	similar	among	studies,	although	inside	city	differences	are	reflected	more	accurately	in	Study	2	and	Study	3.	The	method	 used	 to	 estimate	 exposures	 involves	 measuring	 pollution	 at	 the	 community	 level,	followed	by	developing	regressions	to	estimate	exposure	for	individuals.	The	levels	of	exposure	were	relatively	high	in	Study	1	(PM2.5	IQR:	23.67-30.45	µg/m³),	which	is	consistent	with	exposure	levels	in	many	developing	countries.	Exposure	levels	in	Study	2	(PM2.5	IQR:	14.12-19.08	µg/m³)	and	Study	3	(PM2.5	IQR:	12.9-15.7	µg/m³),	were	lower,	which	is	consistent	with	exposure	levels	in	advanced	economies.	For	comparison,	WHO	guidelines	recommend	a	maximum	annual	mean	PM2.5		exposure	of	10	µg/m³	(9).		While	Study	1	and	Study	2	use	carotid	intima-media	thickness	as	the	sole	surrogate	indicator	for	subclinical	 atherosclerosis,	 Study	3	 reports	both	 carotid	 intima-media	 thickness	 and	 coronary	artery	calcification.	Of	the	three	appraised	studies,	only	Study	2	found	a	significant	association	between	PM2.5	 and	 intima-media	 thickness.	 Such	 association,	 however,	was	not	 replicated	 in	Study	 3	 which	 had	 a	 larger	 sample	 size,	 a	 significantly	 longer	 follow-up,	 and	 an	 improved	exposure	measurement.	Study	1	found	no	association	between	PM2.5	exposure	and	intima-media	thickness	but	did	find	some	association	between	the	black	carbon	component	of	PM2.5	and	left	carotid	intima-media	thickness.	The	association,	however,	is	possibility	an	artifact	of	the	Multiple	Testing	Problem,	especially	as	it	was	not	present	for	the	left	carotid	artery,	and	was	not	replicated	in	 Study	 3.	However,	 Study	 3	 found	 a	 strong	 association	 between	PM2.5	 and	 coronary	 artery	calcium	progression,	which	was	robust	to	stratified	tests	and	sensitivity	analysis.		Although	 using	 carotid	 intima-media	 thickness	 as	 a	 surrogate	 indicator	 of	 atherosclerosis	 is	common	 in	 the	 literature	 (10),	 its	 usefulness	 has	 been	 questioned	 (11),	 especially	when	 the	progression	of	intima-media	thickness	is	being	studied	(12).	In	contrast,	both	presence	(13)	and	progression	(14)	of	calcium	plaques	in	coronary	arteries	are	known	to	be	a	predictor	of	ischemic	Adibi,	Mohammad	Amin		 11	vascular	events.	Coronary	artery	calcium	has	also	been	shown	to	be	a	much	stronger	predictor	of	coronary	disease	events	compared	with	intima-media	thickness	(15).		Overall,	it	seems	that	progression	in	coronary	artery	calcium	is	a	better	surrogate	indicator	for	atherosclerosis	 in	 cohort	 studies.	 Study	 3	 provides	 long-term	 prospective	 follow-up	 of	 an	extraordinarily	 well-characterized	 population	 regarding	 both	 exposure	 and	 potential	confounders	and	 is	 the	best	evidence	 in	the	area.	Study	3	 is	 the	first	 to	report	an	association	between	PM2.5	and	coronary	artery	calcium	progression,	and	its	results	provide	strong	biological	support	for	the	previously	observed	pollution-related	increase	in	cardiovascular	events.		Public	Health	and	Policy	Implications	A	 growing	 body	 of	 observational	 evidence	 suggests	 a	 strong	 relationship	 between	 long-term	exposure	 to	 traffic-related	 particulate	 pollutants	 and	 developing	 cardiovascular	 disease.	 The	findings	are	consistent	with	a	causal	relationship	between	traffic-related	pollution	and	the	risk	of	coronary	 artery	 disease,	 and	 support	 a	 global	 effort	 to	 reduce	 exposure	 to	 these	 pollutants,	especially	in	developing	countries	where	pollution	levels	have	been	particularly	high.		Conclusion	The	evidence	suggests	an	association	between	 increasing	particulate	pollution	and	subclinical	atherosclerosis,	demonstrated	through	an	increase	in	the	rate	of	progression	of	coronary	artery	calcium.	This	is	consistent	with	the	previous	knowledge	on	association	of	long-term	exposure	to	particulate	pollution	and	increased	risk	of	cardiovascular	events.	These	findings	add	to	the	body	of	evidence	for	a	causal	relationship	between	particulate	pollution	and	the	risk	of	cardiovascular	events	by	providing	evidence	of	biological	plausibility.			 	Adibi,	Mohammad	Amin		 12	References:	1.		 Brook	RD,	Franklin	B,	Cascio	W,	Hong	Y,	Howard	G,	Lipsett	M,	et	al.	Air	pollution	and	cardiovascular	disease:	A	statement	for	healthcare	professionals	from	the	expert	panel	on	population	and	prevention	science	of	the	American	Heart	Association.	Circulation.	2004;109(21):2655–71.		2.		 Hoek	G,	Krishnan	RM,	Beelen	R,	Peters	A,	Ostro	B,	Brunekreef	B,	et	al.	Long-term	air	pollution	exposure	and	cardio-	respiratory	mortality:	a	review.	Environ	Heal	[Internet].	2013;12(1):43.	Available	from:	3.		 Suwa	T,	Hogg	JC,	Quinlan	KB,	Ohgami	A,	Vincent	R,	Van	Eeden	SF.	Particulate	air	pollution	induces	progression	of	atherosclerosis.	J	Am	Coll	Cardiol.	2002;39(6):935–42.		4.		 Heller	RF,	Verma	A,	Gemmell	I,	Harrison	R,	Hart	J,	Edwards	R.	Critical	appraisal	for	public	health:	A	new	checklist.	Public	Health.	2008;122(1):92–8.		5.		 Su	TC,	Hwang	JJ,	Shen	YC,	Chan	CC.	Carotid	intima-media	thickness	and	long-term	exposure	to	traffic-related	air	pollution	in	middle-aged	residents	of	Taiwan:	A	cross-sectional	study.	Environ	Health	Perspect.	2015;123(8):773–8.		6.		 Adar	SD,	Sheppard	L,	Vedal	S,	Polak	JF,	Sampson	PD,	Diez	Roux	A	V.,	et	al.	Fine	Particulate	Air	Pollution	and	the	Progression	of	Carotid	Intima-Medial	Thickness:	A	Prospective	Cohort	Study	from	the	Multi-Ethnic	Study	of	Atherosclerosis	and	Air	Pollution.	PLoS	Med.	2013;10(4).		7.		 Kaufman	JD,	Adar	SD,	Barr	RG,	Budoff	M,	Burke	GL,	Curl	CL,	et	al.	Association	between	air	pollution	and	coronary	artery	calcification	within	six	metropolitan	areas	in	the	USA	(the	Multi-Ethnic	Study	of	Atherosclerosis	and	Air	Pollution):	A	longitudinal	cohort	study.	The	Lancet.	2016;		8.		 Lee	JH,	Wu	CF,	Hoek	G,	de	Hoogh	K,	Beelen	R,	Brunekreef	B,	et	al.	Land	use	regression	Adibi,	Mohammad	Amin		 13	models	for	estimating	individual	NOx	and	NO2	exposures	in	a	metropolis	with	a	high	density	of	traffic	roads	and	population.	Sci	Total	Environ.	2014;472:1163–71.		9.		 World	Health	Organization.	WHO	Air	quality	guidelines	for	particulate	matter,	ozone,	nitrogen	dioxide	and	sulfur	dioxide:	global	update	2005:	summary	of	risk	assessment.	Geneva	World	Heal	Organ	[Internet].	2006;1–22.	Available	from:	10.		 Lorenz	MW,	Markus	HS,	Bots	ML,	Rosvall	M,	Sitzer	M.	Prediction	of	clinical	cardiovascular	events	with	carotid	intima-media	thickness:	A	systematic	review	and	meta-analysis.	Circulation.	2007;115(4):459–67.		11.		 Den	Ruijter	HM,	Peters	SAE,	Anderson	TJ,	Britton	AR,	Dekker	JM,	Eijkemans	MJ,	et	al.	Common	carotid	intima-media	thickness	measurements	in	cardiovascular	risk	prediction:	a	meta-analysis.	JAMA	[Internet].	2012;308(8):796–803.	Available	from:	12.		 Lorenz	MW,	Polak	JF,	Kavousi	M,	Mathiesen	EB,	Völzke	H,	Tuomainen	T-P,	et	al.	Carotid	intima-media	thickness	progression	to	predict	cardiovascular	events	in	the	general	population	(the	PROG-IMT	collaborative	project):	a	meta-analysis	of	individual	participant	data.	Lancet	[Internet].	2012;379(9831):2053–62.	Available	from:	13.		 Sangiorgi	G,	Rumberger	JA,	Severson	A,	Edwards	WD,	Gregoire	J,	Fitzpatrick	LA,	et	al.	Arterial	calcification	and	not	lumen	stenosis	is	highly	correlated	with	atherosclerotic	plaque	burden	in	humans:	A	histologic	study	of	723	coronary	artery	segments	using	nondecalcifying	methodology.	J	Am	Coll	Cardiol.	1998;31(1):126–33.		14.		 McEvoy	JW,	Blaha	MJ,	Defilippis	AP,	Budoff	MJ,	Nasir	K,	Blumenthal	RS,	et	al.	Coronary	artery	calcium	progression:	an	important	clinical	measurement?	A	review	of	published	reports.	J	Am	Coll	Cardiol	[Internet].	2010;56(20):1613–22.	Available	from:	Adibi,	Mohammad	Amin		 14	15.		 Gepner	AD,	Young	R,	Delaney	JA,	Tattersall	MC,	Blaha	MJ,	Post	WS,	et	al.	Comparison	of	coronary	artery	calcium	presence,	carotid	plaque	presence,	and	carotid	intima-media	thickness	for	cardiovascular	disease	prediction	in	the	multi-ethnic	study	of	atherosclerosis.	Circ	Cardiovasc	Imaging	[Internet].	2015;8(1):e002262–e002262.	Available	from:		


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