View source for ERF of omega-3 fatty acids

[[Category:Health effects]]
[[Category:Fish]]
[[Category:Exposure-response functions]]
{{Variable|moderator=Olli}}

== Question ==

What is the exposure-response function '''([[ERF]]) of omega-3 fatty acids''' on several health end points?

== Answer ==

<rcode embed=1>
library(OpasnetUtils)

objects.latest("Op_en5830", code_name = "initiate") # [[ERF of omega-3 fatty acids]] ovariables ERF, threshold.

oprint(summary(EvalOutput(ERF_omega3)))

</rcode>

== Rationale ==

{{attack|# |This article should be checked:
* Is fish oil good for you? Depends on your DNA. Elizabeth Pennisi. Science 17 September 2015 [http://news.sciencemag.org/biology/2015/09/fish-oil-good-you-depends-your-dna]
|--[[User:Jouni|Jouni]] ([[User talk:Jouni|talk]]) 10:35, 7 October 2015 (UTC)}}

=== Data ===

<t2b index="Exposure agent,Response,Sex,Exposure,Exposure unit,ER function,Scaling,Observation" locations="Threshold,ERF" desc="Description" unit="-">
DHA|Change in child's IQ points||Maternal intake through placenta|mg /kg bw /day|ERS|BW|0|0.07 +- 0.01|Cohen et al. 2005; Gradowska 2013; Standard deviation
DHA|Change in child's IQ points||Maternal intake through placenta|mg /day|ERS|None|0|0.0013 (0.0008 - 0.0018)|Cohen et al. 2005; also according to Zeilmaker 2013
Omega3|Coronary heart disease mortality||Ingested intake of EPA+DHA from fish|mg /day|RR|None|0|0.9980 +- 0.000396|Mozaffarian and Rimm 2006; Gradowska 2013 slope = -0.002, SD = exp(-0.002)-exp(-0.002+3.97E-4)
Omega3|CHD arrythmia mortality||Ingested intake of EPA+DHA from fish|mg /day|Relative Hill|None|200|-0.3|Mozaffarian and Rimm 2006
Omega3|CHD2 mortality||Ingested intake of EPA+DHA from fish|mg /day|Relative Hill|None|47|-0.17 (-0.25 - -0.088)|Cohen et al 2005. "antiarrhythmic effect". No-exposure is <1 serving/mo, therefore ED50 = two servings per month = 1400 mg/mo = 47 mg/d
Omega3|CHD2 mortality||Ingested intake of EPA+DHA from fish|mg /day|RR|None|0|0.99951 (0.99934 - 0.99989)|Cohen et al 2005 "antiatherosclerotic effect". 1-0.039*0.01
Omega3|Stroke mortality||Ingested intake of EPA+DHA from fish|mg /day|Relative Hill|None|47|-0.12 (-0.25 - 0.01)|Cohen et al. 2005
Omega3|Stroke mortality||Ingested intake of EPA+DHA from fish|mg /day|RR|None|0|0.9998 (0.99934 - 1.00027)|1-0.02*0.01, Cohen et al 2005: −2.0% 	95% CI: +2.7% to −6.6%
Fish|Subclinical brain infarct (one or more) prevalence||Ingested intake of tuna/other fish|≥3 times/week vs. <1/month|RR|None|0|0.74 (0.54 - 1.01)|Virtanen et al. 2008; 95% CI
Fish|Any prevalent subclinical brain infarct prevalence||Ingested intake of tuna/other fish|Each one serving per week|RR|None|0|0.93 (0.88 - 0.994)|Virtanen et al. 2008; 95% CI
Fish|Subclinical brain infarct (one or more)incidence||ngested intake of tuna/other fish|≥3 times/week vs. <1/month|RR|None|0|0.56 (0.30 - 1.07)|Virtanen et al. 2008; 95% CI
Fish|Any incident subclinical brain infarct incidence||Ingested intake of tuna/other fish|Each one serving per week|RR|None|0|0.89 (0.78 - 0.993)|Virtanen et al. 2008; 95% CI
Fish|Status of cerebral white matter grade score||Ingested intake of tuna/other fish|Each one serving per week|ERS|None|0|0.038|Virtanen et al. 2008;  95% CI
</t2b>

; ERF publications 

{| {{prettytable}}
|+ ERF data as described in original articles
!Exposure agent||Trait||Response metric||Exposure route||Exposure metric||Exposure unit||ERF parameter||Threshold||ERF||Description
|----
|DHA||Child´s IQ||Change in IQ points||Placenta||Maternal intake||mg/kg bw/day||ERS||0||0.07(±0.01)||Cohen et al. 2005; Gradowska 2013
|----
|Omega3||CHD||Δlog(CHD mortality rate)||Ingestion||Intake from fish||mg/day EPA+DHA||ERS||0||-0.002 (±3.97E-4)||Mozaffarian and Rimm 2006; Gradowska 2013
|----
|DHA and EPA||Stroke||Incidence||Ingestion||Dietary intake of EPA+DHA||520 mg /day vs. 148 mg /day||RR||0||0.72 (0.54-0.96)||Multivariable- and PCB-adjusted RR (95% CI) Bergkvist et al. 2014
|----
|Fish||Subclinical brain infarct (one or more)||Prevalence||Ingestion||Intake of tuna/other fish||=3 times/week vs. <1/month||RR||0||0.74(0.54-1.01)||Virtanen et al. 2008
|----
|Fish||Any prevalent subclinical brain infarct||Prevalence||Ingestion||Intake of tuna/other fish||Each one serving per week||Decrease in RR %||0||7(0.6-12)||Virtanen et al. 2008
|----
|Fish||Subclinical brain infarct (one or more)||Incidence||Ingestion||Intake of tuna/other fish||=3 times/week vs. <1/month||RR||0||0.56(0.30-1.07)||Virtanen et al. 2008
|----
|Fish||Any incident subclinical brain infarct||Incidence||Ingestion||Intake of tuna/other fish||Each one serving per week||Decrease in RR %||0||11(0.7-22)||Virtanen et al. 2008 
|----
|Fish||Status of cerebral white matter||Grade score||Ingestion||Intake of tuna/other fish||Each one serving per week||Increase in grade score %||0||3.8||Virtanen et al. 2008
|----
|Fish||Cerebrovascular disease||Incidence||Ingestion||Intake of fish|| 2-4 versus ≤1 servings a week||RR||0||0.94 (0.90-0.98)||95% CI, Meta-analysis based on 18 and eight studies Chowdhury et al,. 2015
|----
|Fish||Cerebrovascular disease||Incidence||Ingestion||Intake of fish|| ≥5 versus ≤1 servings a week ||RR||0||0.88 (0.81-0.96)||95% CI, Meta-analysis based on 18 and eight studies Chowdhury et al,. 2015
|----
|Fish||Cerebrovascular disease||Incidence||Ingestion||Intake of fish|| Increment of two servings per week||Reduced risk ||0||0.04  (0.01-0.07)||95% CI, Meta-analysis based on 18 and eight studies Chowdhury et al,. 2015
|----
|Fish||thrombotic infarction||Incidence||Ingestion||Intake of fish||2 or more times per week vs. <1 serving per month||RR||0||0.49 (0.26-0.93)||95% CI, Iso et al. 2001
|----
|}

Exposure-response of fish oil intake for MI risk in adults is indexed by variable age. It applies to age categories > 18 years.

The study by Cohen et al. 2005 <ref> Cohen, J.T., PhD, Bellinger, D.C, PhD, W.E., MD, Bennett A., and Shaywitz B.A. 2005b. A Quantitative Analysis of Prenatal Intake of n-3 Polyunsaturated Fatty Acids and Cognitive Development. American Journal of Preventive Medicine 2005;29(4):366–374).</ref> estimates that increasing maternal docosahexaenoic acid (DHA) intake by 100 mg/day increases child's IQ by 0.13 points {{disclink|Other references}}. This value represents central estimate while the upper and lower bound for this ERF is 0.08 and 0.18. Triangular distribution is used.

In a recent study, 3660 over 65-year-old individuals were monitored for five years, and the change in small brain infarctions was observed by magnetic resonance imageing. The infaction risk was 25 % lower in those who ate at least three portions of omega-3-rich fish meals per week, and 13 % lower in those who ate one meal per week.
<ref>Fish consumption and risk of subclinical brain abnormalities on MRI in older adults
Jyrki K. Virtanen, David S. Siscovick, Will T. Longstreth, Lewis H. Kuller, Dariush Mozaffarian
Neurology 2008;71:439–446.</ref>

Fernandez-Jarne et al. <ref>Fernandez-Jarne E, Garrido FA, Gutierrez AA, Arrillaga CDF, Martinez-Gonzales MA. Dietary intake of n-3 fatty acids and the risk of acute myocardial infarction: a case-control study. (In Spanish) 2002;118:121–5.</ref> examined the relationship between intake of fish and n-3 PUFA and the risk of first acute myocardial infarction (AMI) in a low risk population from Navarre (Spain). They found that the n-3 PUFA intake has a protective effect on AMI. The adjusted odds ratio (OR) for the second and third tertile of n-3 PUFA intake were 0.44 (95% Cl, 0.21-0.91) and 0.47 (95% Cl, 0.22-1.00), respectively. The trend test was not statistically significant. {{Disclink| Time unit for ERF of n-3 PUFA}}

Mozaffarian and Rimm <ref name="Rimm"> Mozaffarian D., Rimm E.B., Fish intake, contaminants, and human health. Evaluating the risks and the benefits. (Reprinted) JAMA, 2006. Vol 296, No. 15 </ref> estimated that at intakes between 0 and 250 mg/d, the relative risk of coronary heart disease (CHD) death is lower by 14.6% (95% CI: 8% to 21%) per each 100 mg/d of EPA and DHA intake and that at higher intakes ( > 250 mg/d) the risk reduction is 0.0% (95% CI: -0.9% to 0.8%) per each 100 mg/d. 

The ERF of omega-3 fatty acids (DHA+EPA) intake from fish (in unit of mg/kg bw-day) on the CHD mortality is estimated based on information provided in <ref name="Rimm" />. First, the central estimate and the 95% CI for the change (in this case decrease) in natural logarithm of relative risk (RR) of CHD mortality per unit change in omega-3 fatty acids intake (in unit of mg/day) in both intake intervals were derived. In general, the relationship between the percent change in RR (%RR) associated with c-unit increase in omega-3 fatty acids intake and the incremental change in lnRR (beta) per unit change in omega-3 fatty acids intake is beta = (1/c)*ln((%RR/100)+1). Normal distribution was chosen to describe the uncertainty in the parameter of the log-linear model for RR in each intake interval. For intake of EPA+DHA between 0 and 250 mg/day the mean and the standard 
deviation of parameter distribution are -0.0016 and 0.0004, for higher intakes 0 and 0.0005. Then, the distribution of ERF of omega-3 fatty acids intake from fish in units of mg/kg bw-day was obtained by multiplying ERFs of omega-3 fatty acids intake measured in mg/day by the body weight of adult.  

In cohort studies comparing categories of fish intake the pooled relative risk for cerebrovascular disease was demonstrated based ob 26 prospective cohort studies and 12 randomised controlled trials with aggregate data on 794 000 non-overlapping people and 34 817 cerebrovascular outcomes by a review by Chowdhury et al. 2015 <ref> Chowdhury et al. 2012 Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. [http://www.ncbi.nlm.nih.gov/pubmed/23112118 ]</ref>

In a study by Iso et al. 2001 <ref>Iso et al. 2001. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001;285(3):304-312. doi:10.1001/jama.285.3.304. [http://www.ncbi.nlm.nih.gov/pubmed/11176840] </ref> a significant inverse associations between fish intake and age- and smoking-adjusted risk of total stroke, ischemic stroke, and thrombotic infarction, specifically lacunar infarction was found. After further adjustment for other cardiovascular and selected dietary variables, the inverse remained significant for thrombotic infarction and lacunar infarction, with a reduced risk of these stroke subtypes among women who ate fish 2 or more times per week. The multivariate RRs were 0.49 (95% CI, 0.26-0.93; P = .03), and 0.28 (95% CI, 0.12-0.67; P = .004), respectively. We found no excess risk of hemorrhagic stroke, either intraparenchymal or subarachnoid hemorrhage, among women who ate fish frequently.

;Unit: lnRR/ 1 (mg/kg bw-day) change in EPA+DHA intake from fish 
;Beneris distributions:For intakes of EPA+DHA from fish between 0 and 250 mg/day: N(-0.0016,0.0004)*BW
:For intakes of EPA+DHA from fish higher than 250 mg/day: N(0,0.0005)*BW

{| {{prettytable}}
|+'''Summary of dose–response relationships<ref name="cohen">Cohen JT, Bellinger DC, Shaywitz BA. A quantitative analysis of prenatal methyl mercury exposure and cognitive development. Am J Prev Med. 2005 Nov;29(4):353-65. [http://www.ncbi.nlm.nih.gov/pubmed/16242602]</ref>
|----
! Health effect|| Relationship|| Central estimate|| Uncertainty
|----
|rowspan="2"| Fish consumption and CHD mortality|| ΔRR for some fish consumption vs no fish consumption (&lt;1 serving/month)|| −17%|| 95% CI <sup>a</sup>: −8.8% to −25%
|----
|| ΔRR per additional serving/week|| −3.9%|| 95% CI <sup>a</sup>: −1.1% to −6.6%
|----
|rowspan="2"| Fish consumption and stroke incidence|| ΔRR for some fish consumption vs no fish consumption (&lt;1 serving/month)|| −12%|| 95% CI <sup>a</sup>: +1.0% to −25%
|----
|| ΔRR per additional serving/week|| −2.0%|| 95% CI <sup>a</sup>: +2.7% to −6.6%
|----
|| MeHg exposure and cognitive development|| ΔIQ per μg/g total Hg in maternal hair|| −0.7 pts|| Bounds: 0 to 1.5 pts
|----
|| DHA intake and cognitive development|| ΔIQ per g/day maternal intake of DHA|| 1.3 pts|| Bounds: 0.8 to 1.8 pts
|----
|}
<sup>a</sup> 95% CI is based on the distribution for this coefficient calculated from the regression analysis used to develop the dose–response relationship
for CHD or stroke.
CHD, coronary heart disease; CI, confidence interval; DHA, docosahexaenoic acid; MeHg, methyl mercury; pts, points; RR, relative risk.
Serving size was 100 g.

Here we need to convert the serving size to omega-3 intake. It depends on the average omega-3 content in the diets of the patients in the studies, and it is not known to us. Therefore, we may assume that it is higher than in lean fish (0 - 0.5 %) and lower than in fatty fish (1-2 %), i.e. say 0.7 % or 700 mg per serving. Therefore, the published RR changes (per servings/week) must be multiplied by 1 per (servings * 700 mg/serving / (week * 7 d/week) = 0.01 * RR changes per mg/d. CHD2 is used as the trait to prevent double counting with the other ERFs based on Mozaffarian and Rimm.

In addition, Cohen<ref name="cohen"/> concluded that the ERFs for CHD and stroke are non-linear with a larger reduction in risk between non-consumers and some-consumers (the limit defined as 1 serving per month). In addition, a linear incremental benefit was estimated for intakes more than 1 serving per week. This results in two independent ERFs where the low-dose "antiarrhythmic" effect follows Relative Hill function and the high-dose "antiatherosclerotic" effect follows RR function. Cohen assumed a negative correlation between these, but this is not easy to implement with the current HIA ovariables and therefore we ignore the correlation; this results in an increase of the estimated uncertainty in the model.

In a recent large cohort study by Engeset et al. (2015) <ref> Engeset et al. 2014]: Fish consumption and mortality in the European Prospective Investigation into Cancer and Nutrition cohort [http://link.springer.com/article/10.1007%2Fs10654-014-9966-4 </ref> no associations were seen for consumption of total fish, lean, or fatty fish and either total mortality or cause-specific mortality among men; broadly similar results were obtained for women. The statistical significant associations found in the non-calibrated analyses disappeared in the calibrated analyses and bootstrap analyses.

=== Calculations ===

<rcode name="initiate" label="Initiate ovariables" embed=1 store=1>
library(OpasnetUtils)

d <- opbase.data("Op_en5830")
d$Obs <- NULL
colnames(d) <- gsub(" ", "_", colnames(d))
d$Result <- ifelse(d$Result == "", "0", as.character(d$Result))

ERF_omega3 <- Ovariable("ERF_omega3", data = d[d$Observation == "ERF", colnames(d) != "Observation"])

threshold_omega3 <- Ovariable("Threshold_omega3", data = d[d$Observation == "Threshold", colnames(d) != "Observation"])

objects.store(ERF_omega3, threshold_omega3)
cat("Ovariables ERF, threshold stored.\n")

</rcode>

== See also ==

* [[ERF of methyl mercury]]
* [http://www.kampus.uku.fi/tiedotteet/tiedote.shtml?v=2008&tied=12179163101552 A press release from the University of Kuopio (in Finnish)]
* Reviews by Henna Karvonen in Beneris:
** [[Impact of fish consumption on nutrient intakes]]
** [[‎‎Cardiovascular dose-responses of fish consumption]]
** [[Mental health dose-responses of fish consumption]]
** [[Immunological disease dose-responses of fish consumption]]
** [[Diabetes and glucose dose-responses of fish consumption‎]]
** [[Developmental dose-responses of fish consumption]]
** [[Cancer dose-responses of fish consumption]]
** [[Bone dose-responses of fish consumption]]
** [[All-cause mortality dose-response of fish consumption‎]]

== References  ==

<references />