EAL

DLM: Homocysteine, Folate, B6 or B12 (2007-2011)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To combine individual participant data from all relevant observational studies to produce reliable estimates of the associations of total plasma Hcyt with ischemic heart disease (IHD) and stroke, with adjusting for confounding.

Inclusion Criteria:

--MEDLINE database search for articles published from January 1966 to January 1999

--terms used for search: coronary heart disease, MI, CVA, stroke, CVD, Hcyt, hyperHcyt

--also hand-searched references of original and review articles

--data must be available by Jan 1999 on total blood Hcyt concentration, sex, age at entry, and age at event for individual data

--cases and controls at least 40 years of age at baseline

--measured plasma Hcyt concentrations between 3 and 40 mmol/L

Exclusion Criteria:

--studies only measuring blood concentration of free Hcyt or total Hcyt only after methionine-loading test or if relevant individual data is incomplete

--prospective studies of participants selected on basis of existing CVD, DM, renal impairment, or some other disease in order to avoid confounding by disease

Description of Study Protocol:

--analysis done for all ages together and then with 3 age bands (40-54, 55-64, ³ 65 years)

--analyzed prospective and retrospective studies separately in order to assess impact of possible reverse causality and to decrease bias from control selection or participation

Data Collection Summary:

--investigators agreeing to participate had to provide data on individuals’: date of birth, sex, blood Hcyt concentrations, any non-fatal or fatal MI or occlusive CAD, any non-fatal or fatal stroke or transient cerebral ischemic attack

--if available, also collected: history of heart disease event, prior CVA event, DM, smoking status, alcohol consumption, blood concentration of total and HDL-C and creatinine, systolic and diastolic blood pressure

--classified study as prospective if: blood sample to measure Hcyt collected before 1 heart disease or stroke event

--classified as retrospective if: blood sample collected after event in cases

§ “Population-based” if: controls selected randomly from same source population as cases

§ “Other” if: controls were spouse controls or patients with other illness

Description of Actual Data Sample:

--obtained individual data from 30 studies, including:

§ 18/28 eligible retrospective

§ 12/13 eligible prospective

--5073 IHD events:

§ 1968 came from prospective studies

§ 2496 from retrospective studies with population controls

§ 609 from retrospective studies with other controls

--1113 stroke events:

§ 463 from prospective studies

§ 344 from retrospective studies with population controls

§ 306 from retrospective studies with other controls

Summary of Results:

--significant heterogeneity between results from study designs (x²₂=27, p<0.001)

--no evidence that associates Hcyt level with IHD was influenced by age, sex, smoking, levels of blood pressure or blood cholesterol, or mean Hcyt concentrations in controls, or size of study

--Hcyt levels less strongly related to IHD and stroke risk in healthy population

--after adjustment for cardiac risk factors and regression dilution bias in prospective studies: 25% lower usual Hcyt level (about 3 mmol/L) was associated with an 11% lower IHD risk (OR=0.89, 95% CI: 0.83-0.96) and 19% lower stroke risk (OR=0.81, 95% CI: 0.69-0.95)

Author Conclusion:

--risks are weaker in prospective studies than retrospective. This may reflect bias in retrospective studies due to differences in selecting appropriate controls or effects in changes in treatment, renal function, etc.

Funding Source:

Government:

European Union's BIOMED Program

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Quality Criteria Checklist: Review Articles
Relevance Questions
	1.	Will the answer if true, have a direct bearing on the health of patients?	Yes
	1.	Will the answer if true, have a direct bearing on the health of patients?	Yes
	2.	Is the outcome or topic something that patients/clients/population groups would care about?	Yes
	2.	Is the outcome or topic something that patients/clients/population groups would care about?	Yes
	3.	Is the problem addressed in the review one that is relevant to dietetics practice?	Yes
	3.	Is the problem addressed in the review one that is relevant to dietetics practice?	Yes
	4.	Will the information, if true, require a change in practice?	Yes
	4.	Will the information, if true, require a change in practice?	Yes

Validity Questions
	1.	Was the question for the review clearly focused and appropriate?	Yes
	1.	Was the question for the review clearly focused and appropriate?	Yes
	2.	Was the search strategy used to locate relevant studies comprehensive? Were the databases searched and the search termsused described?	Yes
	2.	Was the search strategy used to locate relevant studies comprehensive? Were the databases searched and the search termsused described?	Yes
	3.	Were explicit methods used to select studies to include in the review? Were inclusion/exclusion criteria specified andappropriate? Wereselectionmethods unbiased?	Yes
	3.	Were explicit methods used to select studies to include in the review? Were inclusion/exclusion criteria specified andappropriate? Wereselectionmethods unbiased?	Yes
	4.	Was there an appraisal of the quality and validity of studies included in the review? Were appraisal methodsspecified,appropriate, andreproducible?	Yes
	4.	Was there an appraisal of the quality and validity of studies included in the review? Were appraisal methodsspecified,appropriate, andreproducible?	Yes
	5.	Were specific treatments/interventions/exposures described? Were treatments similar enough to be combined?	Yes
	5.	Were specific treatments/interventions/exposures described? Were treatments similar enough to be combined?	Yes
	6.	Was the outcome of interest clearly indicated? Were other potential harms and benefits considered?	Yes
	6.	Was the outcome of interest clearly indicated? Were other potential harms and benefits considered?	Yes
	7.	Were processes for data abstraction, synthesis, and analysis described? Were they applied consistently acrossstudies and groups? Was thereappropriate use of qualitative and/or quantitative synthesis? Was variation in findings among studies analyzed? Were heterogeneity issued considered? If data from studies were aggregated for meta-analysis, was the procedure described?	Yes
	7.	Were processes for data abstraction, synthesis, and analysis described? Were they applied consistently acrossstudies and groups? Was thereappropriate use of qualitative and/or quantitative synthesis? Was variation in findings among studies analyzed? Were heterogeneity issued considered? If data from studies were aggregated for meta-analysis, was the procedure described?	Yes
	8.	Are the results clearly presented in narrative and/or quantitative terms? If summary statistics are used, are levels ofsignificance and/or confidence intervals included?	Yes
	8.	Are the results clearly presented in narrative and/or quantitative terms? If summary statistics are used, are levels ofsignificance and/or confidence intervals included?	Yes
	9.	Are conclusions supported by results with biases and limitations taken into consideration? Are limitations ofthe review identified anddiscussed?	Yes
	9.	Are conclusions supported by results with biases and limitations taken into consideration? Are limitations ofthe review identified anddiscussed?	Yes
	10.	Was bias due to the review's funding or sponsorship unlikely?	Yes
	10.	Was bias due to the review's funding or sponsorship unlikely?	Yes