Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.
paper
Primary
Public
- Authors
- Culverhouse, Robert C; Bowes, Lucy; Breslau, Naomi; Nurnberger, John I; Burmeister, Margit; Fergusson, David M; Munafò, Marcus; Saccone, Nancy L; Bierut, Laura J; 5-HTTLPR, Stress, and Depression Consortium
- Year
- 2013
- Journal
- BMC psychiatry
- PMID
- 24219410
- DOI
- 10.1186/1471-244X-13-304
- PMCID
- PMC3840571
BACKGROUND: Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions. METHODS/DESIGN: To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression. STUDY ELIGIBILITY CRITERIA: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias. DATA SOURCES: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results. DISCUSSION: Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.
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| # | Section | Preview |
|---|---|---|
| 40 | Methods/Design — Data management, analysis, and meta-analysis — Heterogeneity | A priori group comparisons for heterogeneity will include the following: |
| 41 | Methods/Design — Data management, analysis, and meta-analysis — Heterogeneity | ●Longitudinal versus cross-sectional studies. |
| 42 | Methods/Design — Data management, analysis, and meta-analysis — Heterogeneity | ●Different measures of depression (DSM-IV criteria and other measures). |
| 43 | Methods/Design — Data management, analysis, and meta-analysis — Heterogeneity | ●Different stress exposure scales. |
| 44 | Methods/Design — Data management, analysis, and meta-analysis — Heterogeneity | ●Interview versus questionnaire reports. |
| 45 | Methods/Design — Data management, analysis, and meta-analysis — Heterogeneity | ●Self-report versus report by others. |
| 46 | Methods/Design — Data management, analysis, and meta-analysis — Heterogeneity | Should heterogeneity be detected, we will report meta-analysis results from homogeneous subgroups as… |
| 47 | Methods/Design — Analysis models | In our exploration of the relationship between 5-HTTLPR variation, stress, and depression, we will… |
| 48 | Methods/Design — Analysis models | In the original report by Caspi and colleagues [15], a depression outcome at age 26 was assessed… |
| 49 | Methods/Design — Analysis models | Analyses involved both a logistic regression (multiplicative) model where depression diagnosis was… |
| 50 | Methods/Design — Analysis models | As stated above, our analyses will fall into two main groups of data: a well-characterized, narrowly… |
| 51 | Methods/Design — Analysis models | Using these approaches, we intend to balance the competing factors affecting power: sample size and… |
| 52 | Methods/Design — Analysis models | Under this protocol, data from a particular study may be appropriate for inclusion in one or more of… |
| 53 | Methods/Design — Plan details | The primary model of interest, a focused analysis of 5-HTTLPR variation, consists of two arms (arms… |
| 54 | Methods/Design — Primary analysis 1: analysis of the impact of 5-HTTLPR variation in young adults | In keeping with the original study and following reports that effects of any GxE may be expected to… |
| 55 | Methods/Design — Primary analysis 1: analysis of the impact of 5-HTTLPR variation in young adults | Two arms differentiated by stressor will be the co-primary foci for this set of analyses. |
| 56 | Methods/Design — Primary analysis 1: analysis of the impact of 5-HTTLPR variation in young adults — Arm A: childhood maltreatment | ●Narrower Stressor |
| 57 | Methods/Design — Primary analysis 1: analysis of the impact of 5-HTTLPR variation in young adults — Arm A: childhood maltreatment | ●No time limit on gap between maltreatment and depression |
| 58 | Methods/Design — Primary analysis 1: analysis of the impact of 5-HTTLPR variation in young adults — Arm A: childhood maltreatment | ●Stress exposure assumed to occur before depression, but need not be documented |
| 59 | Methods/Design — Primary analysis 1: analysis of the impact of 5-HTTLPR variation in young adults — Arm A: childhood maltreatment | Childhood maltreatment has been reported as a particular stressor of interest for understanding the… |
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