Association of Intima‐Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque: Individual Participant Data Meta‐Analysis of 20 Prospective Studies

Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I 2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I 2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I 2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

C arotid intima-media thickness (cIMT) and carotid plaque are commonly used imaging markers for the development and progression of atherosclerosis, the pathophysiological mechanism underlying most cardiovascular diseases (CVDs). Both cIMT and carotid plaque can be measured noninvasively using highresolution B-mode ultrasound. The 2 markers have been implicated in cardiovascular risk assessment, showing robust associations with common cardiovascular risk factors, 1-3 atherosclerosis elsewhere in the arterial system, 4 and the risk of developing a CVD event. [5][6][7][8] Observational studies investigating the association between cIMT and carotid plaque have produced variable results. Although cross-sectional studies consistently showed that elevated cIMT values are associated with presence of carotid plaque, [9][10][11][12][13][14][15][16][17] longitudinal studies investigating the association of baseline cIMT values with incident carotid plaque have yielded mixed results. 14,[16][17][18][19][20][21][22][23][24][25][26][27][28][29] We have recently summarized the evidence on this topic in a literature-based meta-analysis that involved data from 7 general population cohort studies with a total of 9341 participants without preexisting carotid plaque. 30 In aggregate, it showed that individuals in the top quartile compared with those in the bottom quartile of baseline common carotid artery intima-media thickness (CCA-IMT) had a relative risk of 1.78 (95% CI, 1.53-2.07) of developing first-ever carotid plaque. Because this meta-analysis relied on literaturebased aggregated data, it was unable to apply consistent statistical methods with respect to adjustment for confounders, participant-level inclusion criteria, and uniform definitions of exposure and outcome variables. In addition, it could only inspect effects of potential effect modifiers across averaged values or percentages, making it vulnerable to ecological fallacy. 31 To address this gap in knowledge, we conducted an individual participant data meta-analysis of 21 494 participants from 20 studies within the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium with the aim of precisely characterizing the association of baseline CCA-IMT with the risk of developing a firstever carotid plaque during follow-up.

METHODS
The data sets supporting the conclusions of this article are not made publicly available because of legal restrictions arising from the data distribution policy of the Proof-ATHERO collaboration and from the bilateral agreements between the consortium's coordinating center and participating studies, but they may be CLINICAL PERSPECTIVE What Is New?
• This study, based on participant-level data on 21 494 individuals from 20 studies, performed the most comprehensive analysis of the relationship between carotid intima-media thickness and incident carotid plaque available to date. • Carotid intima-media thickness measured at the common carotid artery was positively and approximately log-linearly associated with the long-term risk of developing carotid plaque. • This association was independent of cardiovascular risk factors and was robust across several subgroup and sensitivity analyses.
What Are the Clinical Implications?
• This study provides evidence for the role of carotid intima-media thickness as a risk marker for atherosclerotic disease, which may help to identify individuals at risk of developing advanced atherosclerotic lesions earlier.
requested directly from individual study investigators. Studies that shared individual participant data have obtained informed consent of the study participants and ethical approval by their respective institutional review boards. This study conforms to the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data (PRISMA-IPD) guidelines. 32 The PRISMA-IPD checklist is provided in Table S1.

Data Collection and Eligibility Criteria
Data were sought from the Proof-ATHERO consortium; a detailed description of this collaboration has been published elsewhere. 33 For inclusion in the current analysis, participants were required to have data pertaining to (1) baseline CCA-IMT and (2) carotid plaque status (yes versus no) at baseline and at least at one visit during follow-up. The baseline visit was defined as the first visit, at which carotid plaque status was available, and follow-up as subsequent visits. We excluded participants with a baseline history of CVD (defined as coronary heart disease or stroke) or preexisting carotid plaque at baseline from the analysis. Furthermore, to avoid overfitting and convergence issues of statistical models, we excluded studies that recorded <20 events of incident carotid plaque. Moreover, we searched the literature for additional prospective studies on the association of baseline CCA-IMT with incident carotid plaque in individuals free of carotid plaque at baseline that were published until December 1, 2022. We used the search terms ("intima-media thickness" [all fields] OR "IMT" [all fields] OR "intima media thickness" [all fields] AND "plaque" [all fields] AND "incident" [all fields] OR "prospective" [all fields]) in PubMed and TS=("intima-media thickness" OR "IMT" OR "intima media thickness") AND TS=("plaque" AND ["incident" OR "prospective"]) in Web of Science.

Ascertainment of CCA-IMT and Carotid Plaque
Details on the study-specific definitions of CCA-IMT and carotid plaque are provided in Table S2 and have been described previously. 33 In quantifying CCA-IMT, we gave preference to mean CCA-IMT values or, alternatively, used maximum CCA-IMT. When studies provided cIMT measurements at several locations of the CCA (ie, near and far wall, left and right side, and different insonation angles), we used the arithmetic mean of all available values. When measuring cIMT, most studies focused on a 10-mm long segment at the distal part of the CCA (Table S2 and Figure S1). Incident carotid plaque was defined as the development of firstever plaque during follow-up in any segment of the carotid artery (ie, left or right CCA, carotid bifurcation, or internal carotid artery). Fourteen studies (70%) defined carotid plaque as focal thickening, and some others relied on different thresholds of cIMT (Table S2).

Statistical Analysis
Statistical analyses were conducted according to a predefined analysis plan. We calculated odds ratios (ORs) for incident plaque using a 2-stage approach. We first estimated ORs within each study separately, and then combined study-specific ORs using random-effects meta-analysis using the method of moments procedure of DerSimonian and Laird. Between-studies heterogeneity was quantified with the I 2 statistics. 34 We conducted complete-case analyses, if not stated otherwise.
In the primary analysis, we used logistic regression models to estimate ORs for incident plaque per SD higher level of CCA-IMT, defining the SD of CCA-IMT within each study separately. The CCA-IMT distribution was checked for normality by visually inspecting quantile-quantile plots. We report ORs (1) adjusted for age, sex, and trial arm; and (2) further adjusted progressively for ethnicity, smoking, history of diabetes, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipid-lowering medication, antihypertensive medication, estimated glomerular filtration rate, and hs-CRP (highsensitivity C-reactive protein). We also conducted analyses that expressed ORs per 0.1-mm higher level of baseline CCA-IMT. To inspect the shape of association between baseline CCA-IMT and incident plaque, we calculated ORs across study-specific CCA-IMT quintiles, pooled them using multivariate random-effects metaanalysis, 35 plotted them against the mean CCA-IMT value within each quintile, and added the best-fitting line through the OR estimates. We evaluated log linearity of the association between baseline CCA-IMT and incident carotid plaque by visually inspecting whether OR estimates lie on the corresponding best-fitting lines. In this analysis, we used floating absolute risks 36 to calculate 95% CIs for quintile groups (including the reference group), thereby enabling head-to-head comparisons between effect sizes of any 2 of the quintiles.
We also investigated effect modification with formal tests of interaction across clinically relevant predefined variables (ie, age, sex, lipid-lowering medication, and low-density lipoprotein cholesterol at baseline and development of CVD during follow-up). We used metaregression 37 to test for differences by selected study-level characteristics (ie, study type and type of CCA-IMT measurement). In subgroup analyses, we applied Bonferroni correction 38 to account for multiple testing (ie, P values ≤0.0071 [0.05/7 tests] were deemed as statistically significant). In addition, we investigated whether ORs varied by median duration of follow-up using meta-regression. 37 Moreover, we conducted sex-specific analyses and estimated pooled ORs separately for women and men.
Finally, we conducted sensitivity analyses that: (1) took into account the time to plaque development by use of Cox regression (after ensuring that the proportional hazards assumption was met on the basis of Schoenfeld residuals and the graphical inspection of log[−log] plots), estimating the date of carotid plaque development as the visit at which carotid plaque had first been detected or, alternatively, as the midpoint between this and the preceding visit; (2) used long-term average CCA-IMT values ("usual levels") estimated with regression calibration 39 on the basis of repeated CCA-IMT measurements over time; (3) used within-study multiple imputation of missing values suggested by Burgess et al 40 (ie, imputed sporadically missing values in each study separately [80 data sets] before applying the Rubin rule and then combining study-specific effect sizes with random-effects meta-analysis); (4) omitted participants with a large CCA-IMT value (>1.5 mm), which could be indicative of undetected carotid plaque; and (5) omitted studies that had defined carotid plaque as CCA-IMT above a specific threshold rather than as focal thickening. We additionally conducted a separate sensitivity analysis that compared the association of baseline CCA-IMT with carotid plaque development at the same side of the neck (ie, right CCA-IMT with right carotid plaque and left CCA-IMT with left carotid plaque) and at the opposite side of the neck (ie, right CCA-IMT with left carotid plaque and left CCA-IMT with right carotid plaque).
In addition, we meta-analyzed the results of the studies from the Proof-ATHERO consortium with the studies we found in the literature for which we were not able to obtain individual participant data. We focused on the Proof-ATHERO studies included in our multivariable-adjusted meta-analysis to enhance the comparability to the studies from the literature. Again, we meta-analyzed ORs for incident carotid plaque per SD higher baseline CCA-IMT using random-effects meta-analysis.
All statistical tests were 2-sided, and we deemed P≤0.05 as statistically significant, unless specified otherwise. Statistical analyses were conducted using Stata version 15.1 (StataCorp).

Contributing Data and Study Characteristics
The derivation of the study sample contributing to the present study is outlined in Figure 1. Of the 74 studies involved in the Proof-ATHERO consortium, we excluded 48 that did not record incident carotid plaque. After further excluding participants who did not meet the prespecified inclusion criteria and excluding studies that recorded <20 incident carotid plaque events, a total of 20 studies involving 21 494 participants remained for analysis. 15,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] Table 1 and Table S3 summarize key characteristics of the studies and participants we analyzed. Twelve studies recruited participants from the general population, 6 recruited participants from high-risk populations (ie, individuals with baseline coronary atherosclerosis, renal disease, or other vascular risk factors), and 2 were clinical trials (involving individuals on hemodialysis and with heterozygous familial hypercholesterolemia). The pooled mean age at baseline was 56 years (SD, 9 years); 55% of the participants were women.  The odds appeared to increase log-linearly across CCA-IMT quintiles when adjusting for age, sex, and trial arm as well as in the multivariable-adjusted model.
The pooled OR for first-ever carotid plaque development, adjusted for age, sex, and trial arm, was 1.40 (95% CI, 1.31-1.50; I 2 =63.9%) per SD higher level of baseline CCA-IMT (for study-specific estimates, see Figure S2). The corresponding OR per 0.1-mm higher baseline level of CCA-IMT was 1.30 (95% CI, 1.23-1.38; I 2 =71.8%). As shown in Table 2, the association was slightly weakened when the OR was further adjusted for potential confounding variables. In a model further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low-and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication, the OR per SD higher baseline CCA-IMT was 1.34 (95% CI, 1.24-1.45; I 2 =59.4%; 14 studies; 16 297 participants; 6381 incident carotid plaques). The ORs were virtually identical when further adjusted for estimated glomerular filtration rate or log-transformed hs-CRP values. In subgroup analyses (Figure 3), there was no evidence for effect modification by age, sex, intake of lipid-lowering medication, lowdensity lipoprotein cholesterol, development of CVD during follow-up, type of study, and type of CCA-IMT measure, when we considered a multiplicity-adjusted threshold for statistical significance (all P>0.0071). In addition, we found no statistically significant difference in ORs by median duration of follow-up, as demonstrated  Table S4, results were also similar in sex-specific analyses. The age-and trial arm-adjusted OR for incident carotid plaque per SD higher baseline CCA-IMT was 1.

Sensitivity Analyses
In sensitivity analyses, we observed similar ORs when we multiplied imputed missing values, excluded individuals with CCA-IMT values >1.5 mm, or restricted analyses to studies that defined carotid plaque as focal thickening ( Figure 4A). Stronger associations were observed when we considered long-term averages ("usual levels") of CCA-IMT values, which we estimated on the basis of repeated CCA-IMT measurements taken at a median of 2 occasions (range, 2-9 occasions). Median time between 2 consecutive CCA-IMT measurements was 3.0 years (interquartile range, 2.3-5.4 years). The OR per SD higher "usual" CCA-IMT was 1.71 (95% CI, 1.54-1.89; I 2 =63.9%) when adjusted for age, sex, and trial arm and 1.65 (95% CI, 1.44-1.88; I 2 =59.4%) in the multivariable-adjusted model. When we used Cox regression and estimated the dates of plaque development as the visit at which plaque had first been detected, the hazard ratio (HR) for incident plaque per SD higher baseline CCA-IMT was 1.24 (95% CI, 1.17-1.30; I 2 =74.4%) when adjusted for age, sex, and trial arm and 1.16 (95% CI, 1.09-1.24; I 2 =74.8%) in the multivariable-adjusted model. When we estimated dates of plaque development as the midpoint between the visit at which plaque had first been detected and the preceding visit, HRs for incident plaque per SD higher baseline CCA-IMT were 1.28 (95% CI, 1.22-1.33; I 2 =64.8%) when adjusted for age, sex, and trial arm and 1.22 (95% CI, 1.16-1.29; I 2 =65.7%) in the multivariable-adjusted model. Finally, side-specific analyses revealed somewhat stronger associations for an ipsilateral development than a contralateral development of carotid plaque ( Figure 4B).
consortium that were included in the multivariableadjusted meta-analysis with aggregated data of these 5 studies, the pooled OR for incident carotid plaque per SD higher baseline CCA-IMT was 1.33 (95% CI, 1.24-1.42; I 2 =54.1%; 18 studies; 19 295 participants).

DISCUSSION
In the present individual participant data meta-analysis embedded in the Proof-ATHERO consortium, we investigated the association of CCA-IMT values with the development of incident first-ever carotid plaque during follow-up. We observed an OR for plaque development of 1.40 (95% CI, 1.31-1.50) per SD higher level of baseline CCA-IMT, which was reduced slightly in a multivariable adjustment model. We also demonstrated that odds increased approximately log-linearly across quintiles of baseline CCA-IMT. Finally, associations were robust in several sensitivity analyses and across a range of clinically relevant participant characteristics (eg, traditional risk factors and intake of medication) and study methods (eg, in assessing CCA-IMT).

Comparison With Previous Findings
We have previously investigated the relationship between CCA-IMT and development of carotid plaque in a literature-based meta-analysis that considered 7 general population studies with a total of 9341 participants and 1288 events of carotid plaque. 30 In this analysis preceding the current study, we had observed a pooled relative risk for incident carotid plaque of 1.78 (95% CI, 1.53-2.07), when comparing individuals in the top quartile of baseline CCA-IMT with individuals in the bottom quartile. Although this effect size is comparable to the effect size in the current study (see results across quintiles in Figure 2), a key strength of the current analysis is that it included 6 times more incident outcomes and could therefore quantify the association more precisely (in addition to other advantages related to the individual participant data access). We were also able to include hitherto unpublished findings from 15 studies and extended the analysis to high-risk populations and clinical trials. When meta-analyzing the studies contributing to the Proof-ATHERO consortium with the aggregated data of the additional studies we found in the literature, 14,17,27-29 Figure 2. Odds ratios (ORs) for incident carotid plaque across quintiles of baseline common carotid artery intima-media thickness (CCA-IMT) in participants with complete data on age, sex, and trial arm (A) and variables used for multivariable adjustment* (B).
The dashed lines indicate the best-fitting lines through the odds ratio estimates. *Adjusted for age at baseline, sex, trial arm, ethnicity, smoking status at baseline, history of diabetes at baseline, systolic blood pressure at baseline, body mass index at baseline, low-density lipoprotein cholesterol at baseline, high-density lipoprotein cholesterol at baseline, intake of lipid-lowering medication at baseline, and intake of antihypertensive medication at baseline. .1%) per SD higher CCA-IMT, which is nearly the same result as in the present multivariable-adjusted primary analysis. Our findings are also in line with results from other studies in the literature that analyzed the association of CCA-IMT with carotid plaque differently. The Tromsø study, for instance, observed a positive association between baseline cIMT and a higher number of plaques at follow-up. 19 The SHIP (Study of Health in Pomerania) reported that individuals with elevated CCA-IMT had a higher risk for developing additional plaques in previously unaffected arterial segments. 18 In contrast to these studies and our report, the Reykjavik Risk Evaluation for Infarct Estimates study found no statistically significant association between CCA-IMT and formation of a new plaque. 20

Ultrasound Methods Used in the Contributing Studies
Measurement of cIMT and carotid plaque is generally performed noninvasively with high-resolution B-mode ultrasound. cIMT is defined as the so-called doubleline pattern, representing the distance between the lumen-intima and the media-adventitia interfaces. 60 The 2011 Mannheim cIMT and plaque consensus recommends cIMT to be measured at the far wall of the CCA in an area free of carotid plaque. 61 In 2008, the American Society of Echocardiography also recommended measuring CCA-IMT at the far wall of the carotid artery in their Consensus Statement but, contrarily, to include sections with carotid plaque. 62 In the studies contributing to the present report, there were some differences in how CCA-IMT was assessed (Table S2 and Figure S1). cIMT was often measured at different sections of the CCA, at the left and/or right side of the neck, and at the near and/or far wall of the CCA. To reduce variability and include a broad range of information from the entire CCA, we averaged all the available measurements to obtain an overall CCA-IMT value. Moreover, in a meta-regression analysis (Figure 3), we observed that the association was similarly strong in studies reporting mean CCA-IMT and studies reporting maximum CCA-IMT. Besides different definitions of CCA-IMT, studies also varied in terms of carotid plaque assessment (Table S2). The Mannheim cIMT and plaque consensus defines carotid plaque as focal thickening CCA indicates common carotid artery; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; IMT, intima-media thickness; LDL, low-density lipoprotein; and OR, odds ratio.
*Restricted to individuals having information on all variables included in the model. † Adjusted for age at baseline, sex, trial arm, ethnicity, smoking status at baseline, history of diabetes at baseline, systolic blood pressure at baseline, body mass index at baseline, low-density lipoprotein cholesterol at baseline, high-density lipoprotein cholesterol at baseline, intake of lipid-lowering medication at baseline, and intake of antihypertensive treatment at baseline. of at least 0.5 mm or 50% of its surrounding area or as cIMT >1.5 mm. 61 Similarly, the American Society of Echocardiography recommends defining carotid plaque as "(1) any focal thickening thought to be atherosclerotic in origin and encroaching into the lumen of any segment of the carotid artery (protuberant-type plaque) or (2) in the case of diffuse vessel wall atherosclerosis, when carotid intima-media thickness measures ≥1.5 mm in any segment of the carotid artery (diffuse-type plaque)." 63 Although most of the studies contributing to our analysis defined carotid plaque as focal structure, some others defined it as cIMT above a predefined threshold. The latter may be problematic in the present analysis because cIMT is assumed to thicken progressively over time, and a direct association between elevated baseline cIMT and carotid plaque development in those studies would therefore be a logical consequence. Reassuringly, though, when we excluded these studies in a sensitivity analysis, the effect size pooled across the remaining studies was similar as in the primary analysis (OR, 1.38 [95% CI, 1.29-1.47]). Another potential challenge is that early stage of plaque development may sometimes be misclassified as elevated cIMT. 61 Therefore, we conducted a sensitivity analysis that omitted individuals with CCA-IMT >1.5 mm, which could be indicative for carotid plaque. Again, this analysis yielded results comparable to the primary analysis, with an overall OR for carotid Figure 3. Comparison of the strength of association between baseline common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque across various subgroups. The models are additionally adjusted for age, sex, and trial arm, if appropriate. *P values from interaction for categorical participantlevel variables (ie, sex, lipid-lowering medication, and cardiovascular disease [CVD] during follow-up) and continuous participant-level variables (ie, age and low-density lipoprotein [LDL] cholesterol) and P values from meta-regression for study-level variables (ie, study type and CCA-IMT type). After correcting for multiple testing, P≤0.0071 (0.05/7) was deemed statistically significant. Participant-level subgroup analyses include only studies that contribute data to all levels of a subgroup. OR indicates odds ratio.

Clinical Implications
As atherosclerosis often develops over years without symptoms or detection, early identification of vulnerable individuals is the key to prevent its clinical sequelae. Current evidence shows that increased cIMT relates to unfavorable levels of risk factors, [64][65][66] presence of atherosclerosis elsewhere in the arterial system, 4 and the Figure 4. Sensitivity analyses (A) and side-specific analyses (B) of the association between baseline common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque. Odds ratios were obtained from logistic regression analysis, and hazard ratios were obtained from Cox regression analysis. *Imputed variables (percentage of missing values that were imputed): CCA-IMT (3.9%), ethnicity (0.1%), smoking status (3.4%), history of diabetes (4.5%), systolic blood pressure (1.5%), body mass index (1.1%), low-density lipoprotein cholesterol (4.8%), high-density lipoprotein cholesterol (3.6%), lipid-lowering medication (2.2%), and antihypertensive medication (1.7%). † Adjusted for age at baseline, sex, trial arm, ethnicity, smoking status at baseline, history of diabetes at baseline, systolic blood pressure at baseline, body mass index at baseline, low-density lipoprotein cholesterol at baseline, high-density lipoprotein cholesterol at baseline, intake of lipid-lowering medication at baseline, and intake of antihypertensive medication at baseline. ‡ In this model, date of carotid plaque development was estimated as the visit at which carotid plaque had first been detected. § In this model, date of carotid plaque development was estimated as the midpoint between the visit at which carotid plaque had first been detected and the preceding visit. || Adjusted for age at baseline, sex, and trial arm. risk of future CVD events. 6,7 We have previously shown in an analysis of 119 clinical trials that different types of interventions reduce progression of cIMT and that the greater reductions in cIMT progression are associated with greater reductions in CVD risk, endorsing its usefulness as a surrogate marker. 67 Leading on from this, we now provide further evidence for the role of cIMT as a risk marker for atherosclerotic disease, which may help to identify individuals at risk of developing advanced atherosclerotic lesions earlier.

Strengths and Limitations
The present analysis has several strengths. First, we analyzed data of the Proof-ATHERO consortium, the worldwide largest consortium with data on repeated assessments of atherosclerosis and CVD, and included 20 different studies with >21 000 individuals. Thus, a major strength of the current analysis is its large sample size, which allows estimating effect sizes with adequate precision. Second, we included data from studies in a variety of clinical settings, thereby enhancing the generalizability of our findings to various populations. Third, we excluded individuals with a history of CVD, reducing the potential influence of subsequent drug treatments or frequent medical checks on the development of carotid plaques. Fourth, access to individual participant data allowed us to harmonize outcomes, exposures, and levels of adjustment, and perform various participant-level sensitivity analyses. Fifth, in a sensitivity analysis, we capitalized on the serial CCA-IMT measurements available in our studies and estimated ORs for incident carotid plaque based on long-term averages of CCA-IMT rather than a single baseline measurement, thereby taking into account within-person variation of CCA-IMT during follow-up. Sixth, because we had access to participant-level data, we were able to study the shape of association between CCA-IMT and development of carotid plaque across fifths of baseline CCA-IMT. Seventh, compared with our previous literature-based meta-analysis, individual participant data meta-analysis enabled a sophisticated analysis of effect sizes across participant-level subgroups. Our study also has limitations. First, there were differences in how the individual studies defined and measured CCA-IMT and carotid plaque. Second, because carotid plaque status was only available at the study visits and not in between, there was uncertainty about the exact time point of plaque development. For this reason, we prespecified to use logistic regression in our primary analysis. When we used Cox regression based on the estimated time to plaque development, HRs were highly significant, although numerically lower than ORs, as expected when the rare disease assumption is not met (39% developed the outcome plaque). Third, because the present meta-analysis focused on plaque status, we cannot draw any conclusions about the relationship of CCA-IMT with plaque quality, size, or architecture, which are more detailed measures to quantify and characterize carotid plaque. 8 Fourth, our analysis includes long-term follow-up studies, with baseline examinations typically taking place in 1990s to early 2000s, 33 and ultrasound devices have improved significantly since then. Consequently, it can be assumed that it would nowadays be possible to obtain ultrasound images with higher resolution, which would also enable us to identify plaques of smaller dimension. Furthermore, although recent guidelines also suggest measuring 3-dimensional carotid plaque by applying modern ultrasound techniques, 63 we were only able to analyze 2-dimensional carotid plaque data because of the unavailability in our long-term follow-up studies. Also, we only investigated ultrasound-based markers measured in the carotid arteries. Further research is needed on whether our results also hold for other vascular beds (eg, the femoral arteries). 8 Finally, plaque data on specific carotid arterial segments (ie, CCA, carotid bifurcation, and internal carotid artery) were sparse and could not be considered in our analysis, which prevented us from investigating the association between CCA-IMT and segment-specific development of carotid plaque.

CONCLUSIONS
In this large-scale meta-analysis based on participantlevel data, CCA-IMT was associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors. The association was robust across sensitivity analyses and similarly strong for women and men and for individuals at different ages.

Supplemental Material
Appendix List of Proof-ATHERO study group members Tables S1-S4 Figures S1-S4

Rationale 3
Describe the rationale for the review in the context of what is already known. 9 Objectives 4 Provide an explicit statement of the questions being addressed with reference, as applicable, to participants, interventions, comparisons, outcomes and study design (PICOS). Include any hypotheses that relate to particular types of participant-level subgroups. 10

Protocol and registration 5
Indicate if a protocol exists and where it can be accessed. If available, provide registration information including registration number and registry name. Provide publication details, if applicable.

10
Eligibility criteria 6 Specify inclusion and exclusion criteria including those relating to participants, interventions, comparisons, outcomes, study design and characteristics (e.g. years when conducted, required minimum follow-up). Note whether these were applied at the study or individual level i.e. whether eligible participants were included (and ineligible participants excluded) from a study that included a wider population than specified by the review inclusion criteria. The rationale for criteria should be stated.

10-11
Identifying studiesinformation sources 7 Describe all methods of identifying published and unpublished studies including, as applicable: which bibliographic databases were searched with dates of coverage; details of any hand searching including of conference proceedings; use of study registers and agency or company databases; contact with the original research team and experts in the field; open adverts and surveys. Give the date of last search or elicitation.

10-11
Identifying studiessearch Study selection processes 9 State the process for determining which studies were eligible for inclusion.

10-11
Data collection processes 10 Describe how IPD were requested, collected and managed, including any processes for querying and confirming data with investigators. If IPD were not sought from any eligible study, the reason for this should be stated (for each such study).
10, doi: 10.1159/00 0508498 If applicable, describe how any studies for which IPD were not available were dealt with. This should include whether, how and what aggregate data were sought or extracted from study reports and publications (such as extracting data independently in duplicate) and any processes for obtaining and confirming these data with investigators. Data items 11 Describe how the information and variables to be collected were chosen. List and define all study level and participant level data that were sought, including baseline and follow-up information. If applicable, describe methods of 2tandardizing or translating variables within the IPD datasets to ensure common scales or measurements across studies.

IPD integrity A1
Describe what aspects of IPD were subject to data checking (such as sequence generation, data consistency and completeness, baseline imbalance) and how this was done.

10-13
Risk of bias assessment in individual studies.

12
Describe methods used to assess risk of bias in the individual studies and whether this was applied separately for each outcome. If applicable, describe how findings of IPD checking were used to inform the assessment. Report if and how risk of bias assessment was used in any data synthesis.

11-13
Specification of outcomes and effect measures 13 State all treatment comparisons of interests. State all outcomes addressed and define them in detail. State whether they were prespecified for the review and, if applicable, whether they were primary/main or secondary/additional outcomes. Give the principal measures of effect (such as risk ratio, hazard ratio, difference in means) used for each outcome.

14
Describe the meta-analysis methods used to synthesise IPD. Specify any statistical methods and models used. Issues should include (but are not restricted to):  Use of a one-stage or two-stage approach.  How effect estimates were generated separately within each study and combined across studies (where applicable).  Specification of one-stage models (where applicable) including how clustering of patients within studies was accounted for.  Use of fixed or random effects models and any other model assumptions, such as proportional hazards.  How (summary) survival curves were generated (where applicable).  Methods for quantifying statistical heterogeneity (such as I 2 and  2 ).  How studies providing IPD and not providing IPD were analysed together (where applicable).  How missing data within the IPD were dealt with (where applicable).

11-14
Exploration of variation in effects A2 If applicable, describe any methods used to explore variation in effects by study or participant level characteristics (such as estimation of interactions between effect and covariates). State all participant-level characteristics that were analysed as potential effect modifiers, and whether these were pre-specified.

11-13
Risk of bias across studies 15 Specify any assessment of risk of bias relating to the accumulated body of evidence, including any pertaining to not obtaining IPD for particular studies, outcomes or other variables.

11-13
Additional analyses 16 Describe methods of any additional analyses, including sensitivity analyses. State which of these were pre-specified.

Study selection and IPD obtained 17
Give numbers of studies screened, assessed for eligibility, and included in the systematic review with reasons for exclusions at each stage. Indicate the number of studies and participants for which IPD were sought and for which IPD were obtained. For those studies where IPD were not available, give the numbers of studies and participants for which aggregate data were available. Report reasons for non-availability of IPD. Include a flow diagram. Study characteristics 18 For each study, present information on key study and participant characteristics (such as description of interventions, numbers of participants, demographic data, unavailability of outcomes, funding source, and if applicable duration of follow-up). Provide (main) citations for each study. Where applicable, also report similar study characteristics for any studies not providing IPD. Table 1, Table S2 IPD integrity A3 Report any important issues identified in checking IPD or state that there were none. 10 Risk of bias within studies 19 Present data on risk of bias assessments. If applicable, describe whether data checking led to the up-weighting or down-weighting of these assessments. Consider how any potential bias impacts on the robustness of meta-analysis conclusions.

14-16
Results of individual studies 20 For each comparison and for each main outcome (benefit or harm), for each individual study report the number of eligible participants for which data were obtained and show simple summary data for each intervention group (including, where applicable, the number of events), effect estimates and confidence intervals. These may be tabulated or included on a forest plot.

Figure S2
Results of syntheses 21 Present summary effects for each meta-analysis undertaken, including confidence intervals and measures of statistical heterogeneity. State whether the analysis was pre-specified, and report the numbers of studies and participants and, where applicable, the number of events on which it is based.
15-17, Figure 2, Figure 3, Figure S2, When exploring variation in effects due to patient or study characteristics, present summary interaction estimates for each characteristic examined, including confidence intervals and measures of statistical heterogeneity. State whether the analysis was pre-specified. State whether any interaction is consistent across trials. Provide a description of the direction and size of effect in terms meaningful to those who would put findings into practice.

Risk of bias across studies 22
Present results of any assessment of risk of bias relating to the accumulated body of evidence, including any pertaining to the availability and representativeness of available studies, outcomes or other variables.

15-17
Additional analyses 23 Give results of any additional analyses (e.g. sensitivity analyses). If applicable, this should also include any analyses that incorporate aggregate data for studies that do not have IPD. If applicable, summarise the main meta-analysis results following the inclusion or exclusion of studies for which IPD were not available.
15-17, Table 2, Figure 4, Table S4, Figure S3 Discussion Summary of evidence 24 Summarise the main findings, including the strength of evidence for each main outcome. 17

Strengths and limitations 25
Discuss any important strengths and limitations of the evidence including the benefits of access to IPD and any limitations arising from IPD that were not available.

21-22
Conclusions 26 Provide a general interpretation of the findings in the context of other evidence. 18 Implications A4 Consider relevance to key groups (such as policy makers, service providers and service users). Consider implications for future research.

Funding 27
Describe sources of funding and other support (such as supply of IPD), and the role in the systematic review of those providing such support.   Analyses for women and men are restricted to the same studies. *Restricted to individuals having information on all variables included in the model. †Adjusted for age at baseline, sex, trial arm, ethnicity, smoking status at baseline, history of diabetes mellitus at baseline, systolic blood pressure at baseline, body mass index at baseline, low-density lipoprotein cholesterol at baseline, high-density lipoprotein cholesterol at baseline, intake of lipid-lowering medication at baseline, and intake of antihypertensive treatment at baseline. Abbreviations: CCA-IMT, common-carotid artery intima-media thickness; CI, confidence interval; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; OR, odds ratio; SD, standard deviation. Figure S1. Location of CCA-IMT measurement.
The model has been adjusted for age at baseline, sex, and trial arm. Abbreviations: CCA-IMT, common-carotid artery intima-media thickness; CI, confidence interval; OR, odds ratio; SD, standard deviation. Figure S3. Subgroup analysis of association between baseline CCA-IMT and incidence of carotid plaque by median duration of follow-up.
The P value is derived from meta-regression. Each bubble depicts a study. The centres of the bubbles indicate point estimates for odds ratios for development of carotid plaque per standard deviation higher level of baseline common-carotid artery carotid intima-media thickness plotted against median durations of follow-up for each study. Odds ratios are adjusted for age at baseline, sex, and trial arm. The sizes of the bubbles are proportional to the inverse variances of the estimates. Abbreviations: OR, odds ratio.