Supplementary Appendix

Supplement to: Jacobs DR Jr, Woo JG, Sinaiko AR, et al. Childhood cardiovascular risk factors and adult cardio-
vascular events. N Engl J Med 2022;386:1877-88. DOI: 10.1056/NEJMoa2109191

This appendix has been provided by the authors to give readers additional information about the work.
This supplement contains the following items:

Contents
Original SAP (from the grant proposal)................................................................................................... 2
Final SAP ..................................................................................................................................................... 6
Summary of Amendments to the SAP .................................................................................................. 10
References ................................................................................................................................................ 13
Original SAP (from the grant proposal)
1. Introduction/Aims
This study is an observational follow-up of 7 epidemiologic cohorts begun in children in the
1970s to 1990s in the US, Finland and Australia, with the goal of identifying the relationships
between measured childhood cardiovascular risk factors and adjudicated adult cardiovascular
disease. This SAP is the verbatim wording from the grant application (except for reordering for
clarity), written prior to a complete understanding of the data structure.

Aim (Childhood Analyses): To evaluate relationships between childhood CV risk factors and
adult CV endpoints.
Hypothesis 1: Adverse childhood/adolescent (age 3‐19) CV risk factor levels (BMI, lipids
[total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides], BP) are related to
increased incidence of CV endpoints in adulthood.
Hypothesis 2: A CV risk score weighting childhood/adolescent risk factors (BMI, lipids,
BP, age, sex and race/ethnicity) is a stronger predictor of adult CV endpoints than any
individual risk factor.
Hypothesis 3: The relationship of individual risk factors or CV risk score with adult CV
endpoints becomes stronger with increasing age from childhood (age 3‐11) to
adolescence (age 11‐19).
Aim (Adulthood and Childhood Analyses): To evaluate the association of CV risk score
trajectories on adult CV endpoints.
Hypothesis 4: Trajectories in the CV risk score from childhood (age 3–11) through
adolescence (age 11–19) (i.e., high-high, high-low, low-high, low-low) are better
predictors of adult CV endpoints than risk scores in either childhood (age 3–11) or
adolescence (age 11–19) alone.
Hypothesis 5: Extension of trajectories in the CV risk score from childhood/adolescence
(age 3–19) through adulthood (age > 25) increases prediction of adult CV endpoints
beyond the childhood/ adolescence (age 3–19) risk scores or trajectories alone.

2. Population to be Analyzed
The analytic sample will consist of all participants who were located and consented for this
questionnaire-based follow-up, plus decedents identified by National Death Index (NDI) search.

3. Baseline Characteristics
We will initially study age, sex, and cohort distributions of all predictor variables, as well as
observed adjudicated event rates by cohort.

4. Childhood Risk Factors

The predictor set is height, weight, BMI, systolic and diastolic BP, total cholesterol, triglycerides,
LDL cholesterol, and HDL cholesterol. In the primary analysis across all childhood ages (3‐19
years), we will use each participant’s youngest observation for the predictors. The predictors will
be transformed to age‐ and sex‐specific z-scores (using internally derived with predictors
centered at the mean and divided by the standard deviation) to account for sex and
developmental differences in normal levels of childhood CV risk factors during childhood.

5. Outcome Assessment
The major outcome is presence/absence of fatal or non‐fatal CV events, with all event types
considered as a composite variable. Outcomes to be adjudicated include fatal or non-fatal
coronary heart disease, myocardial infarction, peripheral artery disease, stroke, aneurysm,
angina pectoris, transient ischemic attack, and heart failure. We recognize the latter three
may be more subjective and difficult to diagnose and, therefore all events will require hospital
record verification. Heart failure due to non-CV disease (e.g., cardiomyopathy, cocaine use)
will be excluded. Hypertension and type 2 diabetes will not be considered as outcomes.
The hospital records required to adjudicate the event will depend on the endpoint reported,
following guidelines similar to the CARDIA Study’s protocol. Data requested may include
discharge summary, ICD codes and specific CV event related documents such as ECG,
cardiac enzymes, echocardiogram, catheterization and surgical reports, as appropriate.
Medical records will be abstracted at each site and entered into a de-identified web portal for
centralized adjudication. Adjudicators will remain blinded with regard to the case’s cohort of
origin during the review process. Because identification of cases from Finland and Australia
will partially or fully rely on health care registries, adjudication algorithms using registry data
will be developed and tested for consistency with the medical records-based adjudication.

6. Statistical Methods
Prediction of events will employ Cox‐proportional hazards (CoxPH) regression using time to
event or censoring (i.e., date of last CV disease-free contact or death). For hypothesis 1, in
primary analyses each of the variables in the predictor set will be analyzed as a continuous
variable both separately and jointly. The sample at risk varies according to predictor variable
(Table 4). Age, sex, and race/ethnicity will be included as covariates. Goodness of fit will be
assessed by visually examining splines and/or representing the predictor variable in categories,
such as quartiles.

For hypothesis 2, we will use information about shape of the prediction curve from hypothesis 1
to construct and test risk scores that combine BMI, blood lipid, and BP z‐scores, as well as age,
sex, and race/ethnicity. Given available sample numbers (Table 4), we will represent blood
lipids with total cholesterol and triglycerides in one risk score (RS1) and with LDL‐C, HDL‐C,
and triglycerides in a second (RS2). First, we will run a CoxPH regression with all risk-factor z-
scores entered simultaneously to calculate a risk score from the regression function. Second,
we will calculate a weighted average of the risk factor z-scores (defined so a higher score
indicates higher risk). We will construct a receiver operating characteristic (ROC) curve by
mapping observed event counts against predicted ones. The prediction results will be compared
by the area under the curve (AUC) statistics. AUC for prediction from these risk scores will be
compared to prediction obtained from demographics or demographics plus individual risk factors
alone. We will use the Net Reclassification Improvement 3 statistic to examine extent of
improvement of clinical classification compared to more basic models of demographics or single
risk factors. Depending on the sample size in a given analysis, we will alternately plan to
conduct a split‐sample cross‐validation of the risk scores. Our expectation is that the risk scores
have substantially greater predictive capability than does any single CV risk factor.
For hypothesis 3 we will evaluate whether and how risk prediction varies by age of childhood
measurement. We expect strength of prediction to be greater in adolescence than in childhood,
so we will test age interaction both with a continuous risk factor*age term in the regression
models and in age strata (age 3‐11, age 11‐19 years). Expected numbers of participants with at
least 1 observation within the two age windows are given in Table 4 (participants seen only
once would enter only 1 age window). For each outcome variable, a single, repeated measures
Poisson regression will describe the prediction in two age strata. For a given risk factor or risk
score (R) and an indicator for age 3‐11 or 11‐19 (IA), and using the youngest measurement in
each age window, this will have terms Age, R, and IA*R. The coefficient for IA*R describes and
provides a test for the difference in prediction for measurements in the two age windows, in a
model that pools all available predictor information from each participant. If there is no age
interaction, the regression coefficients from individual risk factors and from the combined risk
score will indicate which childhood/adolescent risk factor levels predict future CV disease
regardless of age at first CV risk factor measurement.

The studies included in this proposal were designed with differing sets of measurements and
ages of follow-up. Thus, missing predictor values are not always related to differential follow‐up,
but may represent noninformative missing where missing data can be imputed without
introducing bias. We will use correlations across time within an individual, across risk factors, or
among demographically similar cohorts. The imputed data are not observed so standard errors
of resulting estimates will be adjusted to incorporate the increased uncertainty. 4 Finally, we will
conduct a sensitivity analysis to confirm that no bias is introduced via imputation.

Trajectories of CV risk score over childhood and adolescence

In this aim we examine whether risk factor changes within childhood/adolescence or between
childhood/adolescence and adulthood might affect CV risk in adulthood. Analysis methods for
hypotheses 4 and 5 will be similar, differing primarily in the age ranges considered for the
trajectories. Hypothesis 4 will examine Risk Score 1 (RS1) trajectories between age 3‐11 and
age 11‐19 using ~9000 participants with component z‐scores for RS1 in both childhood and
adolescence. Hypothesis 5 will model trajectories between childhood/adolescence (age 3‐19)
and adulthood (age ≥25) using ~6000 participants with RS1 measurements in both age ranges.
If Hypothesis 3 results suggest an interaction between age 3‐11 and age 11‐19 periods,
Hypothesis 5 will then restrict analysis to trajectories between adolescence (age 11‐19) and
adulthood. For both hypotheses, trajectories will be defined using SAS PROC TRAJ, which
classifies participants into group‐based trajectories over time using latent class analysis. We
anticipate 4 important trajectories, each with similar prevalence: low RS1 in both age windows,
increasing RS1 across age windows, high RS1 in both age windows, and decreasing RS1
across age windows. Trajectory group membership will then be used in analysis of CV
endpoints, using CoxPH regression and a random effects meta-analysis, 1,2 as in the childhood
Aim. As with the childhood Aim, propensity methods will be explored in relation to potential
follow‐up bias.

7. Sensitivity Analyses
By cohort: The event rate of the major outcome or the distribution of the predictors (childhood
risk factors) may differ across the cohorts, so cohort-specific baseline hazards will be estimated
to account for these discrepancies. For every regression analysis, we will conduct a random-
effects meta-analysis1, 2 to address heterogeneity of statistical effects across the cohorts, with a
forest plot drawn to help visualize and evaluate differences between cohort-specific estimates
and the pooled estimate of the relative hazard for each predictor.
Fatal vs. Fatal/nonfatal events: Fatal CV events will be known in almost all of the 41,006
participants with any childhood measurements, including non‐responders to our health
questionnaire. Expected numbers of fatal CV events will be inadequate for detecting expected
relations to the individual risk factors or risk score. However, these data are still useful for
studying potential bias in the sample recruited. If the responders are not a biased sample, there
will be general consistency of findings using CV death as the outcome in the whole sample with
the findings using fatal or non‐fatal CV events in the responders. We will also explore total
mortality in sensitivity analyses to examine whether there are any unintended adverse
associations.
Bias from loss to follow-up: Potential loss‐related bias will be assessed by testing for differences
in childhood CV risk factor levels between participants and non‐participants. Analytically, we will
compute the probability (propensity) of the adult follow‐up as a function of demographics and
childhood risk factors and will weight each subject case with the inverse of the computed
probability in the proposed analyses.
Selection of childhood measurements: For hypothesis 3, for participants with multiple measures
within an age range, we will conduct sensitivity analyses where the oldest measurement within
an age stratum is used, or when the average of all measurements within an age stratum is
used. These sensitivity analyses supplement and describe the goodness of fit of the model with
a continuous age interaction term.
Secondary Analyses for the Aim: Other variables available in smaller subsets will be examined
in exploratory analyses, including adolescent smoking, blood glucose and insulin, diet, physical
activity, and socioeconomic status (SES). These factors are important for understanding
potential leverage points for changing CV risk factors in childhood, but have insufficient power to
include in primary analyses.
Bias in adjudication: Adjudication of all true CV endpoints will depend on two main factors: 1)
likelihood that the event was diagnosed or treated in a medical facility, and 2) likelihood that
medical records are available and complete. While events requiring hospital admission likely will
be captured for all participants, less severe conditions not requiring hospitalization might remain
unidentified. Reduced access to medical care may result in some misclassification of true
events as non-events; however, past studies have shown that false negative reporting of
diagnosed CV events is uncommon. Discrepancies in underreporting across cohorts will be
addressed by cohort-specific baseline hazards.
Final SAP
1. Introduction/Aims
This study is an observational follow-up of 7 epidemiologic cohorts begun in children in the
1970s to 1990s in the US, Finland and Australia, with the goal of identifying the relationships
between measured childhood cardiovascular risk factors and adjudicated adult cardiovascular
disease.

Aim (Childhood Analyses): To evaluate relationships between childhood CV risk factors and
adult CV endpoints.
Hypothesis 1: Adverse childhood/adolescent (age 3‐19) CV risk factor levels (BMI, total
cholesterol, triglycerides, systolic BP and youth smoking) are related to increased
incidence of CV endpoints in adulthood.
Hypothesis 2: A CV risk score equally weighting childhood/adolescent risk factor age-
sex standardized z-scores (BMI, total cholesterol, triglycerides, systolic BP and youth
smoking) is a stronger predictor of adult CV endpoints than any individual risk factor.
Hypothesis 3: The relationship of individual risk factors or CV risk score with adult CV
endpoints becomes stronger with increasing age from childhood (age 3‐11) to
adolescence (age 12‐19).
Aim (Adulthood and Childhood Analyses): To evaluate the association of CV risk score
trajectories on adult CV endpoints.
Hypothesis 4 was deleted because only about 50% of participants had repeated
measures within age 3-19.
Hypothesis 5: Changes in the CV risk score from childhood/adolescence (age 3–19)
through adulthood (age > 20) increases prediction of adult CV endpoints beyond the
childhood/ adolescence (age 3–19) risk scores alone.

2. Sample to be Analyzed
The analytic sample will consist of all participants with sufficient information available for follow-
up or searching using the National Death Index (NDI) and with at least one risk factor (BMI, total
cholesterol, triglycerides, systolic BP and youth smoking) measured prior to age 20 (n=38,589).
Participants who had an event, died or were followed up prior to age 25 were excluded from
analysis based on expected rarity of CVD before that age, a decision at the initiation of the grant
period. Inclusion in the analytic sample consisted of three potential groups: those who were
located and consented for this questionnaire-based follow-up; decedents identified by NDI
search; and those not located in the NDI searches and thus presumed alive.

The analytic sample for the analysis of Hypothesis 5, incorporating adult measured risk factors,
will include the subsample of childhood participants who had any measured adult risk factor
(BMI, total cholesterol, ln(triglycerides), or systolic BP) at or after age 20 but prior to any known
cardiovascular event (n=13,401).

In each of these analysis streams, bias will be removed and the sample size will be maintained
by multiple imputation, under the plausible assumption of Missing At Random (MAR).

3. Baseline Characteristics
We will initially study age, sex, and cohort distributions of all predictor variables, as well as
observed adjudicated event rates by cohort. We will also compare distributions of these factors
as well as race, parental education and own education across outcome classifications.

4. Childhood and Adult Risk Factors

The predictor set is BMI, total cholesterol, triglycerides, systolic BP, and youth smoking. In the
primary analysis across all childhood ages (3‐19 years), we will use each participant’s average
of all available observations for the predictors. The predictors will be transformed to age‐ and
sex‐specific z-scores (using internally derived with predictors centered at the mean and divided
by the standard deviation) to account for sex and developmental differences in normal levels of
childhood CV risk factors during childhood. A z-score will be formed for each variable for each
visit based on the sex and 3 year age group (3-5, 6-8, 9-11, 12-14, 15-17, 18-19) at which the
visit was done. We then will average the individual visit z-scores within person over visits within
a 3-year window, then average across 3 year windows to form the larger windows (3-19, 3-11,
12-19). Smoking will be coded as on the z-score scale as 0 (average) for nonsmokers and 2
(high extreme) for smokers.
We define the adult risk score using the same formal strategy to facilitate comparison with
childhood data. Age ranges start with 20-22 years. Change in combined risk z-scores (adult
minus childhood) will also be calculated.
5. Outcome Assessment
The major outcome is presence/absence of fatal or non‐fatal CV events, with all event types
considered as a composite variable. Outcomes to be adjudicated include fatal or non-fatal
coronary heart disease, myocardial infarction, peripheral artery disease, stroke, aneurysm,
angina pectoris, transient ischemic attack, and heart failure. We recognize the latter three may
be more subjective and difficult to diagnose and, therefore all events will require medical record
verification. Heart failure due to non-CV disease (e.g., cardiomyopathy, cocaine use) will be
excluded. Hypertension and type 2 diabetes will not be considered as outcomes.
The medical records required to adjudicate the event will depend on the endpoint reported,
following guidelines similar to the CARDIA Study’s protocol. Data requested may include
discharge summary, ICD codes and specific CV event related documents such as ECG, cardiac
enzymes, echocardiogram, catheterization and surgical reports, as appropriate. Medical
records will be abstracted at each site and entered into a de-identified web portal for centralized
adjudication. Adjudicators will remain blinded with regard to the case’s cohort of origin during
the review process. Because identification of cases from Finland will partially or fully rely on
health care registries, adjudication algorithms using registry data will be developed and tested
for consistency with the medical records-based adjudication.
6. Statistical Methods
Primary analyses will employ multiply imputed data for the child analyses (n=38,589) and
separately for the child and adult analyses (n=13,401). Observed numbers of events and
distributions will also be reported. The studies included in this proposal were designed with
differing sets of measurements and ages of follow-up. Thus, missing predictor values are not
always related to differential follow‐up but may represent noninformative missing (MAR) where
missing data can be imputed from measured variables to reduce bias. We will implement
multiple imputation (10 imputations using chained equations with fully conditional specification)
to impute both childhood risk factors and nonfatal events in those not recontacted during follow-
up, assuming missing at random (MAR). Childhood risk factors will be imputed for all individuals
in the final analysis dataset (n=38,589), and adult event status imputation will be conducted.
Both childhood and adult imputation will use a three-stage approach. The first imputation will
estimate risk factors and nonfatal event status among all participants. The second imputation
will estimate nonfatal event status separately for individuals who self-reported events that could
not be adjudicated. The third imputation will estimate age at event for all imputed nonfatal
events, with the age at end of follow-up or death used for imputed non-events.
Life tables stratified by risk factor categories will be plotted. Prediction of events will employ
Cox‐proportional hazards (CoxPH) regression using age as the time axis and time to event or
censoring (i.e., date of last CV disease-free contact or death). For hypothesis 1, each of the
variables in the predictor set will be analyzed as a continuous variable. Averages of ages at
childhood measurements and of calendar year of childhood measurements, sex, race, and
study cohort will be included as covariates in all models. Goodness of fit will be assessed by
visually examining splines and/or representing the predictor variable in categories, such as
quartiles. Proportional hazards assumptions will be evaluated by testing the interaction of
log(age) with the risk factor and the linear fit assumption will be tested by plotting spline fits of
the hazard ratio. If the proportional hazards assumption is violated, earlier vs. later events will
be visualized.
For hypothesis 2, assuming general similarity of log hazard coefficients across risk factors in
hypothesis 1, we will construct a risk score that combines equally weighted BMI, total
cholesterol, ln(triglycerides, systolic BP z‐scores, and youth smoking scaled to a z-score . Our
expectation is that the risk score has substantially greater predictive capability than does any
single CV risk factor.
For hypothesis 3 we will evaluate whether and how risk prediction varies by age of childhood
measurement (age 3‐11, age 12‐19 years). We expect strength of prediction to be greater in
adolescence than in childhood, so we will test age interaction with a continuous risk factor*age
group term in the regression models using repeated terms for the age specific value of the risk
factor under investigation and robust variance estimation.
Changes in CV risk score between childhood and adulthood
In this aim we examine whether risk factor changes between childhood/adolescence and early
adulthood might affect CV event risk in later adulthood. For hypothesis 5, we will model two-
point change between the average of all measures during childhood/adolescence (age 3‐19)
and the average of all measures during adulthood (age ≥20) in the subset with measures in both
age ranges (n=13,401).
We will use CoxPH regression of the childhood and adult risk factor z-scores simultaneously in
the model. Two parameterizations of the regression will be considered, one with childhood
measurement and adult measurement as separate independent variables, the other with
childhood measurement and change (adult age minus childhood age) as the separate
independent variables, recognizing that different interpretations may arise from reparameterized
models, even though they have exactly the same likelihood 7. In addition, we will calculate the
correlations for each variable across different age ranges pertinent to ages 3-11, 12-19, and 20
or more, the variables being defined as the average of all z-scores within the particular age
range under consideration (to maximize precision for each person).
7. Sensitivity Analyses
By cohort: The event rate of the major outcome or the distribution of the predictors (childhood
risk factors) may differ across the cohorts, so cohort-specific baseline hazards will be estimated
to account for these discrepancies. For every regression analysis, we will stratify analyses by
cohort to address heterogeneity of statistical effects across the cohorts, to help evaluate
differences between cohort-specific estimates and the pooled estimate of the relative hazard for
each predictor.
Fatal vs. Fatal/nonfatal events: Fatal CV events will be known in almost all of the 38,589
participants with any childhood measurements, including non‐responders to our health
questionnaire. Expected numbers of fatal CV events may be inadequate for detecting expected
relations to the individual risk factors or risk score. However, these data will still be useful for
studying potential bias in the sample recruited. If the responders to questions about nonfatal
CVD events are not a biased sample, there will be general consistency of findings using CV
death as the outcome in the whole sample with the findings using fatal or non‐fatal CV events in
the responders. We will also explore total mortality in sensitivity analyses to examine whether
there are any unintended adverse associations.
Interactions by sex and race: We will evaluate differences in the relationships between
childhood risk factor z-scores and adult CV events by sex and race by testing an interaction
term in the CoxPH model.
Bias from loss to follow-up: Potential loss‐related bias will be assessed by testing for differences
in childhood CV risk factor levels between participants and non‐participants. Analytically, we will
account for loss to follow-up using multiple imputation of both risk factors and outcomes, as
described above.
Selection of childhood measurements: We will study first or last measures as an alternative to
the average of all childhood measures, with the expectation that there will be added precision
from the average.
Bias in adjudication: Adjudication of all true CV endpoints will depend on two main factors: 1)
likelihood that the event was diagnosed or treated in a medical facility, and 2) likelihood that
medical records are available and complete. While events requiring hospital admission likely will
be captured for all participants, less severe conditions not requiring hospitalization might remain
unidentified in the participant’s self-report. Reduced access to medical care may result in some
misclassification of true events as non-events; however, past studies have shown that false
negative reporting of diagnosed CV events is uncommon. We will assess differences among
those with self-reported events regarding those able to be adjudicated vs. not adjudicated and
use the experience of adjudicated events in this group to impute events for those who were not
adjudicable.
Summary of Amendments to the SAP
Amendments occurred because the SAP was written for the R01 proposal before all the design
aspects were in place. Specifically, not known were: final sample sizes for each risk factor
(harmonization of data required some funding and therefore had not been completed at the time
of grant writing), final event rates, success rates in contacting and locating participants, and
ability to obtain medical records. The following summarizes and provides the rationale for the
overarching changes in analytic approach, which are detailed in the Final SAP above.
Section 1: Introduction/Aims
Modification 1 Aims changed to reflect realities of data structure
Rationale The grant application was written before several aspects of the data
were known. The changes here are detailed in other sections of the
Final SAP
Section 2: Sample
Population to be Analyzed
Modification 1 Provide greater specificity for the description of the analysis sample
Rationale We now include reference to specific changes to factors related to
inclusion in or exclusion from the analysis sample.

Section 4: Childhood risk factors

Modification 1 Alteration of variables used in risk score
Rationale We did not form a second risk score, because we did not analyze LDL-
C and HDL-C at this time, given their smaller sample sizes. Based on
data that we harmonized in conjunction with our smoking paper5,
smoking became one of the 5 primary variables. We also did not
include age, sex and race as part of the risk factor z-score, but rather
incorporated age and sex into the development of the z-score, and
adjusted for race.
Modification 2 Use of unweighted vs. weighted risk score
Rationale We decided to base the risk score on the unweighted average of the
4 clinical risk factor z-scores (BMI, systolic BP, triglycerides and total
cholesterol) plus youth smoking. Given the general similarity of the
risk factor coefficients, equal weighting led to a robust risk score
solution.
Modification 3 Development of an adult risk factor z-score
Rationale When it became clear that full trajectories were not feasible, we
determined that construction of a set of adult risk factor z-scores and
a combined risk z-score was needed. This was derived using the same
methods as those used for childhood risk factors, among the subset
of participants with any risk factors measured in adulthood (at or
after age 20).

Section 5: Statistical Analysis

Modification 1 Inclusion of fatal CV as a primary study outcome
Rationale It turned out that, given the strength of the association, the number
of fatal CV events was adequate for detecting expected relations to
the individual risk factors or risk score. Therefore, this analysis of fatal
 CVD events became one of the parallel analysis approaches,
optimizing response rate, eliminating potential bias, and fulfilling the
expected promise of the consistency with the fatal/nonfatal analysis.
Modification 2 Specification of multiple imputation as a primary statistical approach
Rationale The multiple imputation approach was adopted as the primary
statistical approach to estimate associations between risk factors and
outcomes. This section provides additional details about how this was
implemented.
Modification 3 Elimination of Hypothesis 4 testing
Rationale The database had not been fully assembled at the time of grant
writing, there the distribution of number and timing of
measurements per person was not well understood then. After
defining the risk score as the equally weighted sum of risk factor z-
scores (with youth smoking coded 0 or 2), we found that there was
relatively little we could do with studies specific to early childhood
(age 3-11) and adolescence (age 12-19). We therefore dropped
Hypothesis 4.
Modification 4 Use of two-point change model rather than group-based trajectories
Rationale Further, the relatively small number of people with more than 2
measurements meant that estimating trajectories in PROC TRAJ
would not work. This was substituted with individual difference (an
individually-based trajectory) of the average, within person z-score
during adulthood minus the average, within person z-score during
childhood.

Section 7: Sensitivity
Analyses
Modification 1 Exclusion of meta-analysis of cohorts
Rationale We did not do the formal meta-analysis, because two features of the
data became obvious after the data were collected. First, across all 7
cohorts there were almost no CVD events before age 40. Second,
only 4 cohorts for the fatal/nonfatal analysis and 2 cohorts for the
fatal analysis had sufficient events to contribute to the differential
risk observed at ages above 40. Therefore, the added variance due to
between cohort heterogeneity could not be estimated reliably, and
we opted instead to present findings stratified by cohort.
Modification 2 Fatal CV events included as primary outcome
Rationale As indicated above, this analysis was feasible as a primary analysis
due to higher-than-expected mortality due to cardiovascular causes
and strength of the risk factor associations.
Modification 3 Exclusion of consideration of some childhood risk factors
Rationale We did not conduct analyses including glucose, insulin, diet or
physical activity in childhood. Blood glucose and insulin were studied
in relation to diabetes6, but sample sizes were too small for the main
Outcomes analysis. We continue to work on harmonizing diet and
physical activity variables, but these are not currently available.
Modification 4 Addition of sensitivity analyses: interactions by sex and race
Rationale To complement analyses of age group interactions, we were
concerned about differences in relationships by sex and race.
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