History of Traumatic Brain Injury in Relation to Cognitive Functioning,Memory Complaints,and Brain Structure in Mid-Life

Abstract

In this study, we investigated history of traumatic brain injury with loss of consciousness in relation to cognitive functioning, subjective memory complaints, and brain structure in mid-life. This study included 2005 participants (mean age: 47.6 years, standard deviation: 5.0, women: 65%) from the Origins of Alzheimer's Disease Across the Life Course (ORACLE) study between 2017 and 2020. History of traumatic brain injury was defined as at least one lifetime self-reported brain injury with loss of consciousness. Associations of history of traumatic brain injury with (1) cognitive functioning (measured with the 15-Word Learning Test, Stroop Task, Letter–Digit Substitution Test, Word Fluency Test, Purdue Pegboard Test, and Design Organization Test), (2) current subjective memory complaints (present/absent, measured with a survey), and (3) brain structure (total brain volume, frontal and temporal lobe volume, gray matter volume, white matter volume, white matter hyperintensities volume, infarcts, and microbleeds, measured with brain magnetic resonance imaging [MRI]) were assessed using linear or logistical regression models and adjusted for relevant confounders. In total, 250 of 2005 (12%) participants reported a history of traumatic brain injury. Of those who reported the time post-injury (n = 173), most participants (n = 151, 87%) reported that it had occurred >10 years ago. We found no associations between history of traumatic brain injury and any of the cognitive tests. We did find that a history of traumatic brain injury was associated with having mid-life subjective memory complaints (odds ratio [OR]: 1.87; 95% confidence interval [CI]: 1.35, 2.58). This association was also present when investigating only those who reported an injury >10 years ago (OR:1.69; 95% CI: 1.15, 2.50). Additionally, the association was stronger in those with >30 min loss of consciousness (OR: 3.57; 95% CI: 1.48, 8.59) than in those with <30 min loss of consciousness (OR: 1.85; 95% CI: 1.25, 2.74), when compared with those without history of traumatic brain injury. Lastly, we found no associations between history of traumatic brain injury and any of the structural brain MRI outcomes. In conclusion, our study suggests that at least one lifetime traumatic brain injury with loss of consciousness in mid-life is associated with long-term subjective memory complaints, but not with cognitive functioning or brain structure.

Introduction

It is estimated that approximately half of the world's population will experience one or more traumatic brain injuries (TBIs) in their lifetime.¹ In 80–90% the injury is classified as mild,² but severity classifications poorly predict long-term disability.³ TBI may also be a risk factor for long-term cognitive impairments,⁴ subjective memory complaints,⁵ and structural brain magnetic resonance imaging (MRI) abnormalities.⁶

A previous study found poorer cognitive functioning on subtle aspects of attention and working memory 8 years after mild TBI.⁷ There is limited evidence on the functional outcomes of cognitive impairment in middle-aged adults, because cognitive impairment is relatively rare in middle-aged adults.⁸ However, it strongly predicts functional impairment, such as activities of daily living (ADL) impairment, in older adults.^8,9 Another previous descriptive study found memory or concentration complaints after 1 year in 11% of the patients with mild TBI, which significantly increased to 52% after 10 years.⁵ At both follow-up points, patients with impairment of memory and concentration had significantly a lower quality of life than patients without. Additionally, MRI-studies showed whole-brain atrophy 1 year after mild or moderate TBI,^6,10,11 and traumatic microbleeds 5 years after TBI.¹² Structural lesions on brain MRI after TBI in middle-aged adults have been associated with poorer functional and cognitive outcomes,^13,14 but not consistently.¹⁵

Therefore, we investigated the association of a history of at least one self-reported TBI with loss of consciousness with cognitive functioning, subjective memory complaints, and brain structure in middle-aged community-dwelling adults. We considered age, sex, educational attainment, and ethnic origin as possible confounders in our analyses. We investigated depressive symptoms separately as a possible confounder, because they could also be caused by a history of TBI. We performed additional analyses in which we investigated these associations in groups categorized on time since injury and the duration of loss of consciousness.

Methods

Study population

This cross-sectional study was embedded within the Origins of Alzheimer's Disease Across the Life Course (ORACLE) Study.¹⁶ The ORACLE Study was conducted between May 2017 and September 2020 and includes 2083 mothers of the children of the Generation R Study and their partners.¹⁷ The Generation R Study is a prospective birth cohort established in 2002 focusing on the period from fetal life until early adulthood.¹⁷ For the ORACLE study, mothers and their partners were invited to visit the research center. In answers to interview questions, participants reported on their history of brain injury with loss of consciousness, and completed cognitive testing, a survey on current subjective memory complaints, and brain MRI. The interview questions and surveys were conducted separately, with a considerable amount of time in between (∼ 1 h), and they were embedded within a more extensive interview or survey. For this study, we excluded participants with missing data on brain injury with loss of consciousness (n = 76), and those with no data on any of the outcome measures: cognitive testing, subjective memory complaints, and brain MRI (n = 2). In total, 2005 participants were included (n = 1311 women, 65%, see Supplementary Fig. S1). For the analyses on the different outcome measures we only included participants with data available on the outcome measure of interest: cognitive functioning (n = 1993, subjective memory complaints n = 1563, and brain structure n = 1935, see Fig. S1 for the total number of available participants per measurement).

Measurements

TBI

During the research visit participants were asked: “Have you ever lost consciousness after a head injury? (yes/no)”. History of TBI was defined as having had at least one self-reported brain injury with loss of consciousness in the past. Subsequently, participants were asked how long the duration of the loss of consciousness was (days, hours, minutes, or unknown). We categorized the duration of loss of consciousness into <30 min (mild), 30 min to 24 h (moderate), >24 h (severe), or of unknown duration.¹⁸ Although this information was not systematically collected, most participants also reported on when the brain injury had occurred. For these participants, we categorized the time post-injury into <1 year ago, 1–4 years ago, 5–9 years ago, and >10 years ago.

Cognitive functioning

Cognition was measured with six cognitive tests. First, we assessed verbal memory with the number of correct words mentioned during the delayed recall test of the 15-Word Learning Test.¹⁹ Second, we assessed processing and attention with the time it took the participant to complete the third (interference) task of the Stroop Task.²⁰ Because the Stroop Task is highly influenced by reading skills, we adjusted time at the third task for time at the first (reading) task. This adjusted variable has a mean (standard deviation [SD]) of 0 (1). Third, we assessed executive functioning, more specifically information processing speed, with the number of correct filled in letter–digit combinations during the Letter–Digit Substitution Test,²¹ which is a modified version of the Symbol Digit Modalities Test.²² Fourth, we assessed verbal fluency with the number of correct animals mentioned during the Word Fluency Test.²³ Fifth, we assessed dexterity and fine motor speed with the sum of the number of pins placed during the three trials of the Purdue Pegboard Test.²⁴ And sixth, we assessed visuospatial ability with the number of correct filled in boxes of the Design Organization Test.²⁵

Subjective memory complaints

During the research center visit, participants were asked several questions about subjective memory complaints. In this study, we only used the question “Do you experience more difficulty remembering things than before? (yes/no)”.²⁶ The questionnaire on subjective memory complaints was included in the study after March 2018, and was therefore not available for all participants.

Brain structure

We used a 3T GE Discovery MR750w MRI System (General Electric, Milwaukee, WI, USA) with the GE DV24 software package. Images were obtained using an eight-channel head coil. The complete MRI protocol has been extensively described elsewhere.¹⁶ In summary, image quality of all sequences was assessed during and after image processing with manual and automated methods.¹⁶ Three-dimensional (3D) acquired T₁-weighted images were processed through FreeSurfer version 6.0.0 and used to assess the structure of the brain: total brain volume (mL), frontal and temporal lobes volumes (mL), and gray and white matter volumes (mL).²⁷ We investigated the frontal and temporal lobe separately because previous MRI studies have suggested frontotemporal vulnerability after mild TBI.⁶ White matter hyperintensity volume (mL) and cortical and lacunar infarcts (at least one present vs. absent) were rated visually on a two-dimensional (2D) axial fluid-attenuated inversion recovery (FLAIR) sequence. We combined cortical and lacunar infarcts in our study because of the small number of cortical infarcts. Microbleeds (at least one present vs. absent) were visually rated on a T₂*-weighted sequence.

Covariables

Educational attainment and ethnic origin were assessed with questionnaires during several previous research visits in the context of the Generation-R study.¹⁷ We used the information of the latest visit available and categorized completed education into: (1) no education or primary education, (2) secondary education, and (3) higher education. Participants self-reported their ethnic origin and the variable was dichotomized into European and non-European. Depressive symptoms were assessed during the research visit using the Center for Epidemiological Studies Depression Scale (CES-D).^28,29 The CES-D score ranges from 0 to 60, with higher scores indicating more depressive symptoms. If answers were missing, a weighted average score was calculated; questionnaires with <15 of the 20 answers were counted as missing. The CES-D questionnaire was included in the study after March 2018 and was therefore not available for all participants.

Statistical analysis

We used multiple linear regression models for continuous outcomes and logistical regression models for dichotomous outcomes. Only participants with data available on the outcome measure were included in the models, and missing data of covariables (ranging from 1% to 21%) were imputed five times using chained equations and the analyses were pooled across imputations. Additionally, we Z-score standardized all continuous variables in our models in order to facilitate comparison of the different outcomes with each other. We Z-score standardized all the continuous variables, including all cognitive test scores, based on the current sample mean and SD. We analyzed the six cognitive tests, subjective memory complaints, and brain MRI outcomes in three models. In Model 1 we adjusted for age and sex, and, only for the brain MRI outcomes, intracranial volume. In Model 2 we additionally adjusted for educational attainment and ethnic origin. In Model 3 we additionally adjusted for CES-D score. We investigated the effect of depressive symptoms separately, because depressive symptoms could also be caused by a brain injury. We then repeated the analyses in groups based on the time post-injury (groups: 0–10 years ago, >10 years ago, unknown timing, reference: no TBI). And lastly, we repeated the analyses in groups based on the duration of the loss of consciousness (groups: >30 min, unknown duration, reference: no TBI). Results of the linear and logistical regression models are presented as the adjusted mean difference or odds ratio (OR) with 95% confidence intervals (95% CI). All statistical analyses were performed in R.4.0.4.

Results

The mean (SD) age of our sample was 47.6 (5.0) years, and 65% of the participants were women. In total, 250 (12%) participants reported a history of TBI. Of the participants who reported the timing of their TBI (n = 173), most (n = 151, 87%) reported that it had occurred >10 years ago. Additionally, most participants (n = 156, 62%) reported loss of consciousness of <30 min and 64 participants (26%) did not remember the duration of loss of consciousness. See Table 1 for all characteristics of the study population.

Table 1.

Characteristics of the Study Population

Characteristic
Sex, women	1311 (65)
Age, years	47.6 (5.0)
Educational attainment
None or primary	41 (2)
Secondary	651 (33)
Higher	1283 (65)
Ethnic origin, European	1507 (80)
Center for Epidemiologic Studies Depression scale (CES-D), score	7.7 (0.4)
Traumatic brain injury with loss of consciousness, present	250 (12)
Duration loss of consciousness, available	250/250 (100)
< 30 min	156 (62)
30 min to 24 h	23 (9)
> 24 h	7 (3)
Unknown	64 (26)
Timing of traumatic brain injury, available	173/250 (71)
> 10 years ago	151 (87)
5-9 years ago	8 (5)
1-4 years ago	8 (5)
< 1 year ago	6 (3)
Cognitive testing
15-Word Verbal Learning Test (WLT), number of correct words	8.2 (2.8)
Stroop Interference Task, standardized score	0.0 (1.0)
Letter Digit Substitution Test (LDST), number of correct combinations	36.5 (6.3)
Word Fluency Test (WFT), number of correctly named animals	27.6 (6.4)
Design Organization Test (DOT), number of correctly filled in boxes	37.4 (9.3)
Purdue Pegboard Test (PPB), sum of placed pins over three trials	39.4 (4.3)
Subjective memory complaints, present	476 (30)
Brain MRI measures
Total brain volume, mL	1101 (111)
Frontal lobes volume, mL	171 (18)
Temporal lobes volume, mL	105 (11)
Total white matter volume, mL	462 (58)
Total gray matter volume, mL	639 (58)
White matter hyper intensities volume, mL	0.5 (0)
Cerebral microbleeds, at least one present	191 (10)
Cortical infarcts, at least one present	15 (1)
Lacunar infarcts, at least one present	65 (3)

Continuous variables are presented as mean (standard deviation) if normally distributed or median (interquartile range) if not normally distributed, numbers are presented as n (%). Total available for variables with missings: educational attainment n = 1975 (99%), ethnic origin n = 1894 (94%), CES-D score n = 1577 (79%), subjective memory complaints n = 1563 (78%), 15-WLT n = 1921 (96%), Stroop n = 1924 (96%), LDST n = 1969 (98%), WFT n = 1865 (93%), DOT n = 1503 (75%), PPB n = 1239 (62%), all brain volumes n = 1880 (94%), white matter hyperintensity volume n = 1845 (92%), microbleeds n = 1863 (93%), infarcts n = 1909 (95%).

MRI, magnetic resonance imaging.

We found a weak association between history of TBI and lower scores on the Purdue Pegboard Test (adjusted mean difference: -0.16 per SD; 95% CI: -0.32, -0.00), with slight attenuation after adjustment for depressive symptoms (adjusted mean difference: -0.15 per SD; 95% CI: -0.31, 0.01; see Table 2). History of TBI was associated with having subjective memory complaints after adjustment for confounders (OR: 1.92; 95% CI: 1.41, 2.63), and after adjustment for depressive symptoms (OR: 1.87; 95% CI: 1.35, 2.58; see Table 2). We found no associations between history of TBI and any of the structural brain MRI outcomes (see Table 3). Additionally, the association between history of TBI and subjective memory complaints was also present when investigating only those >10 years post-injury (OR: 1.69; 95% CI 1.15, 2.50; Supplementary Table S1. Also, the association of history of TBI with subjective memory complaints was stronger in those with >30 min loss of consciousness (OR: 3.57; 95% CI: 1.48, 8.59), than in those with <30 min loss of consciousness (OR: 1.85; 95% CI 1.25. 2.74), when compared with those with no history of TBI (Supplementary Table S2). Lastly, we also did not find associations between history of TBI and any cognitive tests or structural brain MRI measures when analyzing groups separately based on the time since injury (see Supplementary Tables S1 and S3), or the duration of the loss of consciousness (Supplementary Tables S2 and S4).

Table 2.

Association Between History of Traumatic Brain Injury With Loss of Consciousness and Cognitive Testing and Subjective Memory Complaints

	Mean difference in cognitive test score (95% CI)						Odds ratio (95% CI)
Model	15-Word Learning Test (WLT)	Stroop Interference Task	Letter-Digit Substitution Test (LDST)	Word Fluency Test (WFT)	Design Organization Test (DOT)	Purdue Pegboard Test (PPB)	Subjective memory complaints
1	-0.04 (-0.17; 0.08)	0.01 (-0.12; 0.14)	-0.11 (-0.24; 0.02)	-0.10 (-0.24; 0.04)	0.00 (-0.15; 0.16)	-0.18 (-0.33; -0.02)	1.91 (1.40; 2.61)
2	-0.03 (-0.16; 0.10)	-0.01 (-0.14; 0.12)	-0.08 (-0.20; 0.05)	-0.05 (-0.18; 0.07)	0.03 (-0.11; 0.17)	-0.16 (-0.32; -0.00)	1.92 (1.41; 2.63)
3	-0.03 (-0.16; 0.09)	-0.02 (-0.15; 0.10)	-0.07 (-0.19; 0.05)	-0.05 (-0.18; 0.08)	0.04 (-0.10; 0.18)	-0.15 (-0.31; 0.01)	1.87 (1.35; 2.58)

Analyses per outcome were done in those with data available on the outcome measure: 15-WLT n = 1921, Stroop Task n = 1924, LDST n = 1969, WFT n = 1865, DOT n = 1503, PPB n = 1239, subjective memory complaints n = 1563. All cognitive tests were standardized. Model 1: Adjusted for age and sex. Model 2: As model 1, but additional adjustment for educational attainment and ethnic origin. Model 3: As model 2, but additional adjustment for Center for Epidemiologic Studies Depression scale score.

CI, confidence interval.

Table 3.

Association of History of Traumatic Brain Injury With Loss of Consciousness With Brain Structure

	Mean difference in brain volume (95% CI)						Odds ratio (95% CI)
Model	Total brain	Frontal lobes	Temporal lobes	White matter	Gray matter	White matter hyperintensities	Microbleeds	Infarcts
1	-0.01 (-0.05; 0.06)	-0.02 (-0.06; 0.10)	-0.02 (-0.06; 0.10)	-0.01 (-0.06; 0.08)	-0.01 (-0.05; 0.06)	-0.01 (-0.14; 0.13)	1.01 (0.63; 1.56)	1.33 (0.68; 2.40)
2	0.01 (-0.05; 0.07)	0.02 (-0.06; 0.10)	0.02 (-0.05; 0.10)	0.01 (-0.06; 0.08)	0.01 (-0.05; 0.07)	0.00 (-0.13; 0.14)	1.00 (0.64; 1.58)	1.28 (0.68; 2.40)
3	0.01 (-0.05; 0.07)	0.02 (-0.06; 0.10)	0.02 (-0.05; 0.10)	0.01 (-0.06; 0.08)	0.01 (-0.05; 0.07)	-0.00 (-0.14; 0.13)	1.00 (0.63; 1.57)	1.25 (0.66; 2.35)

Analyses per outcome were done in those with data available on the outcome measure: all brain volumes n = 1880, white matter hyperintensity volume n = 1845, microbleeds n = 1863, infarcts n = 1909. All volumetric brain measures were standardized. Model 1: Adjusted for age, sex, and intracranial volume. Model 2: As model 1, but additional adjustment for educational attainment and ethnic origin. Model 3: As model 2, but additional adjustment for Center for Epidemiologic Studies Depression scale score.

CI, confidence interval.

Discussion

In this study of community-dwelling adults, a history of TBI was not associated with mid-life objective cognitive functioning, but was associated with mid-life subjective memory complaints. This association was also present in participants who were >10 years post-injury. The association was stronger in those with >30 min loss of consciousness than in to those with <30 min loss of consciousness, when compared with those without history of TBI. Lastly, we found no association between a history of TBI and brain structure in mid-life.

We found no association between history of TBI and mid-life cognitive functioning. A previous study did find subtle long-term attention and memory deficits 8 years after mild TBI.⁷ However, this study only found these deficits when examining non-traditional specific measures of complex attention and working memory; namely, problems with continuation to completion of the Paced Auditory Serial Addition Test (PASAT) and excessive Proactive Interference.⁷ The study found no significant cognitive differences in a traditional group comparison manner; that is, when comparing the outcomes of 15 different neuropsychological tests between the groups, which is comparable with our findings. This may suggest that there may only be mild long-term attention and concentration deficits after mild TBI, if any. Still, there are more cognitive tests and domains that have not yet been investigated. Previous literature, however, also found no evidence for an association between TBI measured with a single-item TBI questionnaire and neuropathological outcomes.^30

–33 However, studies have shown that more severe TBI can increase the risk of dementia.^34,35

Our study suggests that even >10 years post-injury, persons with a history of TBI more often experience subjective memory complaints. A previous study with a similar post-injury interval lacked a control group without TBI for comparisons.⁵ However, that study found that patients with memory complaints 10 years after mild TBI more often had a lower quality of life than patients without memory complaints.⁵ It is of note that both history of a TBI and subjective memory complaints in our study were self-reported with a single question. However, the fact that the association between history of TBI and subjective memory complaints strengthened with injury severity contributes to the validity of our findings. Still, it is possible that participants have forgotten about their brain injury, especially those with subjective memory complaints, but this would only have led to an underestimation of our findings. Also, our other findings do not support this explanation, as we found no association between history of TBI and cognitive functioning. The nature of chronic subjective memory complaints after TBI seems to be multi-factorial.³⁶ Previous research suggested that particularly chronic situational stress and somatic and communication difficulties were associated with chronic subjective memory complaints.³⁶ Possibly, the association we found was partly explained by these or other uninvestigated factors. However, these factors could also be on the causal pathway, and therefore could be underlying mechanisms. Nonetheless, subjective memory complaints may lead to functional impairment in middle-aged adults,³⁷ and are, in the absence of objective cognitive impairment, also associated with a two times higher risk of dementia in older adults.³⁸ Therefore, if preventing TBI would decrease subjective memory complaints, it could also possibly decrease the risk of functional impairment and dementia, which for dementia has already been suggested.^34,35

We also found no associations between history of TBI and any of the volumetric and focal brain MRI measures, which is largely in line with previous studies. Previous cross-sectional studies on mild TBI also found no association with total brain volumes, even though several small longitudinal studies have documented total brain volume loss over time.⁶ Previous MRI studies have also shown a variety of regional changes after mild TBI, which tend to support the frontotemporal vulnerability, but to date no uniform, widespread changes consistent across all studies have emerged.⁶ This may be in line with our findings, as we also found no decreased frontal or temporal lobe volumes. Previous research in military personnel with persistent cognitive symptoms did find increased white matter hyperintensities after mild TBI,³⁹ but not consistently.¹⁵ Additionally, a longitudinal study in 30 patients did suggest that that traumatic microbleeds can persist up to 5 years after TBI, but this study lacked a control group for comparisons.¹² Our findings suggest no association between history of TBI and white matter hyperintensities and microbleeds. It is of note that we only included a limited number of structural neuroimaging outcomes in our study, whereas there are many other regions of interest.⁶ Also, a recent review emphasizes that structural volumetric findings in TBI are just a single facet of what should be a multi-modality approach to image analysis in TBI.⁶

Our study has several limitations. First, because we relied on self-reported data on a history of brain injury, exact details of the severity and time post-injury were often unknown. We could also only investigate TBI with loss of consciousness, whereas TBI can also occur without loss of consciousness.⁴⁰ Therefore, the 12% TBI prevalence that we found is an under-count of TBI that by definition excludes milder TBIs that do not result in loss of consciousness,⁴¹ which results in case misclassification that can bias findings toward the null. Second, we had no information available on whether participants had multiple brain injuries, which could have led to an overestimation our findings. Third, our measure of subjective memory complaints may have limitations. We used a single question as outcome in our study. However, this question is relevant, as previous studies have shown that persons who answer “yes” to this question have a higher risk of Alzheimer's disease (AD).²⁶ Another possibility is that those who self-report a history of TBI may be those whose TBIs resulted in residual symptoms, and are therefore more likely to report memory complaints than those who do not recall a clinically inconsequential TBI with loss of consciousness. However, this may be less likely, as participants and investigators did not know that the data were going to be used for this research question, and there was a substantial amount of time between asking the two questions on different subjects (>30 min) as both were embedded in a much more extensive interview. Fourth, our method of cognitive assessment was limited by the fact that we did not have more extensive neuropsychological assessments available in order to identify possible subtle long-term attention and memory deficits.⁷ And fifth, because of our cross-sectional design, the causality of our findings remains to be determined.

Strengths of this study include the large population-based sample with control group. This study includes a sample of middle-aged adults, whereas previous studies mostly include samples of older adults. Prior studies in older adults that also used a single-item TBI assessment methods mainly found no association between TBI and later-life cognitive and AD-related pathological outcomes.^30

–33 The current study can therefore be seen as incremental evidence supporting these findings in middle-aged adults. Our study therefore also includes participants who did not visit the emergency department, as many individuals with mild or moderate TBI do not seek medical advice.⁴² Because of the large sample size, we had sufficient statistical power and we were able to adjust for relevant confounders.

Conclusion

In conclusion, we found that participants with history of TBI with loss of consciousness more often had mid-life subjective memory complaints. We found no association between history of TBI with loss of consciousness and objective cognitive functioning or brain structure, which is largely in line with findings of previous research. Further research is needed to investigate the association between history of TBI and subjective memory complaints in adults with TBI without loss of consciousness. Additionally, further research could investigate the functional impairments and adverse health outcomes, such as the dementia risk, associated with TBI-related subjective memory complaints.

Transparency, Rigor, and Reproducibility Statement

The analysis plan for this research question was not formally pre-registered, but both the team member with primary responsibility for the analysis (J.L.Z.) and the supervising author (M.A.I.) certify that the analysis plan was pre-specified. The sample size for this research question was not previously calculated because the research question was specified after the data collection. Data were collected from 2083 participants. Data collection was performed by investigators who were blinded to the research question of this study. Data were acquired according to a standardized protocol between 2017 and 2020, on weekdays between 8:30 AM and 10:00 PM, using a neuropsychological test battery, brain MRI, surveys, and questionnaires. Data were labeled with codes linked to participant identifying information. Specific equipment and software used to perform acquisition and analysis are referenced to in the article. For this study. we excluded participants with missing data on TBI (n = 76), and no data on any of the outcome measures (n = 2). Therefore, the current study includes 2005 participants in total. The key inclusion criteria and primary outcome measures are established standards in the field (see the manuscript for references) and were assessed by investigators with at least a BSc in medicine, psychology, or epidemiology. We took the presence of other relevant clinical conditions and comorbidities into account by using multiple statistical models that included different relevant confounders. The assumptions of the linear regressions were based on linearity, homoscedasticity, independence, and normality. The assumptions of the logistical regressions were based on a binary dependent variable, little multi-collinearity among the independent variables, linearity of independent variables and log odds, and at minimum of 10 cases with the least frequent outcome for each independent variable in the model. Implications of possible violations of these assumptions include incorrect or misleading results. Missing data have been handled using the complete cases approach for the determinant and outcomes, and multiple imputation was used for missing data of covariables, as described in the article. Effect sizes and CIs have been reported in the abstract for primary outcomes and in the main text for all outcomes. Statistical analyses were performed by J.L.Z. whose qualifications include an MSc in epidemiology and medicine. Correction for multiple comparisons was not performed because we chose to report the effect estimates and Cis instead of statistical significance and p values. No replication or external validation studies have been performed or are ongoing at this time, to our knowledge. Because of restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository. However, data can be obtained upon request (datamanagementgenr@erasmusmc.nl). Analytic codes used to conduct the analyses presented in this study are not available in a public repository, but may be available by emailing the corresponding author as of June 20, 2022.

Funding Information

M.A.I. received funding from the European Union's Horizon 2020 research and innovation program (678543, ORACLE). The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam; the Erasmus University Rotterdam; and the Netherlands Organization for Health Research and Development. The funding sources had no role in the design, analyses, interpretation of the data, or decision to submit results of this study.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Supplementary Material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

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