Catherine M Calvin

Ian J Deary
email: ian.deary@ed.ac.uk

Candida Fenton

Beverly Roberts

Geoff Der

Nicola Leckenby

David Batty

G David Batty

Intelligence in youth

Keywords: intelligence, mortality, meta-analysis, socioeconomic factors, systematic review Intelligence, Mortality, Meta-analysis, Socioceconomic Factors, Systematic review. 50

come

with risk of death from all causes throughout adulthood. That is, higher intelligence appears to confer protection. This finding is replicated in prospective cohorts from 55 several Westernized countries [START_REF] Batty | Premorbid (early life) IQ and later mortality risk: systematic review[END_REF] , across different ranges of intelligence [START_REF] Leon | The association of childhood intelligence with mortality risk from adolescence to middle age: findings from the Aberdeen Children of the 1950s cohort study[END_REF] , and in followup periods from early through to late adulthood. [START_REF] Leon | The association of childhood intelligence with mortality risk from adolescence to middle age: findings from the Aberdeen Children of the 1950s cohort study[END_REF][START_REF] Batty | IQ in early adulthood and mortality by middle age: Cohort study of 1 million Swedish men[END_REF][START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF] Intelligence and somatic health may be inextricably linked throughout the life course. However, longitudinal studies help to establish causal pathway models of the effects of one upon the other. For example, morbidities such as diabetes, cancer, 60 stroke and peripheral atherosclerosis, and/or their treatments, are reported to cause a decline in cognitive function after longitudinal follow-up. [START_REF] Arvanitakis | Diabetes mellitus, dementia, and cognitive function in older persons[END_REF][START_REF] Comijs | Somatic chronic diseases and 6-year change in cognitive functioning among older persons[END_REF][START_REF] Kivipelto | Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease[END_REF][START_REF] Okereke | Type 2 diabetes mellitus and cognitive decline in two large cohorts of community-dwelling older adults[END_REF][START_REF] Rafnsson | Cardiovascular diseases and decline in cognitive function in an elderly community population: The Edinburgh Artery study[END_REF][START_REF] Yaffe | The metabolic syndrome, inflammation, and risk of cognitive decline[END_REF] This illness-to-cognitive ability direction of association is a commonplace finding. The reverse direction of association is studied less often, and has only recently come to be recognized under the term 'cognitive epidemiology'. [START_REF] Deary | Introduction to the special issue on cognitive epidemiology[END_REF][START_REF] Deary | Cognitive epidemiology[END_REF] That is, mental ability scores from early life 65 associated with later adulthood morbidities, and before any somatic symptoms or risk factors of disease are manifest, provide evidence that cognitive abilities may be predictive of later health outcomes.

The association between pre-morbid intelligence and adult all-cause mortality was the subject of a systematic review [START_REF] Batty | Premorbid (early life) IQ and later mortality risk: systematic review[END_REF] , in which all nine studies that met the 70 inclusion criteria demonstrated an inverse relationship between intelligence and risk of dying by follow-up. The review did not quantify the association. Furthermore, there were insufficient studies to address comprehensively a number of pertinent questions from this research domain. One issue is whether or not the association between intelligence and mortality is the same in women as in men. For example, it is possible 75 4 that sex differences in the incidence, age at onset of health behaviours, and the extent to which these act as risk factors for disease [START_REF] Anand | Risk factors for myocardial infarction in women and men: Insights from the INTERHEART study[END_REF][START_REF] Schenck-Gustafsson | Risk factors for cardiovascular disease in women[END_REF] , could produce sex-specific intelligence-mortality gradients. Data from many more men than women have been included in intelligence-mortality cohort studies to date, mainly due to some studies using military conscript databases. Moreover, when mixed-sex cohorts report 80 mortality risk as predicted by intelligence for men and women separately, they rarely test for statistical difference but, rather, report the observed trend. With more studies now reporting hazard ratios (HRs) for mortality by sex, there is an opportunity to quantify the predictive effects of intelligence on mortality separately for men and women. 85

A second issue yet to be evaluated systematically is the extent to which intelligence as a predictor of mortality is confounded by early life environmental influences including socioeconomic factors. Socioeconomic status (SES) is established as an important determinant of public health inequalities, [START_REF] Smith | A life course approach to chronic disease epidemiology[END_REF][START_REF] Gallo | Socioeconomic status and health: What is the role of reserve capacity?[END_REF][START_REF] Macintyre | Human biology and social inequality: 39th symposium volume of the Society for the Study of Human Biology[END_REF][START_REF] Marmot | Strategic review of health inequalities in England post-2010[END_REF] including risk of mortality, and it can carry influence in childhood, via factors such as family 90 income and parental education, to predict individual differences in childhood intelligence. [START_REF] Lawlor | Early life predictors of childhood intelligence: Evidence from the Aberdeen children of the 1950s study[END_REF][START_REF] Mcloyd | Socioeconomic disadvantage and child development[END_REF] In this context, therefore, intelligence may be considered a mediating variable on the pathway between early life influences and adult health outcomes. If early social factors substantially confound the link between intelligence and longevity, then adjusting for childhood SES would sizeably attenuate the effect size of the 95 association between intelligence and mortality. In their systematic review [START_REF] Batty | Premorbid (early life) IQ and later mortality risk: systematic review[END_REF] Batty et al identified three out of nine studies that adjusted for childhood SES: one of these showed no change from an unadjusted model, and two had modest attenuating effects, suggesting that intelligence has independent effects on risk of mortality from those of early socioeconomic influences. Due to this small number of studies, the role of 100 childhood SES in the intelligence-mortality link requires further investigation.

One explanation why intelligence may exert an influence on life expectancy is its ability to predict educational outcomes [START_REF] Deary | Intelligence and educational achievement[END_REF] and occupational class, [START_REF] Schmidt | General mental ability in the world of work: Occupational attainment and job performance[END_REF] which can both affect health outcomes via a number of mechanisms, for example the knowledge and living conditions that contribute to better personal health risk assessment, behaviours 105 and management. [START_REF] Torssander | Stratification and mortality -a comparison of education, class, status, and income[END_REF] In population studies these adult SES factors are themselves inversely associated with risk of mortality. [START_REF] Dewalt | Literacy and health outcomes: A review of the literature[END_REF][START_REF] Huisman | Educational inequalities in cause-specific mortality in middle-aged and older men and women in eight western European populations[END_REF][START_REF] Lleras-Muney | The relationship between education and adult mortality in the United States[END_REF] Some prospective cohorts take account of the attenuating effects of education and adult socioeconomic status in estimating the risk of mortality according to intelligence; yet, to date, their influence has not been properly evaluated. 110

Investigators are giving increasing attention to the issues raised here, with a higher rate of publications reporting risk estimates for all-cause mortality according to differences in intelligence since the first systematic review. [START_REF] Batty | Premorbid (early life) IQ and later mortality risk: systematic review[END_REF] There is now an opportunity to reevaluate this augmented literature, this time with a quantitative, meta-analytic approach. The systematic review by Batty et al 1 reported the overall 115 quality of the nine studies as 'moderate', which was in part related to the weak validity of some measures of premorbid intelligence. Therefore, one important change to the systematic process reported here is the inclusion of studies in which only valid cognitive assessments were used. Kilgour et al [START_REF] Kilgour | Associations between childhood intelligence (IQ), adult morbidity and mortality[END_REF] also raised a number of methodological considerations that should be addressed in intelligence-mortality 120 studies, including taking account of ascertainment bias, age, sex, and education. In this paper we address the influence of these factors using sub-group analyses.

Accordingly, the aims of this report are to: (1) quantify the association between pre-morbid intelligence and all-cause mortality; (2) determine whether there 7 criteria listed below were applied to their respective shortlists of papers. The reference 150 lists of the selected articles were then examined, along with review papers on intelligence and mortality, and our own personal files, for articles that the electronic search might have missed. Among the final list of articles, when more than one paper reported intelligence-mortality associations from the same cohort, thereby duplicating data, three authors (CC, DB and ID) agreed upon those papers to be retained, 155 according to criteria of the following order: (1) the article reported HRs for mortality per one standard deviation difference in IQ-type score; (2) the cohort size was larger;

(3) it was the original publication to report the data.

Inclusion Criteria 160

We included published cohort data which fulfilled criteria similar to that of the previous systematic review on intelligence and all-cause mortality 1 : (1) to minimise risk of reverse causality, only cohorts where intelligence test score data were collected at a mean age of 24 years or younger were included (the period classified as childhood and youth according to the World Health Organisation Study Group 28 ); (2) the 165 intelligence and mortality data were collected at the level of the individual; (3) the relationship between intelligence and all-cause mortality was reported quantitatively.

We also stipulated that: (4) the premorbid test should demonstrate an acceptable degree of validity as a measure of intelligence; and (5) the cohort was not selected from a clinical or unrepresentative population. 170

Statistical Analysis

The hazard ratio (HR) with 95% confidence intervals (CI) for all-cause mortality per SD advantage in intelligence test score was the principal outcome variable. For HRs odds ratios (ORs) were treated as HRs, with the caveat that these effect estimates approximate one another [START_REF] Greenland | Interpretation and choice of effect measures in epidemiologic analyses[END_REF] when the incidence of an event (i.e. mortality) is low. [START_REF] Symons | Hazard rate ratio and epidemiological studies[END_REF] In case-control studies reporting intelligence test means for living and deceased, we converted the standardised mean difference to an OR using formulae by Chinn. [START_REF] Chinn | A simple method for converting an odds ratio to effect size for use in meta-analysis[END_REF] We contacted authors if we were unable to derive an overall effect size from their 180 published data.

Fixed effects models were assumed for the aggregation of HRs based on evidence of a low degree of heterogeneity (p < 0.10) [START_REF] Sutton | Methods for metaanalysis in medical research[END_REF] Sub-group analyses were conducted by sex group, for those studies to adjust for SES variables, and by study characteristic groupings for the purposes of sensitivity analysis. MIX 1.5 software 33 185 was used for all analyses and production of plots. The inverse variance method was used to weight studies' effect sizes.

Sensitivity analyses and publication bias

Sensitivity analyses aggregated effect sizes by the following study characteristics: 190 ascertainment rate at follow-up; age at intelligence testing; cohort size; duration of follow-up; average birth year of the cohort; effect size measure (see Table 2 for group parameters). Ascertainment rate may bias the intelligence-mortality effect size if those who emigrate, and are therefore excluded from follow-up, differ on cognitive ability scores compared to those who remain within geographical regions for census. Follow-195 up rates were estimated based on the proportion of participants from the original cohort that were followed up and included in the final analyses, regardless of whether or not intelligence test scores were available for them. Studies were grouped on the basis of <80% or 80-100% ascertainment rates. We aggregated studies according to intellectual function increases with age and, with it, the risk of reverse causation bias in the intelligence-mortality link. Conversely, the validity of cognitive testing may be greater in older cohorts, and these may reflect more homogeneous results compared to results of younger children at intelligence testing for whom there is more measurement error. For the duration of follow-up, we divided studies on the basis of a 205 median split of the years traced for mortality. Although there may be stronger grounds for assuming causality as the time period between intelligence testing and mortality increases, there is also evidence that, by older adulthood, the intelligencemortality association loses significance. [START_REF] Hart | Childhood IQ and all-cause mortality before and after age 65: prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF] The reason for aggregating studies that reported HRs or ORs was to ensure that our treatment of these measures of 210 association did not inflate the overall effect size. We also grouped according to cohort size and decade of birth, as these may also have influenced heterogeneity across the studies. We did not aggregate for population representativeness as one of our criteria ensured the exclusion of clinical samples. However, due to two study cohorts being less representative of the general population (twins and gifted children) than all 215 others, we have reported meta-analytic results with and without their effect sizes. [START_REF] Holsinger | Intelligence in early adulthood and life span up to 65 years later in male elderly twins[END_REF][START_REF] Martin | Childhood cognitive performance and risk of mortality: A prospective cohort study of gifted individuals[END_REF] The funnel plot was used to assess publication bias with standard error on the y-axis as recommended by Sterne and Egger. [START_REF] Sterne | Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis[END_REF] Publication bias was further evaluated with Egger's test of asymmetry, and trim-and-fill adjustment methods. The electronic search resulted in 19 236 publications and, of these, the two reviewers (CC, NL) extracted shortlists of 73 and 69 relevant articles, respectively (<0.4% of 225 total publications), from which 90 non-duplicate publications were retrieved for closer inspection (see Figure 1 for review process). Among these, 64 failed to meet one or more inclusion criteria. A further three studies that met inclusion criteria were identified from the reference lists of the remaining 26 papers, or from review articles or our own records. [START_REF] Deary | IQ at age 11 and longevity: Results from a follow-up of the Scottish Mental Survey[END_REF][START_REF] Furu | Premature death, cognitive ability and socioeconomic background[END_REF][START_REF] Link | The resources that matter: Fundamental social causes of health disparities and the challenge of intelligence[END_REF] Two out of 29 studies were excluded [START_REF] Furu | Premature death, cognitive ability and socioeconomic background[END_REF][START_REF] Link | The resources that matter: Fundamental social causes of health disparities and the challenge of intelligence[END_REF] because we were 230 unable to obtain sufficient data to calculate the intelligence-mortality effect sizes.

220

Results

Systematic retrieval of studies

(Table 1 lists the characteristics of the final 27 studies). We excluded eleven articles from the meta-analysis because they overlapped with cohort data of another report. [START_REF] Hart | Childhood IQ and all-cause mortality before and after age 65: prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF][START_REF] Deary | IQ at age 11 and longevity: Results from a follow-up of the Scottish Mental Survey[END_REF][START_REF] Batty | Premorbid intelligence, the metabolic syndrome and mortality: The Vietnam Experience Study[END_REF][START_REF] Batty | Is low IQ related to risk of death by homicide? Testing a hypothesis using data from the Vietnam Experience Study[END_REF][START_REF] Batty | Does IQ predict total and cardiovascular disease mortality as strongly as other risk factors? Comparison of effect estimates using the Vietnam Experience Study[END_REF][START_REF] Deary | The impact of childhood intelligence on later life: Following up the Scottish mental surveys of 1932 and 1947[END_REF][START_REF] Hemmingsson | Cognitive ability in adolescence and mortality in middle age: A prospective life course study[END_REF][START_REF] Kuh | Childhood cognitive ability and deaths up until middle age: A post-war birth cohort study[END_REF][START_REF] Starr | All-cause mortality in the Aberdeen 1921 birth cohort: Effects of socio-demographic, physical and cognitive factors[END_REF][START_REF] Vagero | Commentary: The associations between height, cognition, and education and their relevance for health studies[END_REF][START_REF] Weiss | Emotionally stable, intelligent men live longer: The Vietnam Experience Study cohort[END_REF] Justification for excluding these data were: (1) the overlapping reports of a sample were generally reported by the same research group resulting in consistent 235 methods of sample selection and data linkage; (2) the majority of overlapping cohorts were of similar size and follow-up duration.

[Figure 1 years. Six cohorts were all-male (five from conscription databases), and the remainder 250 were mixed sex. A variety of cognitive assessments were used across studies, and we identified evidence for each of them as having validity as standardized measures of intelligence. The concurrent or predictive validity of five tests used across nine of the study cohorts [START_REF] Batty | IQ in early adulthood and mortality by middle age: Cohort study of 1 million Swedish men[END_REF][START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF][START_REF] Holsinger | Intelligence in early adulthood and life span up to 65 years later in male elderly twins[END_REF][START_REF] Hemmingsson | The association between cognitive ability measured at ages 18-20 and mortality during 30 years of followup--a prospective observational study among Swedish males born 1949-51[END_REF][START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF][START_REF] Lager | The association of early IQ and education with mortality: 65 year longitudinal study in Malmo, Sweden[END_REF][START_REF] O'toole | Risk factors for mortality in Australian Vietnam-era national servicemen: A case-control study[END_REF][START_REF] Whalley | Longitudinal cohort study of childhood IQ and survival up to age 76[END_REF] have been described elsewhere. [START_REF] Batty | Premorbid (early life) IQ and later mortality risk: systematic review[END_REF] Here we describe evidence for psychometric validity among the seven remaining cohorts. 255

The Binet and Stanford-Binet tests used in two studies [START_REF] Martin | Childhood cognitive performance and risk of mortality: A prospective cohort study of gifted individuals[END_REF][START_REF] Deary | More intelligent, more dependable children live longer: A 55-year longitudinal study of a representative sample of the Scottish nation[END_REF] House series. [START_REF] Thomson | What are Moray House Tests?[END_REF] The first incorporated Moray House tests 57 and 58 in an eleven-plus examination that also assessed language and arithmetic. [START_REF] Pearce | Childhood IQ and deaths up to middle age: The Newcastle Thousand Families Study[END_REF] On this exam, total scores have shown well-established associations with childhood height at ages nine and 13 years. [START_REF] Pearce | Growth in early life and childhood IQ at age 11 years: The Newcastle Thousand Families Study[END_REF] The second 2 used Moray House Picture Tests 1 and 2, which have also shown expected patterns of association with intrauterine and childhood growth. [START_REF] Lawlor | Early life predictors of childhood intelligence: Evidence from the Aberdeen children of the 1950s study[END_REF] The 265 Härnquist test used in the Danish Metropolit study [START_REF] Osler | Socioeconomic position in early life, birth weight, childhood cognitive function, and adult mortality: A longitudinal study of Danish men born in 1953[END_REF] has shown concurrent validity: a general intelligence factor extracted from scores on the test at age 13 years strongly positively correlated (r = 0.78) with a military classification intelligence test taken five years later. [START_REF] Härnqvist | Relative changes in intelligence from 13 to 18: II. Results[END_REF] The Armed Forces Qualification Test (AFQT) used in another study [START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF] strongly correlates with other well-validated IQ tests (median r with seven 270 tests = 0.81), and scores on the four subtests show high loadings on a single g factor, from 0.81 to 0.87. [START_REF] Herrnstein | The Bell Curve[END_REF] Finally, the Vietnam Experience Study 65 used the Army General Records of mortality were ascertained prospectively in seven studies, either by linkage of study members to national register databases [START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF][START_REF] Holsinger | Intelligence in early adulthood and life span up to 65 years later in male elderly twins[END_REF][START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF][START_REF] Pearce | Childhood IQ and deaths up to middle age: The Newcastle Thousand Families Study[END_REF] or by individual 280 follow-up with study participants or their families. [START_REF] Martin | Childhood cognitive performance and risk of mortality: A prospective cohort study of gifted individuals[END_REF][START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF] In the remaining studies, incidence of death was ascertained retrospectively by access to national death registers-in Swedish cohorts record linkage used personal identification numbers rather than person names [START_REF] Batty | IQ in early adulthood and mortality by middle age: Cohort study of 1 million Swedish men[END_REF][START_REF] Hemmingsson | The association between cognitive ability measured at ages 18-20 and mortality during 30 years of followup--a prospective observational study among Swedish males born 1949-51[END_REF][START_REF] Lager | The association of early IQ and education with mortality: 65 year longitudinal study in Malmo, Sweden[END_REF] -with the exception of two studies that did not report methods for extracting death records. 54, 65 285 Ten papers estimated the intelligence-mortality effect size as a HR with CIs, 2-4, 36, 50, 53, 55, 56, 59, 65 two used ORs or logistic regression coefficients, [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF] and two reported means and standard deviations that we converted to ORs. [START_REF] Holsinger | Intelligence in early adulthood and life span up to 65 years later in male elderly twins[END_REF][START_REF] O'toole | Risk factors for mortality in Australian Vietnam-era national servicemen: A case-control study[END_REF] Authors of the two remaining papers provided HRs [START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF][START_REF] Osler | Socioeconomic position in early life, birth weight, childhood cognitive function, and adult mortality: A longitudinal study of Danish men born in 1953[END_REF] in response to email requests, which were unreported in their original publications. 290

[Table 1 about here]

Intelligence-mortality meta-analysis: basic model

In the basic model, the HR from each of the 16 studies was either: unadjusted (n = 2), 295 adjusted for age (n = 3), sex (n = 3), age and sex (n = 3), or was unspecified (n = 5) 1). However, there was a low degree of heterogeneity between the effect sizes of these models (Q = 17.7, I 2 = 15.5%, p = 0.28). In a fixed effects model, a one SD advantage in intelligence was associated with the lower risk of all-cause mortality (HR 0.76, 95% CI 0.75-0.77) (see Figure 3). The exclusion of two studies [START_REF] Holsinger | Intelligence in early adulthood and life span up to 65 years later in male elderly twins[END_REF][START_REF] Martin | Childhood cognitive performance and risk of mortality: A prospective cohort study of gifted individuals[END_REF] based 300 on selected samples (twins and gifted children) did not alter this estimate; neither did the exclusion of two studies that reported ORs and where incidence of death was between 20-40% [START_REF] Holsinger | Intelligence in early adulthood and life span up to 65 years later in male elderly twins[END_REF][START_REF] O'toole | Risk factors for mortality in Australian Vietnam-era national servicemen: A case-control study[END_REF] (data not shown). The statistical weight of the largest study 3 was 70.5%; excluding this cohort from the model made a negligible change to the effect of intelligence on risk of mortality (HR 0.77, 95% CI 0.75-0.80). 305

F o r R e v i e w O n l y 13 (Table
[Figure 3 about here] Sensitivity analyses results are presented in Table 2. Age at intelligence testing may have had a small effect in predicting the risk of mortality. Aggregation of studies 310 in which premorbid intelligence was tested at an average age of between seven to 12 years resulted in a small attenuation (16%) of the risk of mortality (HR 0.79, 95% CI 0.76-0.82) compared to that of 18 to 20 year olds (HR 0.75, 95% CI 0.74-0.77).

Studies of longer follow-up (40 to 69 years) showed a 20% attenuation of the risk of mortality as predicted by a one SD advantage in intelligence (HR 0.80, 95% CI 0.76-315 0.83), compared to those cohorts of shorter follow-up (HR 0.75, 95% CI 0.74-0.77).

Furthermore, there was a trend for cohorts born in the 1910s and 1920s to show an attenuated effect size compared to those cohorts born in the 1930s to 1960s. However, these older age cohorts were also those with a longer duration of follow-up.

Ascertainment bias was unlikely to have affected the total aggregate HR. That 320 is, studies of low ascertainment (62-79%) showed a similar aggregate effect size (HR F o r R e v i e w O n l y 14 0.76, 95% CI 0.75-0.78) to that of studies with 80-100% ascertainment (HR 0.77, 95% CI 0.74-0.80). There was also no observable effect of cohort size on the magnitude of the intelligence-mortality association.

The aggregate effect size for studies reporting ORs resulted in a higher risk of 325 mortality as predicted by intelligence (0.71, 95% CI 0.64-0.79) compared to the aggregate effect size from studies reporting HRs (0.76, 95% CI 0.75-0.78). However, the four studies reporting ORs had among the lowest weightings of the 16 cohorts (0.42-1.08%), which may explain why their inclusion in the basic model was less likely to have incurred statistical bias. 330

Publication bias was first addressed by examination of the funnel plot, which revealed one study [START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF] on the outside of 95% CI parameters (see Figure 4). Egger's test of asymmetry supported a low risk of publication bias (Intercept = 0.10, 95% CI -0.72-0.91, p = 0.81), as did application of trim and fill adjustments in which only one missing study was estimated, and its imputation made no difference to the magnitude 335 of the risk estimate (HR 0.76, 95% CI 0.75-0.78).

[Figure 4 about here]

Stratification by sex 340

Seven studies reported intelligence-mortality effect sizes for men and women separately, and their follow up spanned 24 to 65 years. 2, 51-53, 55, 59, 63 During this period the absolute risk of death was 5.6% for women and 8.2% for men. Four out of the seven studies reported negligible sex differences [START_REF] Leon | The association of childhood intelligence with mortality risk from adolescence to middle age: findings from the Aberdeen Children of the 1950s cohort study[END_REF][START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF][START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF] (two of these formally tested intelligence × sex interaction effects), two reported a stronger effect for men 345

F o r R e v i e w O n l y
15 (one reported a null effect in women with an intelligence × sex interaction effect), [START_REF] Lager | The association of early IQ and education with mortality: 65 year longitudinal study in Malmo, Sweden[END_REF][START_REF] Pearce | Childhood IQ and deaths up to middle age: The Newcastle Thousand Families Study[END_REF] and one reported a stronger effect in women. [START_REF] Whalley | Longitudinal cohort study of childhood IQ and survival up to age 76[END_REF] However, fixed effects models were applied to aggregate the sex-specific HRs, given the evidence for low heterogeneity (Table 2). A one SD advantage in intelligence among women was associated with a 22% lower risk of all-cause mortality (HR 0.78, 95% CI 0.73-0.84), whereas among 350 men there was a 20% reduced risk of mortality per one SD advantage in intelligence (HR 0.80, 95% CI 0.76-0.85). Nevertheless, there was a high degree of overlap in the confidence intervals of these respective effect sizes. Egger's test of asymmetry supported a lack of publication bias among sex-specific cohorts.

[Table 2 about here]

Adjustment for childhood SES

Nine studies that included 18 733 deaths, reported effect size models adjusted for childhood socioeconomic status, measured either by father's occupation or income [START_REF] Leon | The association of childhood intelligence with mortality risk from adolescence to middle age: findings from the Aberdeen Children of the 1950s cohort study[END_REF][START_REF] Martin | Childhood cognitive performance and risk of mortality: A prospective cohort study of gifted individuals[END_REF], 360 50, 51, 56, 59, 61 , the highest socioeconomic index recorded for either parent [START_REF] Batty | IQ in early adulthood and mortality by middle age: Cohort study of 1 million Swedish men[END_REF] , or father's education. [START_REF] Lager | The association of early IQ and education with mortality: 65 year longitudinal study in Malmo, Sweden[END_REF] Heterogeneity was very low in unadjusted (Q = 8.56, I 2 = 6.6%, p = 0.38) and adjusted models (Q = 7.49, I 2 = 0.0%, p = 0.48). In a fixed effects basic model the HR for this sub-group of papers did not deviate from the HR for the 16 studies (HR 0.76, 95% CI 0.75-0.77). However, even after adjustment for childhood SES there 365 was a very small attenuation (by 4%) of the effect size (HR 0.77, 95% CI 0.75-0.79) (see Figure 5). Excluding the large study of over one million Swedish men had no effect on the aggregate effect size of the childhood SES-adjusted model, except to slightly widen the 95% CI parameters (HR 0.77, 95% CI 0.74-0. A tenth publication [START_REF] Kuh | Childhood cognitive ability and deaths up until middle age: A post-war birth cohort study[END_REF] from the systematic review, that could not be included in meta-analysis, reported data consistent with this finding: early life socioeconomic 375 inequalities do little to explain the inverse association between intelligence and allcause-mortality.

Controlling for adult SES and education

There was no evidence for publication bias among studies that controlled for adult 380 SES or education. In five studies that adjusted for adult SES, there were 3070 deaths among 66 301 participants. Socioeconomic status was measured either by occupational social class [START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF][START_REF] Hemmingsson | The association between cognitive ability measured at ages 18-20 and mortality during 30 years of followup--a prospective observational study among Swedish males born 1949-51[END_REF][START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Deary | More intelligent, more dependable children live longer: A 55-year longitudinal study of a representative sample of the Scottish nation[END_REF] , or income. [START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] The unadjusted effect size for this subgroup of studies (HR 0.76, 95% CI 0.72-0.79) matched that of all 16 studies. After adjustment for adulthood SES, the lower risk of mortality predicted by higher 385 intelligence was attenuated by 33.5% from the basic model (HR 0.84, 95% CI 0.78-0.90) (see Figure 5).

Among the six studies that adjusted for educational attainment there were 16 023 deaths out of 1 026 742 participants. [START_REF] Batty | IQ in early adulthood and mortality by middle age: Cohort study of 1 million Swedish men[END_REF][START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Lager | The association of early IQ and education with mortality: 65 year longitudinal study in Malmo, Sweden[END_REF][START_REF] Deary | More intelligent, more dependable children live longer: A 55-year longitudinal study of a representative sample of the Scottish nation[END_REF][START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF][START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] Again, the aggregate effect size for this sub-group of studies in an unadjusted model (HR 0.76, 95% CI 0.74-0.77) was 390 no different from that for all 16 studies. After adjustment for education (HR 0.89, 95% CI 0.86-0.91), the effect of intelligence on mortality was reduced by 54.2% (see Figure 5). Exclusion of the large Swedish cohort [START_REF] Batty | IQ in early adulthood and mortality by middle age: Cohort study of 1 million Swedish men[END_REF] Two further studies from the systematic review, [START_REF] Hemmingsson | Cognitive ability in adolescence and mortality in middle age: A prospective life course study[END_REF][START_REF] Kuh | Childhood cognitive ability and deaths up until middle age: A post-war birth cohort study[END_REF] excluded from metaanalysis due to the type of statistics reported, are consistent with our result. They observed attenuation effects by education of over one third, of the intelligencemortality association.

400

[Figure 5 about here]

Multiple covariates

Eleven studies, including 15 148 deaths, reported effect sizes for the risk of mortality according to intelligence while adjusting for multiple variables 2-4, 50-52, 54, 56, 61, 63, 65 , (see Table 1 for covariates). Among these cohorts, four showed entire attenuation of 405 the intelligence-mortality effect size from unadjusted (or basic) models. [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF][START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF][START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] These studies tended to adjust for adult SES variables with the addition of other important covariates, including education [START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF] or smoking [START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF] among other cardiovascular disease risk factors. [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] The remaining studies reported a smaller degree of attenuation from unadjusted models. Due to the varying number and nature of 410 covariates across the studies it not appropriate to aggregate their effect sizes in metaanalyses.

Discussion

The present meta-analysis of 16 published prospective cohort studies, comprising over 415 consistently-reported association between higher premorbid intelligence and lower mortality risk. A one SD advantage in intelligence in childhood and youth was associated with a 24% lower risk of mortality. The effect was similar in men and women, and was not explained by socioeconomic differences in early life, as 420 indicated by parental occupation or income. The association was attenuated by approximately a third after adjusting for adult SES and by approximately a half after adjusting for educational experience. Intelligence remained a predictor of mortality after these attenuating effects, and removal of one study that carried by far the largest weighting in the models 3 did little to change the magnitude of these effects. 425 This is the first meta-analysis of studies examining the relationship between premorbid intelligence and all-cause mortality. A recent systematic review, which was based on nine identified at that time, reported the inverse association. [START_REF] Batty | Premorbid (early life) IQ and later mortality risk: systematic review[END_REF] Since then the number of publications of the intelligence-mortality association has grown, and the 16 unrelated cohorts we identified represent more than four times as many deaths. We 430 found little evidence of publication bias, and so the estimated risk of mortality according to one SD advantage in intelligence may be generalized to cohorts beyond those included in this meta-analysis, at least to those of the five countries included in the analyses. Our treatment of ORs as HRs in two studies where the absolute risk of death was >5%, which could have incurred statistical error, was not found to inflate 435 the aggregate effect size.

Heterogeneity was not apparent across the studies despite most using different assessments of premorbid intelligence. This may be because most omnibus intelligence tests of the types used in the identified studies show strong loadings on general intelligence, g. [START_REF] Guo | The mechanisms mediating the effects of poverty on children's intellectual development[END_REF] The intelligence-mortality association was however slightly 440 weaker among cohorts of younger ages at cognitive testing, and those of longer As it was the same cohorts that were followed up beyond forty years who were the youngest at intelligence testing, it is difficult to establish which factor would make the larger contribution to attenuating the intelligence-mortality association. However, it seems less likely to have been due to differences in the 445 validity of intelligence tests taken at younger and older ages, given the equally low heterogeneity among these two cohort groupings. It may be that older cohorts at cognitive testing show a steeper intelligence-mortality gradient because of the increased likelihood of bodily insults, or, it is still possible that the association varies according to age at mortality, most likely due to cause of death. 450

Lack of confounding by sex and early life SES

Our observation of negligible differences between men and women in the relative risk of mortality as predicted by intelligence, may be surprising given well-documented sex differences in patterns of risk factors, onset and prevalence of specific diseases, 455 and life expectancies. [START_REF] Wingard | The sex differential in morbidity, mortality, and lifestyle[END_REF] However, there were exceptions in individual studies, with differences between men and women reported, although there seem to be cohortspecific explanations for these. In one study [START_REF] Whalley | Longitudinal cohort study of childhood IQ and survival up to age 76[END_REF] the lower relative risk among men was probably due to the rise in deaths of higher intelligence servicemen during World War II. [START_REF] Corley | Childhood IQ and in-service mortality in Scottish army personnel during World War II[END_REF] In another, the lower relative risk among women could have resulted from a lack 460 of statistical power due to the small number of female deaths. [START_REF] Pearce | Childhood IQ and deaths up to middle age: The Newcastle Thousand Families Study[END_REF] The result from an older birth cohort study [START_REF] Lager | The association of early IQ and education with mortality: 65 year longitudinal study in Malmo, Sweden[END_REF] of a null association among women, could have been influenced by a relatively higher incidence of smoking among well-educated women during an era before the health hazards of smoking were widely known. In general however, data from large post-war birth cohort studies show negligible sex 465 differences in the effects of intelligence in relation to risk of mortality, and results that the mechanisms which explain the intelligence-mortality association act in equal measure for men and women, and it continues to be of interest to study sex differences in cognitive epidemiology. Differences in health behaviours, risk patterns 470 and medical interventions should also be considered when comparing ethnic groups or diverse countries. However, there is currently a lack of cohort data to evaluate how such group differences influence the risk of all-cause mortality as predicted by premorbid intelligence.

F

Socioeconomic conditions in early life, determined by parental occupation or 475 income, were also unlikely confounders. Individual differences in cognitive ability appear to act independently of childhood social inequalities in predicting all-cause mortality. There may of course be alternative early life factors contributing to confounding which were not covariates of the cohorts we reviewed. Among three studies that adjusted for birth weight in multivariate-adjusted models, one reported no 480 change from unadjusted models, [START_REF] Leon | The association of childhood intelligence with mortality risk from adolescence to middle age: findings from the Aberdeen Children of the 1950s cohort study[END_REF] and two reported a risk attenuation of 1% and 4% respectively compared to models that adjusted for childhood SES [START_REF] Osler | Socioeconomic position in early life, birth weight, childhood cognitive function, and adult mortality: A longitudinal study of Danish men born in 1953[END_REF] and education. [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF] However, recent evidence suggests that birth weight may not be the ideal indicator for exposures in the intrauterine environment, which carry their most critical influence on neurological and physiological development during the early prenatal period. [START_REF] Kelly | The Scourge of Asian Flu: In Utero Exposure to Pandemic Influenza and the Development of a Cohort of British Children[END_REF] Other 485 qualitative characteristics in early childhood may further explain the relationship between premorbid intelligence and longevity, [START_REF] Kilgour | Associations between childhood intelligence (IQ), adult morbidity and mortality[END_REF] including style of parenting and cognitive stimulation at home, [START_REF] Guo | The mechanisms mediating the effects of poverty on children's intellectual development[END_REF] or the effects of diet. However, so far, the potential confounding of these early life factors have not been demonstrated, and these other suggested variables are likely to be associated with parental intelligence. 490

Attenuation of the intelligence-mortality association

Education and adult SES were found partially to attenuate the risk of mortality according to one SD advantage in intelligence. Premorbid cognitive ability may act via occupational status and wealth to reduce the risk of mortality, by providing a less 495 hazardous work environment, a safer and more comfortable home environment, and the material means to access better and more immediate medical care. Furthermore, intelligence may be mediated by education to reduce the likelihood of death, perhaps by increasing a person's receptivity to health education messages (thereby reducing negative behaviours such as smoking and excess alcohol consumption, and promoting 500 exercise and healthy eating), and by improving comprehension of medical terminology and instruction that impacts on disease management and prevention.

Nevertheless, the results to date cannot tell us for certain whether education and adult SES are simply partial mediators of the association between intelligence and mortality; or whether the results reflect over-adjustments if both factors are partial 505 surrogates for intelligence; or if these variables confound intelligence-mortality associations. [START_REF] Batty | Education and mortality: The role of intelligence[END_REF] Structural equation modelling can examine for statistical mediation, and one study to employ this technique reported that the effect of general intelligence factor on mortality was entirely mediated by income, education and poor physical health in adulthood. [START_REF] Weiss | Emotionally stable, intelligent men live longer: The Vietnam Experience Study cohort[END_REF] However, in this study, with cognitive ability measured at age 510 20, the association between intelligence and mortality could also have been partially confounded by education. In our meta-analyses, two out of five studies that adjusted for adult SES, [START_REF] Hemmingsson | The association between cognitive ability measured at ages 18-20 and mortality during 30 years of followup--a prospective observational study among Swedish males born 1949-51[END_REF][START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] and three out of six studies adjusting for education, [START_REF] Batty | IQ in early adulthood and mortality by middle age: Cohort study of 1 million Swedish men[END_REF][START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF][START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] [START_REF] Deary | Intelligence and education: causal perceptions drive analytic processes and therefore conclusions[END_REF] Therefore reciprocal dynamic pathways between intelligence, education and adult SES need to be considered.

Few studies in the meta-analysis adjusted for both education and adult SES in 520 the same model. It is suggested that both factors may overlap in their attenuation effects on the intelligence-mortality association, [START_REF] Link | The resources that matter: Fundamental social causes of health disparities and the challenge of intelligence[END_REF] but there is also evidence to show that they are not interchangeable, and have independent effects on health outcomes. [START_REF] Geyer | Education, income, and occupational class cannot be used interchangeably in social epidemiology. Empirical evidence against a common practice[END_REF][START_REF] Martikainen | Change in the total and independent effects of education and occupational social class on mortality: Analyses of all Finnish men and women in the period 1971-2000[END_REF] Among three studies to control simultaneously for adult SES and education, the relative risk of mortality was entirely attenuated. [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF][START_REF] Jokela | IQ, socioeconomic status, and early death: The US National Longitudinal Survey of Youth[END_REF] Interpretation of these 525 findings should also consider the likelihood of over-adjustment. In studies that reported complete attenuation effects of the intelligence-mortality gradient after multivariate adjustments, in addition to controlling for socioeconomic and educational variables, it was noted that three studies adjusted for smoking, [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF][START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] two adjusted for alcohol consumption, [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF][START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] and there were further adjustments made for psychiatric 530 illness, [START_REF] Batty | IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: The Vietnam Experience Study[END_REF] parental interest in a child's education, [START_REF] Jokela | Low Childhood IQ and Early Adult Mortality: The Role of explanatory factors in the 1958 British Birth Cohort[END_REF] or the quality and care of a household. [START_REF] Kuh | Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socioeconomic conditions on premature adult mortality in a British post war birth cohort?[END_REF] These potential explanatory factors are worthy of further investigation, particularly as two of these (smoking and alcohol consumption) are important risk factors for various chronic diseases.

535

Future directions

The present meta-analysis was unable to consider cause of death in the intelligencemortality association, but this would seem an important area for future systematic review, particularly as it was likely to have driven the stronger effect sizes of cohorts followed to younger ages in adulthood. For example, it may be that intelligence has a 540 stronger relation to mortality caused by external events such as accidents, [START_REF] O'toole | Risk factors for mortality in Australian Vietnam-era national servicemen: A case-control study[END_REF] more

F o r R e v i e w O n l y
23 prevalent among younger adults, than cause-specific mortalities more typical in later life. [START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF] Studies have already replicated the inverse association between premorbid intelligence and cardiovascular disease (CVD)-related mortality, with increased effect size magnitudes for coronary heart disease (CHD)-related deaths 3, 75-78 compared to 545 stroke-related deaths. [START_REF] Batty | Childhood intelligence in relation to adult coronary heart disease and stroke risk: Evidence from a Danish birth cohort study[END_REF][START_REF] Hemmingsson | The association between cognitive ability measured at ages 18-20 and coronary heart disease in middle age among men: A prospective study using the Swedish 1969 conscription cohort[END_REF][START_REF] Lawlor | Association of childhood intelligence with risk of coronary heart disease and stroke: Findings from the Aberdeen Children of the 1950s cohort study[END_REF] The relationship between childhood cognitive ability and risk of cancer mortality is also likely to vary by type. [START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF] For example, smoking-related cancers might carry a stronger association with intelligence [START_REF] Hart | Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: Prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF][START_REF] Batty | IQ in early adulthood, risk factors in middle age, and later cancer mortality in men: The Vietnam Experience Study[END_REF][START_REF] Taylor | Childhood IQ and social factors on smoking behaviour, lung function and smoking-related outcomes in adulthood: Linking the Scottish Mental Survey 1932 and the Midspan studies[END_REF] than other cancer types. [START_REF] Batty | IQ in early adulthood, risk factors in middle age, and later cancer mortality in men: The Vietnam Experience Study[END_REF] Specific causes of death are therefore likely to be crucial in providing explanations as to why intelligence predicts life expectancy, and larger cohorts with 550 increased numbers of cause-specific mortalities will help to clarify this issue.

In the present study we found that education and social position in adulthood are factors that may help to account for the intelligence-all-cause mortality association. However, the extent to which these SES indicators act as partial surrogates for intelligence, or mediators and/or confounders of the intelligence-mortality association 555 requires formal testing. Future longitudinal studies of mortality risk with repeated measures of intelligence, education, and adult SES, spanning childhood to adulthood could contribute to do this. Twin studies to determine the extent to which intelligence shares genetic and environmental causes with health, education, and social class, in predicting mortality, will also help to inform this issue. With evidence of associations 560 between cognitive performance and education showing substantial heritability, [START_REF] Bartels | Heritability of educational achievement in 12-year-olds and the overlap with cognitive ability[END_REF][START_REF] Johnson | Genetic and environmental influences on academic achievement trajectories during adolescence[END_REF] it is possible that these variables may share some genetic effects in predicting death.

Although early life SES did not help to explain the intelligence-mortality association and birthweight is another unlikely confounder, future studies could explore alternative early life variables, in particular the intrauterine environment, and 565 how these might simultaneously determine neurological and physiological integrity, • The intelligence-mortality association does not appear to be confounded by gender or early life socioeconomic inequalities.

• Adult SES and education attenuate the intelligence-mortality association by a third and a half, respectively. Improved study design can contribute to a better understanding of the mechanisms involved in this effect, including: lifetime repeated measures of intelligence and SES indicators; detailed early life and adult covariate data, and specific causes of mortality; twin studies that estimate the environmental and genetic contributions to intelligence-SES-mortality associations.

F

  intelligence (cognitive ability, mental ability) test scores, as measured by standardised IQ-type tests in childhood, show an inverse association

  in the association; and (3) conduct sub-group analyses on studies 125 that adjust for early life SES, adult SES and education, to discover their magnitude of influence as potential confounders or mediators of the intelligence-mortality association.130MethodsSystematic Review ProcessAn electronic search was conducted of premorbid intelligence and all-cause mortality in all published articles, letters, abstracts and reviews, using the electronic databases 135 MEDLINE, EMBASE and PSYCHINFO (via Ovid). Searches were limited to articles on humans published in the English language. The databases were searched using a cognitive ability-related term (Aptitude or Cognition* or Cognitive function* or Cognitive ability or Cognitive characteristics or Cognitive style or intellectual ability or Intelligence measures or Intelligence quotient or Intelligence test* or Intelligence* 140 or IQ or Language test* or Memory or Mental abilit* or Mental capacity or problemsolving or Problem solving or Psychological performance or Psychometrics) AND a mortality term (Cause of Death* or Cause of Death trends or Death* or death rate or Incidence or Morbidity or Morbidity trends or Mortality Rate or Mortality risk or Mortality* or Mortality trends), an asterisk allowing the search term to precede a 145 longer word or phrase. The electronic search, conducted on 5 th February 2010, yielded 19 236 articles. Two authors (CC and NL) independently scanned each title and abstract, retrieving articles on the basis of their relevance to intelligence and mortality. The inclusion

  SD disadvantage in intelligence, the reciprocal was used. Reported 175

  testing, firstly because the likelihood of an effect of bodily insults on 200

  about here] 240 Study descriptions for meta-analysis Sixteen prospective longitudinal cohort studies included 22 453 deaths among 1 107 022 participants. These were from five countries: UK (n = 7), USA (n = 5), Sweden (n = 2), Australia (n = 1) and Denmark (n = 1), ranging in size from 862 to 994 262 participants. Figure 2 illustrates these variables according to year of publication, 245 showing a trend for larger cohorts accumulating in more recent years. Premorbid intelligence test scores were taken from school records (n = 10), military or national records (n = 5), or a research database (n = 1). The average age at testing ranged from seven to 20 years, and length of follow-up ranged from 17 to 69

  are wellestablished, age-standardised intelligence tests for children. Scores on the original Stanford-Binet test contain a single underlying factor of cognitive ability 57 , and the Binet scale has concurrent validity with version 12 of the Moray House intelligence test (r ~ 0.80). 56 Two studies included selected tests from the well-validated Moray 260

  = 0.51) scores from the Weschler Adult Intelligence Scale (WAIS), a standardised and well-validated cognitive ability test battery. 275[Figure2about here]

  80). Compared to the this smaller group of studies in which there were 4608 deaths 370 (HR 0.77, 95% CI 0.74-0.80), controlling for childhood SES had no effect on the intelligence-mortality gradient when the influence of this largest weighted study was removed.

  Figure 5). Exclusion of the large Swedish cohort 3 from the model, as expected,

1. 1

 1 million participants and 22 453 deaths, demonstrates and quantifies the

  meta-analyses support this. Equivalent effect sizes by sex still do not mean

•

  genetic influences, leading to lifelong effects on cognition and health. Higher intelligence test scores measured in youth are associated with the reduced risk of mortality by mid-to-late adulthood.

Figure 1 .

 1 Figure 1. Flow diagram of articles selected for systematic review and meta-analysis

Figure 2 . 54 ;

 254 Figure 2. Publication rate of longitudinal cohort studies on intelligence in childhood and youth, and allcause-mortality (n = 27). Circles are shaded to represent country of origin and scaled proportionately to cohort size. One study is missing 54 ; its publication precedes 2000.

Figure 3 .

 3 Figure 3. Risk of all-cause-mortality per one SD advantage in intelligence test scores (n = 16), in a basic model. Squares mark cohort-specific effect sizes, which are proportional to the statistical weight (i.e. inverse variance), and diamond indicates the aggregate effect size. Horizontal lines represent 95% confidence intervals. Odds ratios from four studies 35, 51, 54, 63 are treated as hazard ratios;excluding the two studies with 20-40% risk of death 35, 54 made no change to the summary estimate.

Figure 4 .

 4 Figure 4.

  Figure 5.

Figure 5 .

 5 Figure 5. Risk of all-cause-mortality per one SD advantage in intelligence test scores after adjustment for: (a) childhood SES, (b) adult SES and (c) education. Squares mark cohort-specific effect sizes, which are proportional to the statistical weight (i.e. inverse variance), and diamonds indicate the aggregate effect sizes for studies adjusted for each covariate. Horizontal lines represent 95% confidence intervals.

  had intelligence test scores measured in later youth (19-20 years of age) when most people have completed education. There is evidence for a causal association from childhood 515 intelligence scores to later educational achievement in longitudinal studies, and it is

	also likely educational experience can boost cognitive test scores to some extent.
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	22

Table 1 .

 1 Characteristics of 27 Longitudinal Cohort Studies of Premorbid Intelligence and All-Cause MortalityStudies appear in publication date order; those marked with an asterisk are included in the meta-analysis. ACONF = Aberdeen Children of the 1950s; AFQT = Armed Forces Qualification Test; AGCT = Army If years of follow-up and/or dates were not reported these were estimated according to the longest theoretical time period. b Study included all deceased and a random sample of survivors from the original cohort, twice as large as the deceased group. c Years since cognitive testing is an estimate: in correspondence Holsinger et al reported that the vast majority of conscripts would have been 17-21 years old at testing. d Years since cognitive testing and birth year are approximations based on the mean age of participants at the beginning of follow-up in 1985-86. e Models for sex groups and those that adjusted for adult SES and multiple variables are based on a shorter follow-up period(23-46 years) and therefore a smaller sample size (n = 10 620).

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a

Table 2 .

 2 Summary of HRs for all-cause mortality in relation to a one SD advantage in intelligence in 16 longitudinal cohort studiesNote. All sub-analyses refer to fixed effects models. I 2 (%) = percentage of variation across studies due to heterogeneity. b Insufficient data prevented estimation of ascertainment rate at follow-up. c Number of deaths reported for men and women exclude data from Jokela et al[63] which were unreported. d Removing the influence of by far the largest cohort by Batty et al[3] gave attenuation effects by childhood SES of 0.0% and by education of 45.8%.

	Heterogeneity

a

Acknowledgements

The authors thank the following contributors for providing additional analyses of their data: Tomas Hemmingsson, Tracey Holsinger, Diana Kuh, Anton Lager, Laurie 585 Martin, Merete Osler, Brian O'Toole, and Denny Vågerö.

Funding 570 The work was supported by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative [G0700704/84698)]. Funding from the Biotechnology and Biological Sciences Research Council (BBSRC); Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); and 575 Medical Research Council (MRC) is gratefully acknowledged. David Batty is funded by a Wellcome Trust Fellowship [WBS Code U.1300.00.006.00012.01]. The Medical Research Council (MRC) Social and Public Health Sciences Unit receives funding from the MRC and the Chief Scientist Office at the Scottish Government Health Directorates. 580

Conflict of Interests: The authors have declared that no conflicts of interest exist.

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