International Journal of Cardiology 172 (2014) e406–e408
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Simple reaction time and the risk of cardiovascular mortality Jin-young Min a, Kyoung-bok Min b,⁎ a b
Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea Department of Occupational and Environmental Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 28 December 2013 Accepted 30 December 2013 Available online 10 January 2014 Keywords: Reaction time Mortality Cardiovascular disease Net reclassification improvement Prediction
Introduction: Studies suggest that cognitive abilities predict total and cardiovascular disease mortality as strongly as currently wellestablished risk factors [1,2]. Reaction time, i.e., the time elapsed between a sensory stimulus and the required response, is significantly associated with cognitive ability [3]. As with the cognitive ability– mortality association, slower and more variable reaction times are associated with an increased risk of all-cause and cause-specific mortality [2,4–6]. The importance of reaction time as a risk factor for mortality has been emphasized, by demonstrating that reaction time is a stronger predictor of mortality than other cognitive tests, including IQ [5,6]. However, the extent to which the knowledge of baseline simple reaction time provides clinically meaningful risk information for mortality beyond traditional risk factors is unclear. This study aimed to investigate whether simple reaction time is an indicator of subsequent mortality from all-cause, cardiovascularrelated and coronary artery disease in a nationally representative sample of adults 20–59 years old. Methods: We used the Third Nutrition and Health Examination Survey (NHANES III) database and the NHANES III Linked Mortality File. This study was based on a total of 4770 NHANES III participants aged between 20 and 59 years at the time of the examination, who completed a simple reaction test, who had no a history of coronary heart disease or stroke, and who had no missing Framingham risk factor variables, including age, gender, systolic blood pressure, total and high-density
⁎ Corresponding author at: Department of Occupational and Environmental Medicine, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443721, Republic of Korea. Tel.: +82 31 219 5278; fax: +82 31 241 1697. E-mail address: [email protected] (K. Min). 0167-5273/$ – see front matter © 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.12.257
lipoprotein (HDL) cholesterol categories, diabetes, and smoking status [7]. The primary outcomes included all-cause mortality and cardiovascular disease-related mortality (ICD-10 codes I00–I99). All of the analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA). Cox proportional hazards regression and C statistics were used in the multivariate analyses of the mortality rate. The additional value of simple reaction time to the Framingham risk factors for predicting all-cause and cardiovascular disease mortality was assessed using the net reclassification improvement [8]. The NHANES is a publicly released dataset. Therefore, we did not require informed consent to use this dataset. Accordingly, this study was exempt from approval by the Ajou University Hospital Institutional Review Board. Results: The mean simple reaction time of the overall participants was 240.3 ms (251.1 ms and 263.3 ms for participants with all-cause and cardiovascular mortality, respectively). Participants with all-cause or cardiovascular mortality were more likely to be older, male, and current smokers, and have elevated systolic blood pressure, high total cholesterol levels, and a history of diabetes (data not shown). Systolic blood pressure, smoking, and/or a history of diabetes were significant predictors of all-cause and cardiovascular mortality (Table 1). The addition of the tertiles of simple reaction time was significantly associated with increased risk of all-cause (HR for Q3 vs. Q1, 1.91; 95% CI, 1.23–2.95) and cardiovascular disease (HR for Q3 vs. Q1, 3.39; 95% CI, 1.84–6.24) mortality. However, after the addition of simple reaction time, C statistics were increased only non-significantly (p-value = 0.07), for both allcause and cardiovascular mortality. Table 2 shows the reclassification risk of the Framingham risk factors categories after the addition of simple reaction time. The resultant net reclassification improvement was not significant with the inclusion of simple reaction time for all-cause mortality (0.39%; p-value = 0.79), but significant for cardiovascular disease mortality(9.70%; p-value = 0.0086). Discussion: The baseline simple reaction time was significantly associated with all-cause and cardiovascular disease mortality in adults. We also determined that the addition of simple reaction time provided modest, 9.7% (p-value = 0.0086), but significant improvement in risk reclassification for cardiovascular disease mortality. These data confirm the previous findings of the association between reaction time and cardiovascular mortality [2,4–6] and indicates the potential clinical relevance of incorporating simple reaction time for predicting cardiovascular mortality. As reaction time is more likely to be influenced by less education or social background, it has been accepted as a reliable measure of the brain's processing efficiency [5]. Consistent with the significant association between cognitive ability and mortality [9,10], epidemiologic
J. Min, K. Min / International Journal of Cardiology 172 (2014) e406–e408
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Table 1 Hazard ratio (HR) and C statistic of all-cause and cause-specific mortality according to models with and without tertiles of simple reaction time. Cardiovascular mortalitya
All-cause mortality
Age, per increase 1 year Gender, male vs. female Systolic BP, per increase of 1 mm Hg Cholesterol, per increase 1 mg/dL Total HDL Diabetesb, yes vs. no Current smoking, yes vs. no SRTTc, Q1 vs. Q2 or Q3 Q1 (≤215 ms) Q2 (216–244 ms) Q3 (≥245 ms) C statistics
Model with risk factor only
Model with risk factor and SRTT
Model with risk factor only
Model with risk factor and SRTT
HR or C statistics (95% CI)
HR or C statistics (95% CI)
HR or C statistics (95% CI)
HR or C statistics (95% CI)
0.90 1.08 1.02
(0.88–0.93) (0.82–1.41) (1.01–1.03)
0.90 1.19 1.02
(0.87–0.92) (0.87–1.63) (1.01–1.03)
0.91 1.19 1.03
(0.86–0.96) (0.71–2.00) (1.01–1.05)
0.90 1.38 1.03
(0.85–0.94) (0.79–2.42) (1.01–1.06)
1.00 1.00 1.70 2.66
(0.99–1.00) (0.99–1.01) (1.02–2.84) (1.97–3.58)
1.00 1.00 1.55 2.70
(0.99–1.00) (0.99–1.01) (0.95–2.53) (2.04–3.57)
1.00 1.00 1.30 3.01
(0.99–1.01) (0.98–1.02) (0.62–2.71) (1.84–4.94)
1.00 1.00 0.95 3.31
(0.99–1.01) (0.98–1.02) (0.43–2.13) (2.04–5.38)
1.58 3.39 0.824
(0.80–3.11) (1.84–6.24) (0.784–0.863)
0.756
(0.729–0.783)
Reference 1.31 1.91 0.756
Reference (0.88–1.94) (1.23–2.95) (0.728–0.783)
0.818
(0.780–0.855)
a
Cardiovascular disease-related mortality (ICD-10 codes I00–I99). b A history of diabetes was defined as a fasting plasma glucose level measuring at least 126 mg/dL, a non-fasting plasma glucose level measuring at least 200 mg/dL, current insulin use or a prior physician's diagnosis of diabetes. c A faster mean reaction time was considered a better performance.
studies have indicated that poor reaction time predicts the subsequent mortality in the whole adult age range [2,4–6]. In the Scottish Twenty07 study, Deary and Der (2005) found that psychometric intelligence and reaction times measured at age 56 were significantly associated with mortality, implying an effect size comparable to that of smoking status as well as a better predictor of mortality than IQ [6]. Roberts et al. (2009) assessed the relative effect of the reaction time mean compared with the established risk factors such as smoking, hypertension, and obesity for total and cardiovascular mortality [2]. They revealed that low reaction time was a more powerful contributor for total and cardiovascular disease mortality compared with the established risk factors.
Table 2 Reclassification risk of Framingham risk factors categories after adding SRTT. Original risk category
Reclassification riska No. of participants Low
Moderate
High
3600 71 0
60 496 15
0 22 179
146 7 0
7 83 4
0 5 79
4505 36 0
41 60 7
0 9 14
81 2 0
9 4 0
0 3 3
b
All-cause mortality Participants without all-cause mortality Low risk (b10%) Intermediate risk (10–20%) High risk (N20%) Participants with all-cause mortality Low risk (b10%) Intermediate risk (10–20%) High risk (N20%) Cardiovascular mortalityc Participants without cardiovascular disease mortality Low risk (b10%) Intermediate risk (10–20%) High risk (N20%) Participants with cardiovascular disease mortality Low (b10%) Intermediate risk (10–20%) High risk (N20%)
Our findings reinforce the existing evidence on the association between reaction time and mortality for the whole adult age range. These data emphasize the importance of simple reaction time in the risk prediction of cardiovascular disease mortality and indicate significant net reclassification improvement. The addition of simple reaction time to the traditional risk factors, which in this case were represented by the Framingham risk categories (low, intermediate, and high), provided a significant improvement in the identification of those individuals at risk for future cardiovascular mortality. Thus, the finding from the present study suggests that baseline simple reaction time is at least as useful as the established cardiovascular risk factors. In conclusion, simple reaction time at baseline was an independent predictor for all-cause and cardiovascular mortality in adults aged 20 to 59 years. Furthermore, adding simple reaction time to the Framingham risk factors significantly improved the value of cardiovascular mortality predictions. Although this study has limitations due to a single measurement of simple reaction time at baseline and a long interval between measurement and follow-up, and the mechanisms relating delayed simple reaction time to increased cardiovascular mortality risk remains unclear, we suggest the importance of simple reaction time to cardiovascular mortality and demonstrated that simple reaction time may have the ability to determine the subjects likely to suffer future cardiovascular mortality. Financial support: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant Nos. 2012R1A1A1041318, 2012R1A1A3017058). References
a Net reclassification improvement ascertained whether reclassification assigned participants who did suffer mortality events to a higher risk category and those did not suffer events to a lower category, and computed the differences in the proportions of participants, moving up and down for events and non-events. b All-cause mortality index, −0.09% [−4 of 4443 participants] for participants without events and 0.30% [1 of 331 participants] with events, and 0.39% overall (p-value = 0.79). c Cardiovascular mortality index, 0.15% [7 of 4672 participants] without events, 9.8% [10 of 102 participants] with events, and 9.70% overall (p-value = 0.0086).
[1] Batty GD, Shipley MJ, Dundas R, et al. Does IQ explain socio-economic differentials in total and cardiovascular disease mortality? Comparison with the explanatory power of traditional cardiovascular disease risk factors in the Vietnam Experience Study. Eur Heart J 2009;30:1903–9. [2] Roberts BA, Der G, Deary IJ, Batty GD. Reaction time and established risk factors for total and cardiovascular disease mortality: comparison of effect estimates in the follow-up of a large, UK-wide, general-population based survey. Intelligence 2009;37:561–6. [3] Deary IJ, Der G, Ford G. Reaction times and intelligence differences: A populationbased cohort study. Intelligence 2001;29:389–99. [4] Shipley BA, Der G, Taylor MD, Deary IJ. Cognition and all-cause mortality across the entire adult age range: health and lifestyle survey. Psychosom Med 2006;68:17–24. [5] Shipley BA, Der G, Taylor MD, Deary IJ. Cognition and mortality from the major causes of death: the Health and Lifestyle Survey. J Psychosom Res 2008;65:143–52. [6] Deary IJ, Der G. Reaction time explains IQ's association with death. Psychol Sci 2005;16:64–9.
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J. Min, K. Min / International Journal of Cardiology 172 (2014) e406–e408
[7] D'Agostino Sr RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008;117: 743–53. [8] Pencina MJ, D’Agostino Sr R, D’Agostino Jr R, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–72.
[9] Baker DW, Wolf MS, Feinglass J, Thompson JA. Health literacy, cognitive abilities, and mortality among elderly persons. J Gen Intern Med 2008;23:723–6. [10] Hemmingsson T, Melin B, Allebeck P, Lundberg I. The association between cognitive ability measured at ages 18–20 and mortality during 30 years of follow-up—a prospective observational study among Swedish males born 1949–51. Int J Epidemiol 2006;35:665–70.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Simple reaction time and the risk of cardiovascular mortality Jin-young Min a, Kyoung-bok Min b,⁎ a b
Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea Department of Occupational and Environmental Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 28 December 2013 Accepted 30 December 2013 Available online 10 January 2014 Keywords: Reaction time Mortality Cardiovascular disease Net reclassification improvement Prediction
Introduction: Studies suggest that cognitive abilities predict total and cardiovascular disease mortality as strongly as currently wellestablished risk factors [1,2]. Reaction time, i.e., the time elapsed between a sensory stimulus and the required response, is significantly associated with cognitive ability [3]. As with the cognitive ability– mortality association, slower and more variable reaction times are associated with an increased risk of all-cause and cause-specific mortality [2,4–6]. The importance of reaction time as a risk factor for mortality has been emphasized, by demonstrating that reaction time is a stronger predictor of mortality than other cognitive tests, including IQ [5,6]. However, the extent to which the knowledge of baseline simple reaction time provides clinically meaningful risk information for mortality beyond traditional risk factors is unclear. This study aimed to investigate whether simple reaction time is an indicator of subsequent mortality from all-cause, cardiovascularrelated and coronary artery disease in a nationally representative sample of adults 20–59 years old. Methods: We used the Third Nutrition and Health Examination Survey (NHANES III) database and the NHANES III Linked Mortality File. This study was based on a total of 4770 NHANES III participants aged between 20 and 59 years at the time of the examination, who completed a simple reaction test, who had no a history of coronary heart disease or stroke, and who had no missing Framingham risk factor variables, including age, gender, systolic blood pressure, total and high-density
⁎ Corresponding author at: Department of Occupational and Environmental Medicine, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443721, Republic of Korea. Tel.: +82 31 219 5278; fax: +82 31 241 1697. E-mail address: [email protected] (K. Min). 0167-5273/$ – see front matter © 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.12.257
lipoprotein (HDL) cholesterol categories, diabetes, and smoking status [7]. The primary outcomes included all-cause mortality and cardiovascular disease-related mortality (ICD-10 codes I00–I99). All of the analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA). Cox proportional hazards regression and C statistics were used in the multivariate analyses of the mortality rate. The additional value of simple reaction time to the Framingham risk factors for predicting all-cause and cardiovascular disease mortality was assessed using the net reclassification improvement [8]. The NHANES is a publicly released dataset. Therefore, we did not require informed consent to use this dataset. Accordingly, this study was exempt from approval by the Ajou University Hospital Institutional Review Board. Results: The mean simple reaction time of the overall participants was 240.3 ms (251.1 ms and 263.3 ms for participants with all-cause and cardiovascular mortality, respectively). Participants with all-cause or cardiovascular mortality were more likely to be older, male, and current smokers, and have elevated systolic blood pressure, high total cholesterol levels, and a history of diabetes (data not shown). Systolic blood pressure, smoking, and/or a history of diabetes were significant predictors of all-cause and cardiovascular mortality (Table 1). The addition of the tertiles of simple reaction time was significantly associated with increased risk of all-cause (HR for Q3 vs. Q1, 1.91; 95% CI, 1.23–2.95) and cardiovascular disease (HR for Q3 vs. Q1, 3.39; 95% CI, 1.84–6.24) mortality. However, after the addition of simple reaction time, C statistics were increased only non-significantly (p-value = 0.07), for both allcause and cardiovascular mortality. Table 2 shows the reclassification risk of the Framingham risk factors categories after the addition of simple reaction time. The resultant net reclassification improvement was not significant with the inclusion of simple reaction time for all-cause mortality (0.39%; p-value = 0.79), but significant for cardiovascular disease mortality(9.70%; p-value = 0.0086). Discussion: The baseline simple reaction time was significantly associated with all-cause and cardiovascular disease mortality in adults. We also determined that the addition of simple reaction time provided modest, 9.7% (p-value = 0.0086), but significant improvement in risk reclassification for cardiovascular disease mortality. These data confirm the previous findings of the association between reaction time and cardiovascular mortality [2,4–6] and indicates the potential clinical relevance of incorporating simple reaction time for predicting cardiovascular mortality. As reaction time is more likely to be influenced by less education or social background, it has been accepted as a reliable measure of the brain's processing efficiency [5]. Consistent with the significant association between cognitive ability and mortality [9,10], epidemiologic
J. Min, K. Min / International Journal of Cardiology 172 (2014) e406–e408
e407
Table 1 Hazard ratio (HR) and C statistic of all-cause and cause-specific mortality according to models with and without tertiles of simple reaction time. Cardiovascular mortalitya
All-cause mortality
Age, per increase 1 year Gender, male vs. female Systolic BP, per increase of 1 mm Hg Cholesterol, per increase 1 mg/dL Total HDL Diabetesb, yes vs. no Current smoking, yes vs. no SRTTc, Q1 vs. Q2 or Q3 Q1 (≤215 ms) Q2 (216–244 ms) Q3 (≥245 ms) C statistics
Model with risk factor only
Model with risk factor and SRTT
Model with risk factor only
Model with risk factor and SRTT
HR or C statistics (95% CI)
HR or C statistics (95% CI)
HR or C statistics (95% CI)
HR or C statistics (95% CI)
0.90 1.08 1.02
(0.88–0.93) (0.82–1.41) (1.01–1.03)
0.90 1.19 1.02
(0.87–0.92) (0.87–1.63) (1.01–1.03)
0.91 1.19 1.03
(0.86–0.96) (0.71–2.00) (1.01–1.05)
0.90 1.38 1.03
(0.85–0.94) (0.79–2.42) (1.01–1.06)
1.00 1.00 1.70 2.66
(0.99–1.00) (0.99–1.01) (1.02–2.84) (1.97–3.58)
1.00 1.00 1.55 2.70
(0.99–1.00) (0.99–1.01) (0.95–2.53) (2.04–3.57)
1.00 1.00 1.30 3.01
(0.99–1.01) (0.98–1.02) (0.62–2.71) (1.84–4.94)
1.00 1.00 0.95 3.31
(0.99–1.01) (0.98–1.02) (0.43–2.13) (2.04–5.38)
1.58 3.39 0.824
(0.80–3.11) (1.84–6.24) (0.784–0.863)
0.756
(0.729–0.783)
Reference 1.31 1.91 0.756
Reference (0.88–1.94) (1.23–2.95) (0.728–0.783)
0.818
(0.780–0.855)
a
Cardiovascular disease-related mortality (ICD-10 codes I00–I99). b A history of diabetes was defined as a fasting plasma glucose level measuring at least 126 mg/dL, a non-fasting plasma glucose level measuring at least 200 mg/dL, current insulin use or a prior physician's diagnosis of diabetes. c A faster mean reaction time was considered a better performance.
studies have indicated that poor reaction time predicts the subsequent mortality in the whole adult age range [2,4–6]. In the Scottish Twenty07 study, Deary and Der (2005) found that psychometric intelligence and reaction times measured at age 56 were significantly associated with mortality, implying an effect size comparable to that of smoking status as well as a better predictor of mortality than IQ [6]. Roberts et al. (2009) assessed the relative effect of the reaction time mean compared with the established risk factors such as smoking, hypertension, and obesity for total and cardiovascular mortality [2]. They revealed that low reaction time was a more powerful contributor for total and cardiovascular disease mortality compared with the established risk factors.
Table 2 Reclassification risk of Framingham risk factors categories after adding SRTT. Original risk category
Reclassification riska No. of participants Low
Moderate
High
3600 71 0
60 496 15
0 22 179
146 7 0
7 83 4
0 5 79
4505 36 0
41 60 7
0 9 14
81 2 0
9 4 0
0 3 3
b
All-cause mortality Participants without all-cause mortality Low risk (b10%) Intermediate risk (10–20%) High risk (N20%) Participants with all-cause mortality Low risk (b10%) Intermediate risk (10–20%) High risk (N20%) Cardiovascular mortalityc Participants without cardiovascular disease mortality Low risk (b10%) Intermediate risk (10–20%) High risk (N20%) Participants with cardiovascular disease mortality Low (b10%) Intermediate risk (10–20%) High risk (N20%)
Our findings reinforce the existing evidence on the association between reaction time and mortality for the whole adult age range. These data emphasize the importance of simple reaction time in the risk prediction of cardiovascular disease mortality and indicate significant net reclassification improvement. The addition of simple reaction time to the traditional risk factors, which in this case were represented by the Framingham risk categories (low, intermediate, and high), provided a significant improvement in the identification of those individuals at risk for future cardiovascular mortality. Thus, the finding from the present study suggests that baseline simple reaction time is at least as useful as the established cardiovascular risk factors. In conclusion, simple reaction time at baseline was an independent predictor for all-cause and cardiovascular mortality in adults aged 20 to 59 years. Furthermore, adding simple reaction time to the Framingham risk factors significantly improved the value of cardiovascular mortality predictions. Although this study has limitations due to a single measurement of simple reaction time at baseline and a long interval between measurement and follow-up, and the mechanisms relating delayed simple reaction time to increased cardiovascular mortality risk remains unclear, we suggest the importance of simple reaction time to cardiovascular mortality and demonstrated that simple reaction time may have the ability to determine the subjects likely to suffer future cardiovascular mortality. Financial support: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant Nos. 2012R1A1A1041318, 2012R1A1A3017058). References
a Net reclassification improvement ascertained whether reclassification assigned participants who did suffer mortality events to a higher risk category and those did not suffer events to a lower category, and computed the differences in the proportions of participants, moving up and down for events and non-events. b All-cause mortality index, −0.09% [−4 of 4443 participants] for participants without events and 0.30% [1 of 331 participants] with events, and 0.39% overall (p-value = 0.79). c Cardiovascular mortality index, 0.15% [7 of 4672 participants] without events, 9.8% [10 of 102 participants] with events, and 9.70% overall (p-value = 0.0086).
[1] Batty GD, Shipley MJ, Dundas R, et al. Does IQ explain socio-economic differentials in total and cardiovascular disease mortality? Comparison with the explanatory power of traditional cardiovascular disease risk factors in the Vietnam Experience Study. Eur Heart J 2009;30:1903–9. [2] Roberts BA, Der G, Deary IJ, Batty GD. Reaction time and established risk factors for total and cardiovascular disease mortality: comparison of effect estimates in the follow-up of a large, UK-wide, general-population based survey. Intelligence 2009;37:561–6. [3] Deary IJ, Der G, Ford G. Reaction times and intelligence differences: A populationbased cohort study. Intelligence 2001;29:389–99. [4] Shipley BA, Der G, Taylor MD, Deary IJ. Cognition and all-cause mortality across the entire adult age range: health and lifestyle survey. Psychosom Med 2006;68:17–24. [5] Shipley BA, Der G, Taylor MD, Deary IJ. Cognition and mortality from the major causes of death: the Health and Lifestyle Survey. J Psychosom Res 2008;65:143–52. [6] Deary IJ, Der G. Reaction time explains IQ's association with death. Psychol Sci 2005;16:64–9.
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J. Min, K. Min / International Journal of Cardiology 172 (2014) e406–e408
[7] D'Agostino Sr RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008;117: 743–53. [8] Pencina MJ, D’Agostino Sr R, D’Agostino Jr R, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–72.
[9] Baker DW, Wolf MS, Feinglass J, Thompson JA. Health literacy, cognitive abilities, and mortality among elderly persons. J Gen Intern Med 2008;23:723–6. [10] Hemmingsson T, Melin B, Allebeck P, Lundberg I. The association between cognitive ability measured at ages 18–20 and mortality during 30 years of follow-up—a prospective observational study among Swedish males born 1949–51. Int J Epidemiol 2006;35:665–70.
