Eur Child Adolesc Psychiatry (2017) 26:445–456 DOI 10.1007/s00787-016-0903-9
ORIGINAL CONTRIBUTION
Cognitive functioning in children with internalising, externalising and dysregulation problems: a population‑based study Laura M. E. Blanken1,2 · Tonya White1,3 · Sabine E. Mous1,2 · Maartje Basten1,2 · Ryan L. Muetzel1,2 · Vincent W. V. Jaddoe2,4,5 · Marjolein Wals1,6 · Jan van der Ende1 · Frank C. Verhulst1 · Henning Tiemeier1,5
Received: 10 December 2015 / Accepted: 6 September 2016 / Published online: 19 September 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Psychiatric symptoms in childhood are closely related to neurocognitive deficits. However, it is unclear whether internalising and externalising symptoms are associated with general or distinct cognitive problems. We examined the relation between different types of psychiatric symptoms and neurocognitive functioning in a population-based sample of 1177 school-aged children. Internalising and externalising behaviour was studied both continuously and categorically. For continuous, variablecentred analyses, broadband scores of internalising and externalising symptoms were used. However, these measures are strongly correlated, which may prevent identification of distinct cognitive patterns. To distinguish groups of children with relatively homogeneous symptom patterns, a latent profile analysis of symptoms at age 6 yielded four exclusive groups of children: a class of children with Electronic supplementary material The online version of this article (doi:10.1007/s00787-016-0903-9) contains supplementary material, which is available to authorized users. * Henning Tiemeier [email protected] 1
2
Department of Child and Adolescent Psychiatry, Erasmus MC-Sophia, Rotterdam, The Netherlands The Generation R Study Group, Erasmus MC, Rotterdam, The Netherlands
3
Department of Radiology, Erasmus MC, Rotterdam, The Netherlands
4
Department of Paediatrics, Erasmus MC-Sophia, Rotterdam, The Netherlands
5
Department of Epidemiology, Erasmus MC, room Na‑2818, P.O.Box 2040, 3000 CA Rotterdam, The Netherlands
6
Institute of Psychology, Erasmus University, Rotterdam, The Netherlands
predominantly internalising symptoms, a class with externalising symptoms, a class with co-occurring internalising and externalising symptoms, that resembles the CBCL dysregulation profile and a class with no problems. Five domains of neurocognitive ability were tested: attention/ executive functioning, language, memory and learning, sensorimotor functioning, and visuospatial processing. Consistently, these two different modelling approaches demonstrated that children with internalising and externalising symptoms show distinct cognitive profiles. Children with more externalising symptoms performed lower in the attention/executive functioning domain, while children with more internalising symptoms showed impairment in verbal fluency and memory. In the most severely affected class of children with internalising and externalising symptoms, we found specific impairment in the sensorimotor domain. This study illustrates the specific interrelation of internalising and externalising symptoms and cognition in young children. Keywords Internalising symptoms · Externalising symptoms · Cognition
Introduction In child development, cognitive functioning and psychopathology are closely intertwined. The school-age years are a period of abundant neurodevelopment, characterized by refinement of cognitive skills while, in some children, psychiatric symptoms emerge. Often, a disruption in one area of development is accompanied by impairment in the other, which may reflect a common underlying neurodevelopmental problem [1]. The relation of cognition and psychopathology is particularly well illustrated by developmental
13
446
disorders, such as ADHD and ASD [2], that are often characterized by lower intelligence or even intellectual impairment. While IQ provides a good measure of general cognitive ability, cognition is a broad construct with various domains, each of which can be selectively impaired or intact. There is increasing attention to assess which specific aspects of cognition are impaired in child psychiatric disorders. Such cognitive impairment can be shared across different disorders, but it may also be distinct for different types of psychopathology. Internalising and externalising disorders are two presentations of psychopathology at a young age, that are thought to emerge from partly distinct pathways, both in terms of genetics [3] and underlying brain correlates [4] and predispose for different types of psychopathology later in life [5, 6]. However, it is less clear whether distinct cognitive patterns exist for internalising and externalising symptoms at a young age. Cognitive problems in psychopathology have been studied particularly in the context of executive functioning, a broad construct of different abilities to regulate behaviour, such as the ability to pay attention or to inhibit responses. Externalising disorders such as ADHD and disruptive behavioural disorders have been conceptualised as arising from a set of primarily frontally mediated executive function deficits, including attention, planning, working memory and response inhibition [7–11]. There is more debate about the specific deficits in anxiety and mood disorders, that are primarily related to neural circuitry linking limbic structures to frontal regions [12]. Neuropsychological impairment of executive functioning has been reported [13], most notably in visual and working memory in paediatric or adolescent depression [14, 15], while differences in processing speed have also been reported [16]. Attention has also been implicated in paediatric depression [17]. While some childhood anxiety disorders, like OCD in children occur with impairments of executive functioning abilities like mental set-shifting [18], or full-scale IQ [19] they have also been related to impairment in verbal processing [20]. However, it is unclear whether these differences reflect specific lingual processes or aspects of executive functioning, such as impaired attention or working memory. In addition, some studies focused on the neurocognitive implications of co-occurring high levels of internalising and externalising symptoms, for instance in children with ADHD with comorbid internalising symptoms. These studies show inconsistent results, that vary between better test performance [21], no difference [22], to worse performance in tasks of attention, response inhibition and working memory [23] than children with ADHD only. In general, there is considerable heterogeneity in the literature relating cognition to child psychopathology and studies in young children are relatively scarce. Yet, it is especially important to study younger children, as patterns
13
Eur Child Adolesc Psychiatry (2017) 26:445–456
of emerging psychopathology and impaired cognition can provide more insight in the aetiology relatively unobscured by chronicity of symptoms or treatment effects. Further, the close relation between cognition and psychopathology in young age provides a potentially powerful treatment target for early intervention. So far, many clinical studies tend to focus on a limited range of cognitive domains within small samples of children that have one or more clinically diagnosed psychiatric disorders. Importantly, within this framework, the question of specificity of cognitive impairments cannot be answered by design. Child psychopathology is characterised by a high level of comorbidity between different symptom types, crossing the boundaries of diagnoses. Children that have a high level of externalising symptoms, such as aggression tend to also have internalising symptoms, such as anxiety or depressed mood [24]. Knowledge about specific patterns of cognitive impairment per symptom type could point to specific genetic or neurobiological pathways [8] and help in targeted treatment decisions and predictions of the clinical course of specific symptoms. An alternative to the case–control framework is provided by studying psychopathology on the symptom level, focusing on continuous trait phenotypes [25]. However, various continuously measured psychiatric symptoms are also inter-related. Although the associated cognitive problems may in fact be distinct for each symptom type, the strong correlation between internalising and externalising symptoms can obscure any potential specificity of associations. Therefore, in the current study, we also used a different approach to address the relation of internalising and externalising symptoms and cognition that added an element of specificity. To this aim, we complemented the traditional variable-based approach with a person-centred approach that allows to distinguish between different symptom profiles in case of heterogeneity [26]. Previously, we applied a latent profile analysis (LPA) to quantitative behavioural and emotional symptom data of more than 6,000 children to identify four broad, but exclusive classes with different patterns of symptoms [27]. Three of these classes included children with problem behaviour: a class of children with predominantly externalising symptoms, a class with predominantly internalising symptoms and a small class with both internalising and externalising symptoms that bears a resemblance to the CBCL Dysregulation Profile, a phenotype of high comorbidity that is associated with a broad range of later psychopathology [28]. In this populationbased cohort, the majority of children belonged to a class without psychopathology. The three classes of problem behaviour have so far only been related to a general, global measure of non-verbal intelligence [29]. Here, we aimed to further specify these differences by assessing more specific cognitive sub-domains using an extensive neuropsychological test battery that covers five domains of neurocognitive
Eur Child Adolesc Psychiatry (2017) 26:445–456
ability: attention/executive functioning, language, memory, sensorimotor functioning and visuospatial ability. In the current study, we assessed the relation between cognition and psychiatric symptoms in more than 1,000 school-aged children. In line with recommendations of the RDoC initiative, we used continuous measures of internalising and externalising symptoms to capture the full spectrum of symptom severity, including subclinical symptoms [30]. However, these measures were strongly correlated, so to identify unique patterns of impairment across different symptom types, we used the previously identified problem classes representing more homogeneous groups in terms of symptomatology. Based on the literature, we hypothesised that children with externalising symptoms show poorer performance on the attention/executive functioning domain. Further, we hypothesised that children with internalising symptoms would show moderately impaired test performance in the domains of language, memory and attention. In the class of children with high levels of both internalising and externalising symptoms, we expected widespread impairment, since they likely reflect the most severely affected group. Additionally, we tested if any impairments were independent of demographic and maternal factors or autistic symptoms. Finally, we explored whether any observed differences reflect global cognitive impairment or more specific deficits by adjusting for IQ.
Methods Participants This study included a subgroup of children from the Generation R Study, a multi-ethnic population-based cohort, investigating children’s health, growth and development from foetal life onwards in Rotterdam, the Netherlands. An overview of the Generation R Study design and population is provided elsewhere [31]. As part of a previously described sub-study [32], 1307 participants completed a neuropsychological test battery. In this sub-study, children with specific traits (including autistic traits and externalising disorders, were oversampled (see Supplementary Figure 1 for a consort diagram). Oversampling of children with problem behaviour increased the variability, which improved power of the analyses and helped in achieving a more normal distribution of psychopathology symptoms, which are generally strongly right skewed in the general population. One hundred thirty children had missing information on problem behaviour and were excluded, resulting in a study sample of 1177 children.
447
The study was approved by the Medical Ethics Committee (METC) of the Erasmus Medical Centre. Written informed consent was obtained from the parents of all participants. Internalising and externalising symptoms When the children were approximately 6 years of age, mothers of 6,131 children completed the Child Behaviour Checklist (CBCL/1.5–5). The CBCL is a widely used instrument has been shown to have good reliability and validity [33] and is generalizable across 23 societies [34]. It measures childhood psychiatric symptoms quantitatively; both in the clinical and non-clinical range and thereby captures the full range of severity. It contains internally consistent Internalizing and Externalizing broadband scales that globally correspond to mood and anxiety disorders and disruptive behaviour disorders, respectively [6]. The Internalizing and Externalizing broadband scales are able to measure broad behavioural constructs in early childhood that have been shown to predict later, more specific psychopathology [35, 36]. The Internalising scale consists of the following four scales: Emotionally Reactive; Anxious/Depressed; Somatic Complaints; and Withdrawn. The Externalising scale contains two scales: Attention Problems and Aggressive Behaviour [27]. In our first approach, we related the continuous broadband scores to cognitive functioning. Second, to explore specific cognitive problems of internalising and externalising symptoms, we defined four classes of children with distinct patterns of behavioural and emotional symptoms that were obtained by a latent profile analysis performed on T-scores of CBCL syndrome scales that constitute the internalising and externalising broadband scales. These included a class of children without problems, a class with predominantly internalising symptoms; a class with externalising symptoms and emotional reactivity, further referred to as ‘externalising’; and a class with high scores on both the internalising and externalising scales. This class is referred to as the dysregulation class. Details on the full modelling strategy and fit indices of models including 1 to 5 classes are described by Basten et al. [27]. The model with four classes provided good fit measures, and the most meaningful distinction of qualitatively different profiles. The most likely class memberships derived from this analysis were used in this study (see Table 1 for percentages). This was justified by the high entropy (0.98) of the latent class model [27, 37]. The intrinsic relation of internalising and externalising symptoms, and scores of children in the four classes on these broadband scales are illustrated in Supplementary Figure 2.
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Eur Child Adolesc Psychiatry (2017) 26:445–456
Table 1 Participant characteristics (n = 1177)
Child characteristics Gender (% boy) Ethnicity (%) Dutch Other Western Non-Western Age at CBCL (years) Range Age at NEPSY-II NL (years) Range IQ (non verbal) Range Maternal characteristics Monthly household income (%) High Medium Low Alcohol use during pregnancy (%) Never Until pregnancy was known Continued occasionally Continued frequently Smoking during pregnancy (%) Never Until pregnancy was known Continued
Dysregulation
Internalizing problems
Externalizing problems
No problems group
n = 63
n = 105
n = 171
n = 838
65.1
46.7
65.5
51.3
0.001
49.2 9.5 41.3 6.0 (0.4) 5.0–7.9 7.6 (0.9) 6.3–9.6 95.3 (15.0) 67–135
54.3 5.7 40.0 6.0 (0.4) 5.3–7.7 8.0 (1.0) 6.1–10.7 99.0 (14.1) 61–127
60.2 8.2 31.6 6.0 (0.3) 5.3–7.4 8.0 (1.1) 6.1–10.7 98.9 (15.4) 50–135
74.0 7.9 18.1 6.0 (0.4) 4.9–7.9 7.9 (1.0) 6.1–10.4 103.2 (14.0) 50–142
ORIGINAL CONTRIBUTION
Cognitive functioning in children with internalising, externalising and dysregulation problems: a population‑based study Laura M. E. Blanken1,2 · Tonya White1,3 · Sabine E. Mous1,2 · Maartje Basten1,2 · Ryan L. Muetzel1,2 · Vincent W. V. Jaddoe2,4,5 · Marjolein Wals1,6 · Jan van der Ende1 · Frank C. Verhulst1 · Henning Tiemeier1,5
Received: 10 December 2015 / Accepted: 6 September 2016 / Published online: 19 September 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Psychiatric symptoms in childhood are closely related to neurocognitive deficits. However, it is unclear whether internalising and externalising symptoms are associated with general or distinct cognitive problems. We examined the relation between different types of psychiatric symptoms and neurocognitive functioning in a population-based sample of 1177 school-aged children. Internalising and externalising behaviour was studied both continuously and categorically. For continuous, variablecentred analyses, broadband scores of internalising and externalising symptoms were used. However, these measures are strongly correlated, which may prevent identification of distinct cognitive patterns. To distinguish groups of children with relatively homogeneous symptom patterns, a latent profile analysis of symptoms at age 6 yielded four exclusive groups of children: a class of children with Electronic supplementary material The online version of this article (doi:10.1007/s00787-016-0903-9) contains supplementary material, which is available to authorized users. * Henning Tiemeier [email protected] 1
2
Department of Child and Adolescent Psychiatry, Erasmus MC-Sophia, Rotterdam, The Netherlands The Generation R Study Group, Erasmus MC, Rotterdam, The Netherlands
3
Department of Radiology, Erasmus MC, Rotterdam, The Netherlands
4
Department of Paediatrics, Erasmus MC-Sophia, Rotterdam, The Netherlands
5
Department of Epidemiology, Erasmus MC, room Na‑2818, P.O.Box 2040, 3000 CA Rotterdam, The Netherlands
6
Institute of Psychology, Erasmus University, Rotterdam, The Netherlands
predominantly internalising symptoms, a class with externalising symptoms, a class with co-occurring internalising and externalising symptoms, that resembles the CBCL dysregulation profile and a class with no problems. Five domains of neurocognitive ability were tested: attention/ executive functioning, language, memory and learning, sensorimotor functioning, and visuospatial processing. Consistently, these two different modelling approaches demonstrated that children with internalising and externalising symptoms show distinct cognitive profiles. Children with more externalising symptoms performed lower in the attention/executive functioning domain, while children with more internalising symptoms showed impairment in verbal fluency and memory. In the most severely affected class of children with internalising and externalising symptoms, we found specific impairment in the sensorimotor domain. This study illustrates the specific interrelation of internalising and externalising symptoms and cognition in young children. Keywords Internalising symptoms · Externalising symptoms · Cognition
Introduction In child development, cognitive functioning and psychopathology are closely intertwined. The school-age years are a period of abundant neurodevelopment, characterized by refinement of cognitive skills while, in some children, psychiatric symptoms emerge. Often, a disruption in one area of development is accompanied by impairment in the other, which may reflect a common underlying neurodevelopmental problem [1]. The relation of cognition and psychopathology is particularly well illustrated by developmental
13
446
disorders, such as ADHD and ASD [2], that are often characterized by lower intelligence or even intellectual impairment. While IQ provides a good measure of general cognitive ability, cognition is a broad construct with various domains, each of which can be selectively impaired or intact. There is increasing attention to assess which specific aspects of cognition are impaired in child psychiatric disorders. Such cognitive impairment can be shared across different disorders, but it may also be distinct for different types of psychopathology. Internalising and externalising disorders are two presentations of psychopathology at a young age, that are thought to emerge from partly distinct pathways, both in terms of genetics [3] and underlying brain correlates [4] and predispose for different types of psychopathology later in life [5, 6]. However, it is less clear whether distinct cognitive patterns exist for internalising and externalising symptoms at a young age. Cognitive problems in psychopathology have been studied particularly in the context of executive functioning, a broad construct of different abilities to regulate behaviour, such as the ability to pay attention or to inhibit responses. Externalising disorders such as ADHD and disruptive behavioural disorders have been conceptualised as arising from a set of primarily frontally mediated executive function deficits, including attention, planning, working memory and response inhibition [7–11]. There is more debate about the specific deficits in anxiety and mood disorders, that are primarily related to neural circuitry linking limbic structures to frontal regions [12]. Neuropsychological impairment of executive functioning has been reported [13], most notably in visual and working memory in paediatric or adolescent depression [14, 15], while differences in processing speed have also been reported [16]. Attention has also been implicated in paediatric depression [17]. While some childhood anxiety disorders, like OCD in children occur with impairments of executive functioning abilities like mental set-shifting [18], or full-scale IQ [19] they have also been related to impairment in verbal processing [20]. However, it is unclear whether these differences reflect specific lingual processes or aspects of executive functioning, such as impaired attention or working memory. In addition, some studies focused on the neurocognitive implications of co-occurring high levels of internalising and externalising symptoms, for instance in children with ADHD with comorbid internalising symptoms. These studies show inconsistent results, that vary between better test performance [21], no difference [22], to worse performance in tasks of attention, response inhibition and working memory [23] than children with ADHD only. In general, there is considerable heterogeneity in the literature relating cognition to child psychopathology and studies in young children are relatively scarce. Yet, it is especially important to study younger children, as patterns
13
Eur Child Adolesc Psychiatry (2017) 26:445–456
of emerging psychopathology and impaired cognition can provide more insight in the aetiology relatively unobscured by chronicity of symptoms or treatment effects. Further, the close relation between cognition and psychopathology in young age provides a potentially powerful treatment target for early intervention. So far, many clinical studies tend to focus on a limited range of cognitive domains within small samples of children that have one or more clinically diagnosed psychiatric disorders. Importantly, within this framework, the question of specificity of cognitive impairments cannot be answered by design. Child psychopathology is characterised by a high level of comorbidity between different symptom types, crossing the boundaries of diagnoses. Children that have a high level of externalising symptoms, such as aggression tend to also have internalising symptoms, such as anxiety or depressed mood [24]. Knowledge about specific patterns of cognitive impairment per symptom type could point to specific genetic or neurobiological pathways [8] and help in targeted treatment decisions and predictions of the clinical course of specific symptoms. An alternative to the case–control framework is provided by studying psychopathology on the symptom level, focusing on continuous trait phenotypes [25]. However, various continuously measured psychiatric symptoms are also inter-related. Although the associated cognitive problems may in fact be distinct for each symptom type, the strong correlation between internalising and externalising symptoms can obscure any potential specificity of associations. Therefore, in the current study, we also used a different approach to address the relation of internalising and externalising symptoms and cognition that added an element of specificity. To this aim, we complemented the traditional variable-based approach with a person-centred approach that allows to distinguish between different symptom profiles in case of heterogeneity [26]. Previously, we applied a latent profile analysis (LPA) to quantitative behavioural and emotional symptom data of more than 6,000 children to identify four broad, but exclusive classes with different patterns of symptoms [27]. Three of these classes included children with problem behaviour: a class of children with predominantly externalising symptoms, a class with predominantly internalising symptoms and a small class with both internalising and externalising symptoms that bears a resemblance to the CBCL Dysregulation Profile, a phenotype of high comorbidity that is associated with a broad range of later psychopathology [28]. In this populationbased cohort, the majority of children belonged to a class without psychopathology. The three classes of problem behaviour have so far only been related to a general, global measure of non-verbal intelligence [29]. Here, we aimed to further specify these differences by assessing more specific cognitive sub-domains using an extensive neuropsychological test battery that covers five domains of neurocognitive
Eur Child Adolesc Psychiatry (2017) 26:445–456
ability: attention/executive functioning, language, memory, sensorimotor functioning and visuospatial ability. In the current study, we assessed the relation between cognition and psychiatric symptoms in more than 1,000 school-aged children. In line with recommendations of the RDoC initiative, we used continuous measures of internalising and externalising symptoms to capture the full spectrum of symptom severity, including subclinical symptoms [30]. However, these measures were strongly correlated, so to identify unique patterns of impairment across different symptom types, we used the previously identified problem classes representing more homogeneous groups in terms of symptomatology. Based on the literature, we hypothesised that children with externalising symptoms show poorer performance on the attention/executive functioning domain. Further, we hypothesised that children with internalising symptoms would show moderately impaired test performance in the domains of language, memory and attention. In the class of children with high levels of both internalising and externalising symptoms, we expected widespread impairment, since they likely reflect the most severely affected group. Additionally, we tested if any impairments were independent of demographic and maternal factors or autistic symptoms. Finally, we explored whether any observed differences reflect global cognitive impairment or more specific deficits by adjusting for IQ.
Methods Participants This study included a subgroup of children from the Generation R Study, a multi-ethnic population-based cohort, investigating children’s health, growth and development from foetal life onwards in Rotterdam, the Netherlands. An overview of the Generation R Study design and population is provided elsewhere [31]. As part of a previously described sub-study [32], 1307 participants completed a neuropsychological test battery. In this sub-study, children with specific traits (including autistic traits and externalising disorders, were oversampled (see Supplementary Figure 1 for a consort diagram). Oversampling of children with problem behaviour increased the variability, which improved power of the analyses and helped in achieving a more normal distribution of psychopathology symptoms, which are generally strongly right skewed in the general population. One hundred thirty children had missing information on problem behaviour and were excluded, resulting in a study sample of 1177 children.
447
The study was approved by the Medical Ethics Committee (METC) of the Erasmus Medical Centre. Written informed consent was obtained from the parents of all participants. Internalising and externalising symptoms When the children were approximately 6 years of age, mothers of 6,131 children completed the Child Behaviour Checklist (CBCL/1.5–5). The CBCL is a widely used instrument has been shown to have good reliability and validity [33] and is generalizable across 23 societies [34]. It measures childhood psychiatric symptoms quantitatively; both in the clinical and non-clinical range and thereby captures the full range of severity. It contains internally consistent Internalizing and Externalizing broadband scales that globally correspond to mood and anxiety disorders and disruptive behaviour disorders, respectively [6]. The Internalizing and Externalizing broadband scales are able to measure broad behavioural constructs in early childhood that have been shown to predict later, more specific psychopathology [35, 36]. The Internalising scale consists of the following four scales: Emotionally Reactive; Anxious/Depressed; Somatic Complaints; and Withdrawn. The Externalising scale contains two scales: Attention Problems and Aggressive Behaviour [27]. In our first approach, we related the continuous broadband scores to cognitive functioning. Second, to explore specific cognitive problems of internalising and externalising symptoms, we defined four classes of children with distinct patterns of behavioural and emotional symptoms that were obtained by a latent profile analysis performed on T-scores of CBCL syndrome scales that constitute the internalising and externalising broadband scales. These included a class of children without problems, a class with predominantly internalising symptoms; a class with externalising symptoms and emotional reactivity, further referred to as ‘externalising’; and a class with high scores on both the internalising and externalising scales. This class is referred to as the dysregulation class. Details on the full modelling strategy and fit indices of models including 1 to 5 classes are described by Basten et al. [27]. The model with four classes provided good fit measures, and the most meaningful distinction of qualitatively different profiles. The most likely class memberships derived from this analysis were used in this study (see Table 1 for percentages). This was justified by the high entropy (0.98) of the latent class model [27, 37]. The intrinsic relation of internalising and externalising symptoms, and scores of children in the four classes on these broadband scales are illustrated in Supplementary Figure 2.
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Eur Child Adolesc Psychiatry (2017) 26:445–456
Table 1 Participant characteristics (n = 1177)
Child characteristics Gender (% boy) Ethnicity (%) Dutch Other Western Non-Western Age at CBCL (years) Range Age at NEPSY-II NL (years) Range IQ (non verbal) Range Maternal characteristics Monthly household income (%) High Medium Low Alcohol use during pregnancy (%) Never Until pregnancy was known Continued occasionally Continued frequently Smoking during pregnancy (%) Never Until pregnancy was known Continued
Dysregulation
Internalizing problems
Externalizing problems
No problems group
n = 63
n = 105
n = 171
n = 838
65.1
46.7
65.5
51.3
0.001
49.2 9.5 41.3 6.0 (0.4) 5.0–7.9 7.6 (0.9) 6.3–9.6 95.3 (15.0) 67–135
54.3 5.7 40.0 6.0 (0.4) 5.3–7.7 8.0 (1.0) 6.1–10.7 99.0 (14.1) 61–127
60.2 8.2 31.6 6.0 (0.3) 5.3–7.4 8.0 (1.1) 6.1–10.7 98.9 (15.4) 50–135
74.0 7.9 18.1 6.0 (0.4) 4.9–7.9 7.9 (1.0) 6.1–10.4 103.2 (14.0) 50–142
