Characterizing Subcortical Structural Heterogeneity in Autism.

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large (n=3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.

Examining the Boundary Sharpness Coefficient as an Index of Cortical Microstructure in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder.

Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.

Default Mode Hypoconnectivity Underlies a Sex-Related Autism Spectrum.

BACKGROUND: Females and males differ significantly in the prevalence and presentation of autism spectrum conditions. One theory of this effect postulates that autistic traits lie on a sex-related continuum in the general population, and autism represents the extreme male end of this spectrum. This theory predicts that any feature of autism in males should 1) be present in autistic females, 2) differentiate between the sexes in the typical population, and 3) correlate with autistic traits. We tested these three predictions for default mode network (DMN) hypoconnectivity during the resting state, one of the most robustly found neurobiological differences in autism. METHODS: We analyzed a primary dataset of adolescents (N = 121, 12-18 years of age) containing a relatively large number of females and a replication multisite dataset including children, adolescents, and adults (N = 980, 6-58 years of age). We quantified the average connectivity between DMN regions and tested for group differences and correlation with behavioral performance using robust regression. RESULTS: We found significant differences in DMN intraconnectivity between female controls and females with autism (p = .001 in the primary dataset; p = .009 in the replication dataset), and between female controls and male controls (p = .036 in the primary dataset; p = .002 in the replication dataset). We also found a significant correlation between DMN intraconnectivity and performance on a mentalizing task (p = .001) in the primary dataset. CONCLUSIONS: Collectively, these findings provide the first evidence for DMN hypoconnectivity as a behaviorally relevant neuroimaging phenotype of the sex-related spectrum of autistic traits, of which autism represents the extreme case.

Autism spectrum disorder in Chinese populations: a brief review.

This review summarizes the published work on the prevalence and incidence rates of autism spectrum disorder (ASD) in Chinese populations. The authors searched MEDLINE, Web of Science and the PsycINFO database and identified seven studies that were published in the English language. In mainland China, Li and colleagues reported an autism prevalence rate of 2.38/10,000 but admitted the possibility of underestimation. A higher prevalence of 11/10,000 was reported by Zhang and Ji based on a survey that was conducted in Tianjin, China. In Taiwan, Chien and colleagues reported that the cumulative prevalence of ASD increased from 1.79 to 28.72/10,000 from 1996 to 2005 and the annual incidence rate increased from 0.91 to 4.41/10,000 per year from 1997 to 2005. Another study based on the Taiwan national health insurance database reported a high prevalence rate of 122.8/10,000 for the year 2007. Two studies based on the Taiwan national disability registry data reported an increasing trend of ASD for the period 2000-2007 and 2004-2010, respectively. In Hong Kong, Wong and colleagues estimated that the incidence of ASD was 5.49/10,000 and the average prevalence over the 1986-2005 period was 16.1/10,000. We identified 12 studies through the searching of Chinese databases. The prevalences among these studies varied from 2.8 to 29.5/10,000. While existing data appear to suggest, it remains unclear whether there is a true rise in the prevalence of ASD in ethnic Chinese population across geographic sites. More collaborative research on this topic should be conducted in the future.

Psychological correlates of handedness and corpus callosum asymmetry in autism: the left hemisphere dysfunction theory revisited.

Rightward cerebral lateralization has been suggested to be involved in the neuropathology of autism spectrum conditions. We investigated functional and neuroanatomical asymmetry, in terms of handedness and corpus callosum measurements in male adolescents with autism, their unaffected siblings and controls, and their associations with executive dysfunction and symptom severity. Adolescents with autism did not differ from controls in functional asymmetry, but neuroanatomically showed the expected pattern of stronger rightward lateralization in the posterior and anterior midbody based on their hand-preference. Measures of symptom severity were related to rightward asymmetry in three subregions (splenium, posterior midbody and rostral body). We found the opposite pattern for the isthmus and rostrum with better cognitive and less severe clinical scores associated with rightward lateralization.

Failure to deactivate the default mode network indicates a possible endophenotype of autism.

BACKGROUND: Reduced activity during cognitively demanding tasks has been reported in the default mode network in typically developing controls and individuals with autism. However, no study has investigated the default mode network (DMN) in first-degree relatives of those with autism (such as siblings) and it is not known whether atypical activation of the DMN is specific to autism or whether it is also present in unaffected relatives. Here we use functional magnetic resonance imaging to investigate the pattern of task-related deactivation during completion of a visual search task, the Embedded Figures Task, in teenagers with autism, their unaffected siblings and typically developing controls. FINDINGS: We identified striking reductions in deactivation during the Embedded Figures Task in unaffected siblings compared to controls in brain regions corresponding to the default mode network. Adolescents with autism and their unaffected siblings similarly failed to deactivate regions, including posterior cingulate and bilateral inferior parietal cortex. CONCLUSIONS: This suggests that a failure to deactivate these regions is a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings.

Atypical activation during the Embedded Figures Task as a functional magnetic resonance imaging endophenotype of autism.

Atypical activation during the Embedded Figures Task has been demonstrated in autism, but has not been investigated in siblings or related to measures of clinical severity. We identified atypical activation during the Embedded Figures Task in participants with autism and unaffected siblings compared with control subjects in a number of temporal and frontal brain regions. Autism and sibling groups, however, did not differ in terms of activation during this task. This suggests that the pattern of atypical activation identified may represent a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings. We also found that reduced activation in autism relative to control subjects in regions including associative visual and face processing areas was strongly correlated with the clinical severity of impairments in reciprocal social interaction. Behavioural performance was intact in autism and sibling groups. Results are discussed in terms of atypical information processing styles or of increased activation in temporal and frontal regions in autism and the broader phenotype. By separating the aspects of atypical activation as markers of familial risk for the condition from those that are autism-specific, our findings offer new insight into the factors that might cause the expression of autism in families, affecting some children but not others.

Evaluation of a screening instrument for autism spectrum disorders in prisoners.

UNLABELLED: There have been concerns that individuals with autism spectrum disorders (ASDs) are over-represented but not recognised in prison populations. A screening tool for ASDs in prisons has therefore been developed. AIMS: We aimed to evaluate this tool in Scottish prisoners by comparing scores with standard measures of autistic traits (Autism Quotient (AQ)), neurodevelopmental history (Asperger Syndrome (and High-Functioning Autism) Diagnostic Interview (ASDI)), and social cognition (Ekman 60 Faces test). METHODS: Prison officers across all 12 publicly-run closed prisons in Scotland assessed convicted prisoners using the screening tool. This sample included male and female prisoners and both adult and young offenders. Prisoners with high scores, along with an equal number of age and sex-matched controls, were invited to take part in interviews. Prisoners' relatives were contacted to complete a neurodevelopmental assessment. RESULTS: 2458 prisoners were screened using the tool, and 4% scored above the cut-off. 126 prisoners were further assessed using standardised measures. 7 of those 126 assessed scored 32 or above (cut-off) on the AQ. 44 interviews were completed with prisoners' relatives, no prisoner reached the cut-off score on the ASDI. Scores on the screening tool correlated significantly with AQ and ASDI scores, and not with the Ekman 60 Faces Test or IQ. Sensitivity was 28.6% and specificity 75.6%; AUC was 59.6%. CONCLUSIONS: Although this screening tool measures autistic traits in this population, sensitivity for scores of 32 or above on the AQ is poor. We consider that this limits its usefulness and do not recommend that the tool is routinely used to screen for ASDs in prisons.

Facial emotion recognition in Scottish prisoners.

BACKGROUND: Studies of antisocial populations have found that they show deficits in recognition of facial affect. Such deficits are also found in other populations with clinical conditions such as autism spectrum disorders, schizophrenia and obsessive compulsive disorder. AIMS: We aimed to investigate the hypothesis that facial affect recognition in the Scottish prison population would differ from matched controls. In addition, we aimed to investigate any relationship between facial affect recognition deficits and offence history. METHODS: A sample of serving convicted prisoners, drawn from a larger study, was assessed for ability to recognise facial affect. Other variables were also measured and a self-report offending history obtained. RESULTS: 127 prisoners were assessed in 11 prisons. Male prisoners were significantly worse than age, sex and IQ-matched controls at recognising negative facial emotions, specifically anger, fear, sadness and disgust. Within the sample of prisoners, deficits in fear recognition were associated with a history of previous prison sentences but not previous convictions. With respect to offending history, sex offenders were relatively better at recognising sadness and worse at recognising surprise than the other offenders. These relationships remain after controlling for IQ. CONCLUSIONS: Scottish convicted prisoners show deficits in recognising negative facial emotions in a pattern consistent with other antisocial populations. We also demonstrated a relationship between particular patterns of deficit and types of offending history not previously described.

Health status in the TORCH study of COPD: treatment efficacy and other determinants of change.

BACKGROUND: Little is known about factors that determine health status decline in clinical trials of COPD. OBJECTIVES: To examine health status changes over 3 years in the TORCH study of salmeterol+fluticasone propionate (SFC) vs. salmeterol alone, fluticasone propionate alone or placebo. METHODS: St George's Respiratory Questionnaire (SGRQ) was administered at baseline then every 6 months. MEASUREMENTS AND MAIN RESULTS: Data from 4951 patients in 28 countries were available. SFC produced significant improvements over placebo in all three SGRQ domains during the study: (Symptoms -3.6 [95% CI -4.8, -2.4], Activity -2.8 [95% CI -3.9, -1.6], Impacts -3.2 [95% CI -4.3, -2.1]) but the pattern of change over time differed between domains. SGRQ deteriorated faster in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III & IV relative to GOLD stage II (p < 0.001). There was no difference in the relationship between deterioration in SGRQ Total score and forced expiratory volume in one second (FEV1) decline (as % predicted) in men and women. Significantly faster deterioration in Total score relative to FEV1 % predicted was seen in older patients (≥ 65 years) and there was an age-related change in Total score that was independent of change in FEV1. The relationship between deterioration in FEV1 and SGRQ did not differ in different world regions, but patients in Asia-Pacific showed a large improvement in score that was unrelated to FEV1 change. CONCLUSIONS: In addition to treatment effects, health status changes in clinical trials may be influenced by demographic and disease-related factors. Deterioration in health status appears to be fastest in older persons and those with severe airflow limitation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00268216.

Prevalence of airflow obstruction in patients attending a rapid access chest pain clinic.

BACKGROUND: Many UK hospitals have set-up specialised chest pain clinics to deal promptly and efficiently with cases of possible cardiac chest pain. It is possible that a proportion of patients attending these clinics will have a respiratory cause for their chest pain, or respiratory disease in addition to their cardiac pain. This study aimed to determine the prevalence of airflow obstruction, ischaemic heart disease and dual pathology in such patients. METHODS: Spirometry was performed on patients referred to a rapid access chest pain clinic over a 12-month period (target population of 400 patients). The main outcome measure was the prevalence of airflow obstruction (defined using spirometry), ischaemic heart disease and dual pathology. RESULTS: 405 subjects participated in the study. Abnormal spirometry was detected in 21% of patients (n=85). Airflow obstruction was the predominant lung function abnormality and was detected in 60 patients. Ischaemic heart disease was diagnosed in 21% of patients (n=85). Dual pathology was found in 4% of patients (n=17). CONCLUSIONS: Previous studies have reported a link between impaired lung function and future cardiovascular morbidity and mortality. This study suggests that airflow obstruction is an important alternative differential diagnosis in patients referred to a rapid access chest pain clinic. The identification of abnormal spirometry may help to better risk-stratify patients for future cardiovascular events and allow interventions to be instituted.

Low birthweight and preterm birth in young people with special educational needs: a magnetic resonance imaging analysis.

BACKGROUND: Although neuroanatomical and cognitive sequelae of low birthweight and preterm birth have been investigated, little is understood as to the likely prevalence of a history of low birthweight or preterm birth, or neuroanatomical correlates of such a history, within the special educational needs population. Our aim was to address these issues in a sample of young people receiving additional learning support. METHODS: One hundred and thirty-seven participants aged 13-22 years, receiving additional learning support, were recruited via their schools or colleges and underwent structural magnetic resonance imaging (MRI). Obstetric records, available in 98 cases, included birthweight and gestational data in 90 and 95 cases, respectively. Both qualitative and quantitative voxel-based analyses of MRI data were conducted. RESULTS: A history of low birthweight and preterm birth was present in 13.3% and 13.7% of cases, respectively. Low birthweight and preterm birth were associated with specific qualitative anomalies, including enlargement of subarachnoid cisterns and thinning of the corpus callosum. Low birthweight was associated with reduced grey matter density (GMD) in the superior temporal gyrus (STG) bilaterally, left inferior temporal gyrus and left insula. Prematurity of birth was associated with reduced GMD in the STG bilaterally, right inferior frontal gyrus and left cerebellar hemisphere. Comparison of subjects with no history of low birthweight or preterm birth with a previously defined control sample of cognitively unimpaired adolescents (n = 72) demonstrated significantly greater scores for several anomalies, including thinning of the corpus callosum, loss of white matter and abnormalities of shape of the lateral ventricles. CONCLUSION: Although a two-fold increased prevalence of a history of low birthweight and preterm birth exists within the special educational needs population, other aetiological factors must be considered for the overwhelming majority of cases. Neuroanatomical findings within this sample include qualitative anomalies of brain structure and grey matter deficits within temporal lobe structures and the cerebellum that persist into adolescence. These findings suggest a neurodevelopmental mechanism for the cognitive difficulties associated with these obstetric risk factors.

Autistic traits and cognitive performance in young people with mild intellectual impairment.

Cognitive performance and the relationship between theory of mind (TOM), weak central coherence and executive function were investigated in a cohort of young people with additional learning needs. Participants were categorized by social communication questionnaire score into groups of 10 individuals within the autistic spectrum disorder (ASD) range, 14 within the pervasive developmental disorder range and 18 with few autistic traits. The ASD group were significantly poorer than the other groups on a test of cognitive flexibility. In the ASD group only, there was a strong relationship between executive performance and TOM which remained after controlling for IQ. Our findings suggest that the relationship between cognitive traits may more reliably distinguish autism than the presence of individual deficits alone.

Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies.

BACKGROUND: Structural brain abnormalities have been described in autism but studies are often small and contradictory. We aimed to identify which brain regions can reliably be regarded as different in autism compared to healthy controls. METHOD: A systematic search was conducted for magnetic resonance imaging studies of regional brain size in autism. Data were extracted and combined using random effects meta-analysis. The modifying effects of age and IQ were investigated using meta-regression. RESULTS: The total brain, cerebral hemispheres, cerebellum and caudate nucleus were increased in volume, whereas the corpus callosum area was reduced. There was evidence for a modifying effect of age and IQ on the cerebellar vermal lobules VI-VII and for age on the amygdala. CONCLUSIONS: Autism may result from abnormalities in specific brain regions and a global lack of integration due to brain enlargement. Inconsistencies in the literature partly relate to differences in the age and IQ of study populations. Some regions may show abnormal growth trajectories.

Schizotypal cognitions as a predictor of psychopathology in adolescents with mild intellectual impairment.

BACKGROUND: There is evidence to suggest that among young people with mild intellectual disability there are those whose cognitive difficulties may predict the subsequent manifestation of a schizophrenic phenotype. It is suggested that they may be detectable by simple means. AIMS: To gain adequate cooperation from educational services, parents and students so as to recruit a sufficiently large sample to test the above hypothesis, and to examine the hypothesis in the light of the findings. METHOD: The sample was screened with appropriate instruments, and groups hypothesised as being likely or not likely to have the phenotype were compared in terms of psychopathology and neuropsychology. RESULTS: Simple screening methods detect a sample whose psychopathological and neuropsychological profile is consistent with an extended phenotype of schizophrenia. CONCLUSIONS: Difficulties experienced by some young people with mild and borderline intellectual disability are associated with enhanced liability to schizophrenia. Clinical methods can both identify those with this extended phenotype and predict those in whom psychosis will occur.

Grey matter correlates of early psychotic symptoms in adolescents at enhanced risk of psychosis: a voxel-based study.

A three-fold enhanced risk of schizophrenia is conferred by learning disability. Here we use voxel-based morphometry (VBM) to investigate grey matter correlates of early psychotic and related symptoms in 137 adolescents at enhanced risk of this disorder because of intellectual disability. Anxiety, hallucinations, incoherence of speech and delusions were assessed at clinical interview, and VBM was used to examine linear associations between symptom severity and grey matter density (GMD). We found significant correlations between anxiety and GMD in the right dorsomedial thalamic nucleus, left parahippocampal gyrus and left hippocampus. Incoherence of speech was associated with GMD in the left cerebellar hemisphere. Gender-separate analysis demonstrated correlations between anxiety and GMD in the right dorsomedial thalamic nucleus of males and the right pulvinar nucleus of females, hallucinations and GMD in the right STG of males, delusions and GMD in the left middle temporal gyrus (MTG) of females, and incoherence of speech and GMD in the right MTG of males and both cerebellar hemispheres and right inferior temporal gyrus of females. Findings are consistent with symptom-structure associates previously reported in populations with schizophrenia or at enhanced genetic risk, and suggest an anatomical basis for the psychopathology found in this young nonclinical population.

Structural correlates of intellectual impairment and autistic features in adolescents.

Intellectual disability, a common but under-researched condition, is strongly associated with autism spectrum disorders (ASD). Although studies have investigated the neural correlates of intelligence quotient (IQ) and ASD in intellectually unimpaired subjects, these issues have not been addressed in intellectually impaired subjects. We studied 63 intellectually disabled adolescents receiving additional learning support and 72 controls using whole brain tissue volumes extracted from native space and voxel-based morphometry (VBM) in normalised space. We applied a qualitative and quantitative review of VBM preprocessing and modified the optimised method to establish optimum co-registration of the brains in normalised space. We report tissue density differences at cluster level with adjustment for underlying smoothness. Individuals with intellectual disability had smaller total white matter and total brain tissue volumes than controls, as well as reduced grey matter density in the right cerebellar hemisphere and left temporo-parietal cortex, and reduced white matter density in the posterior corpus callosum. Intellectually disabled subjects were additionally subgrouped according to their degree of reported autistic features. Reduced grey matter density was detected in the thalamus of subjects with autistic features scoring within the pervasive developmental disorder range as compared to subjects below the threshold for ASD, and increased white matter density was detected in the left superior temporal gyrus of subjects scoring above the threshold for autism as compared to subjects below the threshold for ASD.

Estimating the cost-effectiveness of fluticasone propionate for treating chronic obstructive pulmonary disease in the presence of missing data.

OBJECTIVES: To explore the cost-effectiveness of fluticasone propionate (FP) for the treatment of chronic obstructive pulmonary disease (COPD), we estimated costs and quality-adjusted life-years (QALYs) over 3 years, based on an economic appraisal of a previously reported clinical trial (Inhaled Steroids in Obstructive Lung Disease in Europe [ISOLDE]). METHODS: Seven hundred forty-two patients enrolled in the ISOLDE trial who received either FP or placebo had data available on health-care costs and quality of life over the period of the study. The SF-36-based utility scores for quality of life were used to calculate QALYs. A combined imputation and bootstrapping procedure was employed to handle missing data and to estimate statistical uncertainty in the estimated cumulative costs and QALYs over the study period. The imputation approach was based on propensity scoring and nesting this approach within the bootstrap ensured that multiple imputations were performed such that statistical estimates included imputation uncertainty. RESULTS: Complete data were available on mortality within the follow-up period of the study and a nonsignificant trend toward improved survival of 0.06 (95% confidence interval [CI]-0.01 to 0.15) life-years was observed. In an analysis based on a propensity scoring approach to missing data we estimated the incremental costs of FP versus placebo to be 1021 sterling pound(95% CI 619-1338 sterling pound) with an additional effect of 0.11 QALYs (CI 0.04-0.20). Cost-effectiveness estimates for the within-trial period of 17,700 sterling pound per life-year gained (6900 sterling pound to infinity) and 9500 sterling pound per QALY gained (CI 4300-26,500 sterling pound) were generated that include uncertainty due to the imputation process. An alternative imputation approach did not materially affect these estimates. CONCLUSIONS: Previous analyses of the ISOLDE study showed significant improvement on disease-specific health status measures and a trend toward a survival advantage for treatment with FP. This analysis shows that joint considerations of quality of life and survival result in a substantial increase in QALYs favoring treatment with FP. Based on these data, the inhaled corticosteroid FP appears cost-effective for the treatment of COPD. Confirmation or refutation of this result may be achieved once the Towards a Revolution in COPD Health (TORCH) study reports, a large randomized controlled trial powered to detect mortality changes associated with the use of FP alone, or in combination with salmeterol, which is also collecting resource use and utility data suitable for estimating cost-effectiveness.