Outcome Measure In Clinical Studies Research Articles

An update on paediatric asthma

In this Update we will discuss aspects of the definitions, epidemiology, diagnostics, asthma-associated comorbidities, assessment and treatment of asthma including a specific focus on severe asthma in school children. The Update will mainly cover data published during the last 3 yrs. In 2009, an expert panel was tasked to propose a World Health Organization definition of asthma severity and control. The result of this Task Force was a uniform definition of asthma severity, control and exacerbation [1]. As we will discuss later in an overview of asthma outcomes [2], symptom evaluation is the key to the diagnosis and outcome measures in clinical studies. Airway inflammation is one of the pathophysiological characteristics of asthma, which is mediated through infiltration of inflammatory cells, including mast cells, and eosinophilic and neutrophilic granulocytes in the airway wall. This cell infiltration subsequently leads to bronchial hyperresponsiveness (BHR) and, in the case of chronic inflammation, persistent changes of the airways, i.e. airway remodelling [3, 4]. Immunoglobulin (Ig)E-mediated allergy leading to allergic inflammation is common among children with persistent asthma. There are ongoing studies worldwide (the MeDALL initiative) aiming to identify allergic phenotypes [5] and understand the complexity of the IgE related phenotypes in children and adults [6]. The purpose of paediatric asthma treatment is for the child to control symptoms, to be able to lead a normal active life, to have normal lung function and to prevent asthma exacerbations [7, 8]. The care of asthmatic children does not only include the prescription of asthma medication. The families need to be convinced and educated to actually make the parents give the medication as prescribed and in a proper manner [9]. Furthermore, healthcare providers must teach the families how to avoid or …

THE USE OF DELAYED GADOLINIUM ENHANCED MAGNETIC RESONANCE IMAGING OF CARTILAGE AND T2 MAPPING TO EVALUATE ARTICULAR CARTILAGE IN THE NORMAL CANINE ELBOW

Commonly used diagnostic tools used to evaluate articular cartilage lack the sensitivity, specificity, and objectivity to measure early changes associated with osteoarthritis. Two techniques using magnetic resonance (MR) imaging have been developed to detect the biology of articular cartilage are delayed gadolinium-enhanced MR imaging of cartilage (dGEMRIC) and T2 mapping. Both techniques have been validated and are used to study the degenerative and adaptive nature of articular cartilage in people. The use of these techniques as a diagnostic tool in dogs has not been well described. We evaluated articular cartilage in the region of the medial coronoid process (MCP) of six healthy dogs free of detectable orthopedic disease using both MR imaging techniques. Histology and proteoglycan (PG) content of the MCP were used to confirm normal articular cartilage. All dogs had ground reaction forces consistent with normal function. Mean dGEMRIC index (T1 value) was 400 +/- 47 ms and mean T2 value was 56 +/- 8 ms. Intra- and interobserver variability was low. dGEMRIC and T2 values for normal cartilage in the elbow of the dog can be generated reproducibly using 3T MR imaging. Using these techniques as objective outcome measures for clinical studies in dogs with OA conditions should help delineate the efficacy of some disease interventions.

Can Neuropathic Screening Tools Be Used As Outcome Measures?

To examine whether the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) screening tool can satisfy Rasch model expectations and therefore be transformed into an interval level measurement scale, suitable for use as an outcome measure in clinical studies. Rasch analysis (using the software RUMM2020) of LANSS data from both a random selection of all chronic pain patients and also specific chronic pain diagnostic categories. Original LANSS data from a previous study of 2,480 patients with chronic pain were used. Specific diagnostic groups examined included diabetic neuropathy, postsurgical pain, osteoarthritis, posttraumatic injury, and low back pain. The following assessments were made: fit to the Rasch model, scale reliability, scale multi-dimensionality, and differential item functioning. The overall fit to the Rasch model was only acceptable in two groups; diabetic neuropathy and chronic postsurgical pain. For these groups, the scale is unidimensional (measures a single construct) and there is no evidence of differential item functioning across gender and age groups. The scale only has reliability consistent with use at the group level. Neuropathic screening tools such as the LANSS have been used as outcome measures in clinical studies. Rasch analysis demonstrates that the LANSS can be used as such in specific populations of patients with neuropathic pain, however it's reliability in this context does not support use at the individual level and it cannot be used as a generalised measurement tool across pain diagnostic groups. The LANSS remains primarily a diagnostic tool.

Validation of a parent-proxy quality of life questionnaire for paediatric chronic cough (PC-QOL)

BackgroundQuality of life (QOL) measures are an important patient-relevant outcome measure for clinical studies. Currently there is no fully validated cough-specific QOL measure for paediatrics. The objective of this study...

The reliability of identifying bronchial breathing by auscultation

Aims This study was carried out to determine the intra- and inter-rater reliability of identifying bronchial breathing by auscultation, and the effect of education on the ability to identify bronchial breathing. Methods Eighteen children admitted to a tertiary paediatric hospital underwent auscultation and recording of 20 breath sounds using an electronic stethoscope. Breath sounds were independently assessed before and after educational intervention. Intra- and inter-rater reliability were calculated using free-marginal Kappa statistics. Findings Ten raters (six physiotherapists; four paediatricians), were included. Inter-rater reliability had a Kappa value of 0.3 whilst intra-rater reliability ranged from -0.01 to 0.6. Sensitivity increased from 58% to 75% following education, with no change in specificity. Physiotherapists' test scores increased from 76.7 (± 9.3%) to 80.8 (± 5.8%) while the paediatricians' scores decreased from 66.3 (± 4.8%) to 60.0 (± 4.1%) following education (P = 0.038). After education, total test scores improved more in newly qualified professionals than those qualified for over five years (P = 0.01). Conclusion Auscultation of bronchial breath sounds is unreliable in infants and young children and is therefore not a valid outcome measure for clinical studies.

COMMENTARY

COMMENTARY Cellulite is considered a secondary female characteristic1 and has even been demonstrated upon pinching a 6-month-old, female infant's thigh2 … therefore it is reasonable to believe that a significant challenge awaits those seeking to cure this “disease.” Hexsel et al3 should be commended for designing a unique, blinded investigation aimed at visualizing and quantifying the oft cited “fibrous septae” responsible for the pathognomonic peau d'orange appearance of cellulite. They demonstrate convincingly that a relatively thick (>2 mm) vascular and/or lymphatic fibrous tissue network permeates within the subcutaneous tissue underlying skin exhibiting cellulite. In order to be effective, therapeutic approaches for cellulite will have to disrupt these septae. It is unlikely that currently available injectable and superficial energy based devices4 will have a profound effect on these septae, effacing the skin dimpling bothersome to many patients. As this study and the work of others5 reveal, the architecture of fat and cellulite is complex. Despite its expense, MRI should be integrated into controlled studies of treatments intended to reduce the appearance cellulite, just as Goldberg and colleagues recently presented.6 Perhaps broader appreciation of anatomy and refining photography and other outcome measures in clinical studies will eventually lead to sophisticated methods that alleviate this benign but aesthetically bothersome condition. ADAM M. ROTUNDA MD *Newport Beach, CA

Predicting EuroQol (EQ-5D) scores from the patient-reported outcomes measurement information system (PROMIS) global items and domain item banks in a United States sample

BackgroundPreference-based health index scores provide a single summary score assessing overall health-related quality of life and are useful as an outcome measure in clinical studies, for estimating quality-adjusted life years for economic evaluations, and for monitoring the health of populations. We predicted EuroQoL (EQ-5D) index scores from patient-reported outcomes measurement information system (PROMIS) global items and domain item banks.MethodsThis was a secondary analysis of health outcome data collected in an internet survey as part of the PROMIS Wave 1 field testing. For this study, we included the 10 global items and the physical function, fatigue, pain impact, anxiety, and depression item banks. Linear regression analyses were used to predict EQ-5D index scores based on the global items and selected domain banks.ResultsThe regression models using eight of the PROMIS global items (quality of life, physical activities, mental health, emotional problems, social activities, pain, and fatigue and either general health or physical health items) explained 65% of the variance in the EQ-5D. When the PROMIS domain scores were included in a regression model, 57% of the variance was explained in EQ-5D scores. Comparisons of predicted to actual EQ-5D scores by age and gender groups showed that they were similar.ConclusionsEQ-5D preference scores can be predicted accurately from either the PROMIS global items or selected domain banks. Application of the derived regression model allows the estimation of health preference scores from the PROMIS health measures for use in economic evaluations.

Responsiveness and Construct Validity of a Symptom Scale for Acute Otitis Media

Because resolution of symptoms is a primary goal of antimicrobial therapy in children with acute otitis media (AOM), measurement of symptoms in studies of antimicrobial effectiveness in such children is important. We have developed a scale for measuring symptoms of AOM in young children (AOM-SOS), and we present data on its construct validity and responsiveness. We followed children 3 months to 3 years of age with AOM, who were receiving antimicrobial treatment, using the AOM-SOS scale. The scale was administered at the enrollment visit, as a twice-a-day diary measure, and at the follow-up visit (days 5-7). To evaluate construct validity, we examined the correlation, at entry, between AOM-SOS scores and scores on other measures of pain and functional status. To evaluate the scale's responsiveness, we examined the change in scale scores from entry to follow-up. We also examined the levels of agreement between the scale scores and overall assessments of the children by parents. We enrolled 70 children (mean age 12.5 months) of whom 57 returned for follow-up. The magnitude of the correlations between the AOM-SOS scale scores and other measures of pain and functional status ranged from 0.56 to 0.84. The responsiveness of the AOM-SOS, as measured by the standardized response mean was 1.20. These data support the validity and responsiveness of the AOM-SOS; the scale seems to measure effectively both pain and overall functional status in young children with AOM. Changes in score over the first few days of illness were substantial and generally matched the assessments both of parents and of clinicians. The AOM-SOS promises to be useful as an outcome measure in clinical studies of AOM.

Monitoring anti-TNFα treatment in rheumatoid arthritis: responsiveness of magnetic resonance imaging and ultrasonography of the dominant wrist joint compared with conventional measures of disease activity and structural damage

Objectives:To evaluate the responsiveness of magnetic resonance imaging (MRI) and ultrasonography (US) compared with conventional measures of disease activity and structural damage in patients with rheumatoid arthritis (RA) during the...

Personality traits and subjective health in the later years: The association between NEO-PI-R and SF-36 in advanced age is influenced by health status

This study examined the association between personality traits (as measured by the NEO-PI-R) and subjective ratings of mental and physical health (as measured by the SF-36) in two samples of older adults differing in health status (Baltimore Longitudinal Study of Aging, BLSA, n = 393, vs. Medicare Primary and Consumer-Directed Care Demonstration, Medicare PCC, n = 648). The association between personality traits and subjective mental health did not differ significantly across samples. The association between personality and subjective physical health, however, was significantly stronger in the healthy BLSA sample than in the medically challenged Medicare PCC sample. Differences in health conditions and recent hospitalizations partially accounted for this effect. Lifespan developmental considerations and implications for the use of subjective health ratings as outcome measures in clinical studies are discussed.

Too much, too little, too soon, too late? Transfusion and long‐term survival in children

Too much, too little, too soon, too late? Transfusion and long‐term survival in children

Should gait analysis be a part of clinical orthopaedic reports?

Should gait analysis be a part of clinical orthopaedic reports?

Rating Scales for Clinical Studies in Neurology—Challenges and Opportunities

Rating scales are increasingly used as primary or secondary outcome measures in clinical studies in neurology. They are therefore becoming the key dependent variables upon which decisions are made that influence patient care and guide future research. The adequacy of these decisions depends directly on the scientific quality of the rating scales, which is reflected by the increased application of rating scale science (psychometrics) in health outcomes measurement in neuroscience and increasing regulatory involvement by governing bodies such as the US Food and Drug Administration (FDA). However, the majority of clinical studies in neurology that use rating scales are currently inadequate. Two simple examples illustrate some of the key issues.

Motor phenotype assessment in patients with depressive disorders using isometric tongue force analysis – a readout for clinical studies?

Background: Motor symptoms of depression are increasingly appreciated in the setting of research and clinical studies. Psychomotor slowing, for instance, has been identified as criterion for the severity of depression and is currently being assessed in standardized depression rating scales (e.g., Hamilton Rating Scale for Depression, DSM-IV). However, clinical ratings may be biased by subjective error and categorical scales are lacking high sensitivity. Therefore objective and quantitative measures of motor dysfunction would be desirable as possible outcome measures in clinical studies. In Huntington's Disease and ALS isometric tongue force variability (TFV) assessed by measuring tongue protrusion forces (=glossomotography) was shown to be a reliable measure of motor dysfunction and progression of disease (Reilmann et al. 2003, Wansing et al. 2006).

Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis

To investigate the correlation between the degree of dermal fibrosis and myofibroblast infiltration using clinical assessments of skin thickness and hardness in systemic sclerosis (SSc). Eleven patients with diffuse SSc and 10 healthy controls were evaluated using the modified Rodnan skin thickness score and durometry (hardness measurement). Biopsy samples were obtained from the dorsal mid-forearm in all subjects at the baseline visit and again 6-12 months later in patients with SSc. Five of the patients with SSc received treatment with cyclophosphamide (CYC) in the interval between skin biopsies. Biopsy sections were assessed for myofibroblast and hyalinized collagen content by 2 blinded observers. Myofibroblast and hyalinized collagen scores each correlated with the forearm skin score (r = 0.83, P < 0.0001 and r = 0.78, P < 0.0001, respectively) and with the forearm durometry score (r = 0.72, P < 0.0004 and r = 0.69, P < 0.0008, respectively). The change in the dermal hyalinized collagen score correlated with the change in the forearm durometry score (r = 0.74, P < 0.0213). The myofibroblast score decreased in all 5 patients who received CYC and increased in those receiving non-CYC treatments (P < 0.01 for the difference). Myofibroblasts play an important role in the pathogenesis of fibrosis, and our data imply that quantification of myofibroblasts and hyalinized collagen in skin may be a useful outcome measure in clinical studies of SSc.

Measuring Outcomes of Vision Rehabilitation with the Veterans Affairs Low Vision Visual Functioning Questionnaire

To evaluate the sensitivity to change, in patients who undergo vision rehabilitation, of the Veteran Affairs (VA) Low Vision Visual Functioning Questionnaire (LV VFQ-48), which was designed to measure the difficulty visually impaired persons have in performing daily activities and to evaluate vision rehabilitation outcomes. Before and after rehabilitation, the VA LV VFQ-48 was administered by telephone interview to subjects from five sites in the VA and private sector. Visual acuity of these subjects ranged from near normal to total blindness. The VA LV VFQ exhibited significant differential item functioning (DIF) for 7 of 48 items (two mobility tasks, four reading tasks, and one distance-vision task). However, the DIF was small relative to baseline changes in item difficulty for all items. Therefore, the data were reanalyzed with the constraint that item difficulties do not change with rehabilitation, which assigns all changes to the person measure. Subjects in the inpatient Blind Rehabilitation Center (BRC) program showed the largest changes in person measures after vision rehabilitation (effect size = 1.9; t-test P < 0.0001). The subjects in the outpatient programs exhibited smaller changes in person measures after rehabilitation (effect size = 0.29; t-test P < 0.01). There was no significant change in person measures for the control group (test-retest before rehabilitation). In addition to being a valid and reliable measure of visual ability, the VA LV VFQ-48 is a sensitive measure of changes that occur in visual ability as a result of vision rehabilitation. Patients' self-reports of the difficulty they experience performing daily activities measured with this instrument can be used to compute a single number, the person measure that can serve as an outcome measure in clinical studies. The VA LV VFQ-48 can be used to compare programs that offer different levels of intervention and serve patients across the continuum of vision loss.

Infrared-monitored cold response in the assessment of Raynaud's phenomenon.

Evaluation of treatments for Raynaud's phenomenon (RP) requires objective response parameters in addition to clinical activity scores. Thermographic monitoring of fingertip re-warming after cold challenge has been widely used but usually requires sophisticated equipment. We have previously shown that fingertip re-warming after cold challenge follows a first-order transient response curve that can be described by a single variable, designated tau. Here, we describe a novel device termed a duosensor, which records the tau value upon cold challenge in an automated manner. We determined tau values in healthy probands, patients with primary or secondary RP associated with autoimmune disease and patients with scleroderma-associated RP following cold challenge, to determine assay variability, sensitivity and specificity. Duosensor-based thermography exhibited low intraindividual variability in healthy probands. As expected, tau values in RP patients were significantly increased compared with controls (8.08 +/- 3.65 min vs. 3.23 +/- 1.65 min). The duosensor-determined tau value yielded a specificity of 94.6% and predictive value of 95.3% for the presence of RP in a retrospective analysis of 139 patients. Furthermore, in a cohort of scleroderma patients with RP, patient self-assessment of RP severity correlated with tau values. Taken together, the present data suggest that tau value determination provides a suitable outcome measure for clinical studies of novel RP treatments. As the duosensor is a simple stand-alone device requiring no supporting equipment and minimal personnel attention, it should allow RP activity monitoring even in clinical settings with minimal technical infrastructure.

Reductions in and relations between “craving” and drinking in a prospective, open-label trial of ondansetron in adolescents with alcohol dependence

Recently, we reported that ondansetron (a 5-HT 3 antagonist) as an adjunct to cognitive behavioral therapy (CBT) produced significant within-group decreases (improvement) in drinking in adolescents with alcohol dependence. We previously have hypothesized that the mechanism of ondansetron treatment response in adolescents with alcohol dependence should be similar to early onset adult alcoholics, wherein blockade of serotonin-3 receptors may decrease dopamine release and subsequent alcohol consumption and craving. We now suggest that one mechanism by which ondansetron diminishes drinking in adolescents with alcohol dependence is through a reduction in “craving” as measured by the Adolescent Obsessive–Compulsive Drinking Scale (A-OCDS). We conducted an 8-week, prospective, open-label study of ondansetron (4 μg/kg b.i.d.) in 12 adolescents (age 14–20 years) who had alcohol dependence. Results showed that “irresistibility” and total scores as measured by the A-OCDS were correlated significantly with drinking indices (drinks / day, percent days abstinent) at the end of treatment, and that “irresistibility” and total A-OCDS scores decreased significantly by the end of treatment. These preliminary results suggest that the A-OCDS can be useful as an outcome measure in clinical studies of adolescents with alcohol dependence.

Obstructive, occupational, and environmental diseases

The bulk of this issue of Current Opinion in Pulmonary Medicine is devoted to various aspects of chronic obstructive pulmonary disease (COPD) with emphasis on new information. However, subjects of the first two articles were chosen not because of an abundance of new information but because they have yet to receive attention commensurate to their importance. The prevalence of smoking-related COPD in women in the US and other developed countries is increasing. In addition, millions of women in resource-poor countries develop COPD and other respiratory illnesses in large part due to indoor environmental exposures. Anita Varkey explores the risk factors that particularly affect women and offers suggestions for risk reduction. While there is a great deal of interest and work done on sleep-disordered breathing, sleep disorders in COPD and their consequences have been less well studied. Kesavan Kutty provides an up-to-date review of this subject. Of all the medications available for the management of COPD, inhaled corticosteroids have justifiably elicited the most interest because of our increasing understanding of the inflammatory component of the disease. Kristin Highland in an evidence-based review clarifies the indications for use of inhaled corticosteroids in COPD. Linus Santo Tomas and I discuss the importance of quality-of-life issues in patients with COPD. Clinicians will readily recognize that relief of dyspnea is of immediate and paramount importance to patients as it affects all aspects of their everyday life. Appropriately now clinicians and investigators are placing emphasis on quality-of-life measures in treating COPD and also incorporating them as outcome measures in clinical studies. Lung-volume-reduction surgery (LVRS) over the years generated extreme hope and extreme despair. Neither of these extreme emotions is warranted based on the landmark 2003 report of the National Emphysema Treatment Trial. Terrence Trow analyzes the data and its conclusions. It is quite likely that the principle behind LVRS will be expanded in the future for less invasive approaches. Andrew Chan and Roblee Allen review the topic of severe bronchiolitis obliterans both in the post-organ transplant and nontransplant settings. Although this topic was reviewed in recent years, since then there have been refinements in noninvasive diagnostic methods such as pulmonary function tests and high resolution computed tomography in posttransplant patients. The last two articles focus on occupational asthma. Palomo Campo, Zana Lummus, and David Bernstein update the methods used in evaluation of occupational asthma. The table they provide on the pros and cons of each test should be of practical use for clinicians. Eduard Monsó examines the causes of occupational asthma and other respiratory illnesses in greenhouse workers. I thank the authors for their contributions.

Effects of Graves' ophthalmopathy on quality of life.

General health-related quality of life is markedly impaired in patients with Graves' ophthalmopathy (GO), and even worse than in patients with other chronic conditions like diabetes, emphysema or heart failure. A disease-specific quality-of-life questionnaire for GO has been developed, the so-called GO-QOL, consisting of two subscales: one for visual functioning (8 questions referring to limitations due to decreased visual acuity and/or diplopia) and one for appearance (8 questions referring to limitations in psychosocial functioning due to changes in appearance). The GO-QOL was found to be a valid and reliable instrument. A minimal clinically important difference (MCID) in the GO-QOL score was derived from data obtained before and after specific eye treatments. Based on the patient's opinions, changes of > or = 6 points (minor surgery) or > or = 10 points (surgical decompression, immunosuppression) are recommended as MCID. It is concluded that the GO-QOL is an useful instrument for measuring changes over time in visual functioning and appearance of GO patients. The GO-QOL is available in six languages, and can be used as a separate outcome measure in clinical studies.