Lung function made easy: assessing lung size

Spirometry is available in most GP surgeries and provides an invaluable tool for assessing respiratory function in chronic obstructive pulmonary disease (COPD) and asthma. Spirometry alone may not provide the clinician with an accurate assessment of lung disease as it misses two important measurements of lung volume. By measuring Residual Volume (RV) and Total Lung Capacity (TLC) it is possible to determine true restrictive or hyperinflated disease processes. Helium dilution, body plethysmography and nitrogen washout are three different methods which may be used to measure lung volume. These tests are normally only provided in the acute setting. Comparing values of RV and TLC to predicted values makes it possible to grade the severity of disease far more accurately than spirometry. Four case studies of asthma, obesity, COPD and pulmonary fibrosis clearly demonstrate anomalies that may arise when interpreting lung disease from spirometry compared to the interpretation made with additional lung volume data.     

Occupational asthma caused by Ipe (Tabebuia spp) dust.

BACKGROUND: Ipe is a resistant hardwood that contains naphtoquinones. It is easily found and frequently used in South and Central America. Naphtoquinones are skin sensitizers. OBJECTIVE: To describe a case of occupational asthma related to Ipe wood dust. METHODS: The patient was submitted to a clinical evaluation consisting of a respiratory symptom questionnaire, occupational history, serial measurements of lung function by spirometry, skin prick tests, patch tests, specific IgE and specific bronchial provocation tests to Ipe dust. RESULTS: Serial lung function measurements showed sustained regression of obstruction following removal from exposure. Skin prick tests, but not patch tests, were positive to Ipe, and a specific bronchial challenge showed a late asthmatic reaction. Specific IgE search was negative. CONCLUSIONS: Exposure to Ipe wood dust can lead to occupational asthma. The underlying mechanism should be investigated.     

Diagnostic utility of inflammatory biomarkers in asthma: exhaled nitric oxide and induced sputum eosinophil count

BACKGROUND: Even though an inflammatory process is known to be the underlying cause of asthma, diagnosis is based on clinical history, reversible airway obstruction and bronchial hyperresponsiveness according to international guidelines. The fraction of exhaled nitric oxide (FE(NO)) and induced sputum eosinophil count (Eos%) have been used as non-invasive inflammatory biomarkers. OBJECTIVES: The aim of this study was to compare the sensitivity and specificity of FE(NO), Eos% and spirometry and to assess whether their combined use in clinical practice would improve diagnostic yield. METHODS: In 50 patients with asthma symptoms we performed spirometry, a methacholine challenge test, FE(NO) measurement and assessment of Eos% in induced sputum. The standard diagnosis of asthma followed the guidelines of the Global Initiative for Asthma. RESULTS: Twenty-two of the 50 patients were diagnosed with asthma. The sensitivity and diagnostic accuracy were higher for FE(NO) measurement (77%; area under the receiver operating curve [AUC], 0.8) than for spirometry (22%; AUC, 0.63). The sensitivity and specificity of Eos% in induced sputum were 40% and 82%, respectively, and the diagnostic accuracy of Eos% was lower (AUC, 0.58). When both inflammatory biomarkers were used together specificity increased to 76%. CONCLUSIONS: The diagnostic accuracy of FE(NO) measurement was superior to that of the standard diagnostic spirometry in patients with symptoms suggestive of asthma. The use of FE(NO) measurement and induced sputum Eos% together to diagnose asthma in clinical practice is more accurate than spirometry or FE(NO) assessment alone and easier to perform.     

Deep learning facilitates the diagnosis of adult asthma

BackgroundWe explored whether the use of deep learning to model combinations of symptom-physical signs and objective tests, such as lung function tests and the bronchial challenge test, would improve model performance in predicting the initial diagnosis of adult asthma when compared to the conventional machine learning diagnostic method.MethodsThe data were obtained from the clinical records on prospective study of 566 adult out-patients who visited Kindai University Hospital for the first time with complaints of non-specific respiratory symptoms. Asthma was comprehensively diagnosed by specialists based on symptom-physical signs and objective tests. Model performance metrics were compared to logistic analysis, support vector machine (SVM) learning, and the deep neural network (DNN) model.ResultsFor the diagnosis of adult asthma based on symptom-physical signs alone, the accuracy of the DNN model was 0.68, whereas that for the SVM was 0.60 and for the logistic analysis was 0.65. When adult asthma was diagnosed based on symptom-physical signs, biochemical findings, lung function tests, and the bronchial challenge test, the accuracy of the DNN model increased to 0.98 and was significantly higher than the 0.82 accuracy of the SVM and the 0.94 accuracy of the logistic analysis.ConclusionsDNN is able to better facilitate diagnosing adult asthma, compared with classical machine learnings, such as logistic analysis and SVM. The deep learning models based on symptom-physical signs and objective tests appear to improve the performance for diagnosing adult asthma.     

Spirometry can be done in family physicians' offices and alters clinical decisions in management of asthma and COPD

BACKGROUND: Spirometry is recommended for diagnosis and management of obstructive lung disease. While many patients with asthma and COPD are cared for by primary care practices, limited data are available on the use and results associated with spirometry in primary care. OBJECT: To assess the technical adequacy, accuracy of interpretation, and impact of office spirometry. DESIGN: A before-and-after quasiexperimental design. SETTING: Three hundred eighty-two patients from 12 family medicine practices across the United States. PARTICIPANTS: Patients with asthma and COPD, and staff from the 12 practices. MEASUREMENTS: Technical adequacy of spirometry results, concordance between family physician and pulmonary expert interpretations of spirometry test results, and changes in asthma and COPD management following spirometry testing. RESULTS: Of the 368 tests completed over the 6 months, 71% were technically adequate for interpretation. Family physician and pulmonary expert interpretations were concordant in 76% of completed tests. Spirometry was followed by changes in management in 48% of subjects with completed tests, including 107 medication changes (>85% concordant with guideline recommendations) and 102 nonpharmacologic changes. Concordance between family physician and expert interpretations of spirometry results was higher in those patients with asthma compared to those with COPD. DISCUSSION AND CONCLUSIONS: US family physicians can perform and interpret spirometry for asthma and COPD patients at rates comparable to those published in the literature for international primary care studies, and the spirometry results modify care.     

The diagnosis of emphysema, chronic bronchitis, and asthma

Although of some value for understanding etiologic mechanisms, the classic diagnostic categories of asthma and emphysema and especially chronic bronchitis have not served clinicians well for defining prognosis and therapeutic options. Until more useful diagnostic categories are available, the choice of diagnostic tests should be guided more by their clinical usefulness than by their sensitivity and specificity for identifying classic diagnostic categories of obstructive lung disease. A history consistent with asthma is as good evidence of asthma as that provided by most tests, especially if combined with spirometric evidence of complete reversibility of episodes of obstruction. Positive bronchial challenge studies and partial responses to bronchodilators are common in asthma but of limited diagnostic specificity. Tests of allergic function are of limited specificity for asthma, although a low IgE level is rare. Findings of reduced expiratory flows, high TLC, and low DLCO, or radiologic signs of hyperinflation, bullae, and pulmonary vascular deficiency pattern are useful for diagnosing cases of severe emphysema, but they are of limited sensitivity for the detection of mild to moderate disease. Advances in high resolution CT offer promise of earlier diagnosis of emphysema. Making a diagnosis of chronic bronchitis based on defined criteria for chronic sputum production is easy but of limited clinical value. Prospective longitudinal studies and advances in technology promise more clinically useful diagnoses in the future.     

High resolution CT and bronchial reversibility test for diagnosing COPD

BACKGROUND: COPD is defined by airflow limitation that is not fully reversible and is associated with relevant risk factors. The diagnosis requires that other causes of chronic airflow limitation (CAL) be excluded. We assessed the diagnostic utility of high resolution thoracic CT (HRCT) and bronchodilator reversibility to assist in making a diagnosis of COPD. METHODOLOGY: We investigated 516 consecutive patients whose FEV1/FVC was less than 70% after inhalation of bronchodilator. HRCT was performed on all subjects and a final diagnosis was made only after 3 months of treatment and repeated spirometry. RESULTS: Of 516 cases, 54.3% had COPD, 19.8% had asthma plus emphysema, and 13.2% had chronic asthma. The remaining 12.7% of patients with CAL had diffuse panbronchiolitis, bronchiectasis, bronchiolitis obliterans, or other miscellaneous diseases. In these minor diseases HRCT was essential in making a definitive diagnosis. The sensitivities of emphysema on HRCT and of absence of bronchodilator response for the diagnosis of COPD were 81% and 90%, respectively, and the specificities of the tests were 57% and 37%, respectively. In addition, HRCT revealed considerable heterogeneity of COPD. Emphysema was not recognized on HRCT in 18.6% of COPD patients. HRCT also revealed that 17.5% of COPD patients had other pulmonary complications including lung fibrosis compatible with usual interstitial pneumonia in the lung bases. CONCLUSIONS: HRCT and the bronchial reversibility test had reasonable sensitivities but low specificities for diagnosing COPD. HRCT has some additional advantages in detecting heterogeneity and concomitant lung diseases in COPD.     

Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests

International guidelines recommend a range of clinical tests to confirm the diagnosis of asthma. These focus largely on identifying variable airflow obstruction and responses to bronchodilator or corticosteroid. More recently, exhaled nitric oxide (FE(NO)) measurements and induced sputum analysis to assess airway inflammation have been highlighted. However, to date, no systematic comparisons to confirm the diagnostic utility of each of these methods have been performed. To do so, we investigated 47 consecutive patients with symptoms suggestive of asthma, using a comprehensive fixed-sequence series of diagnostic tests. Sensitivities and specificities were obtained for peak flow measurements, spirometry, and changes in these parameters after a trial of steroid. Comparisons were made against FE(NO) and sputum cell counts. Sensitivities for each of the conventional tests (0-47%) were lower than for FE(NO) (88%) and sputum eosinophils (86%). Overall, the diagnostic accuracy when using FE(NO) and sputum eosinophils was significantly greater. Results for conventional tests were not improved, using a trial of steroid. We conclude that FE(NO) measurements and induced sputum analysis are superior to conventional approaches, with exhaled nitric oxide being most advantageous because the test is quick and easy to perform.     

Comparisons of peak diurnal expiratory flow variation, postbronchodilator FEV(1) responses, and methacholine inhalation challenges in the evaluation of suspected asthma

STUDY OBJECTIVES: The validity of peak expiratory flow variation (PEFvar) as defined by National Heart, Lung, and Blood Institute (NHLBI) guidelines as a diagnostic tool for suspected asthma or its comparative value to methacholine inhalation challenge (MIC) or postbronchodilator (BD) FEV(1) responses has not been formally assessed. We prospectively analyzed the correlation of 28 different PEFvar indexes (including 4 NHLBI-compatible indexes) with MIC and pre-BD and post-BD FEV(1) responses in suspected asthmatic subjects with normal findings on lung examination, chest radiography, and baseline spirometry. DESIGN: Participants were asked to record peak expiratory flow four times daily for 2 to 3 weeks, followed by an MIC. During a minimum 6-month follow-up period, a clinical diagnosis of asthma was made or ruled out based on testing results and response to antiasthma therapy. SETTING: Medical school-affiliated subspecialty private practice of allergy, asthma, and immunology. PARTICIPANTS: One hundred twenty-one suspected asthmatic patients with normal findings on lung examination, chest radiography, and baseline spirometry. MEASUREMENTS AND RESULTS: Fifty-seven subjects completed both the peak flow diary and the MIC and were accepted for statistical analysis. There were no statistically significant correlations between any peak expiratory flow index and MIC. Among the three diagnostic tools evaluated, MIC had the highest sensitivity (85.71%). All the PEFvar indexes and post-BD responses had low sensitivity and high false-negative rates. CONCLUSIONS: PEFvar and post-BD FEV(1) responses are poor substitutes for MIC in the assessment of patients with suspected asthma with normal findings on lung examination, chest radiography, and spirometry. Our findings warrant a reconsideration of the NHLBI guidelines recommendation of the utility of PEFvar as a diagnostic tool for asthma in clinical practice.     

Coordinated diagnostic approach for adult obstructive lung disease in primary care.

AIMS: To present an age-stratified approach to the diagnosis of obstructive lung disease based on asthma and COPD guidelines and epidemiology. METHODS: Asthma guidelines emphasize the role of the history and physical examination, with pulmonary function used primarily to confirm the diagnosis. COPD guidelines begin with symptoms and risk exposure, presenting spirometry as the primary diagnostic maneuver. Data from the National Health Interview Survey and the Third National Health and Nutrition Examination Survey illustrate relationships in prevalence of asthma and COPD in nationally representative samples. RESULTS: Asthma prevalence in adults declines with age from 5-10% at age 20-40 to 4-8% above age 60. COPD is uncommon in adults under age 40 but increases with age, surpassing asthma in older adults. CONCLUSIONS: These trends suggest that asthma screening is most useful in adults up to age 40, after which COPD screening and differential diagnosis are of comparable or greater utility.     

Usefulness of the IUATLD respiratory symptoms questionnaire for the differential diagnosis of bronchial asthma and chronic bronchitis

Our objective was to determine the diagnostic value of the questionnaire devised by the International Union against Tuberculosis and Lung Disease (IUATLD) for distinguishing between bronchial asthma and chronic bronchitis. We therefore compared clinical diagnoses established independently by two pneumologists for 211 patients to the patients' responses to the IUATLD questionnaire. The questions were analyzed for their ability to discriminate using the responses as independent variables and the diagnosis as the dependent variable. The individual predictive capacity of each question and the discriminating functions that identified the best clusters of questions were calculated using bayesian analysis. Finally, we compared IUATLD results to tests that assessed lung function (spirometry), obstruction variability (bronchodilator test, peak flow, bronchial challenge test), atopy (prick test, serum IgE), and clinical and biological markers (eosinophilia). The questionnaire correctly diagnosed 91% of the patients and a cluster of five questions registered a sensitivity of 85.6%, specificity of 91.4%, a positive predictive value of 93.1% and a negative predictive value of 82.2%, thus proving superior to the other tests. These results, along with the ease of administering the questionnaire allows us to consider the IUATLD instrument to be a good tool for the differential diagnosis of bronchial asthma and chronic bronchitis.     

临床常用肺功能检查项目及合理选择

肺功能检查包括肺量计测定、支气管舒张激发试验、肺容积测定、弥散功能测定、气道阻力测定、呼吸肌力测定、血气分析和气体交换、心肺运动试验、代谢测定等。各个项目从不同角度反映了呼吸的功能状态,因此在临床实践中,应根据临床所需解答的问题,有针对性地选择检查项目。最常用的是上述前四项,并且经常以组合的方式进行检查。合理选用肺功能项目和组合,可以帮助判断患者的气道病变及其可逆性,以及肺实质、肺血管、呼吸肌或心功能方面的异常。需要注意的是,任何疾病都不能仅凭肺功能检查诊断,因为许多不同疾病可有相似的肺功能异常。肺功能检查应该与临床症状、体征、其他实验室检查和影像学资料相结合,综合考虑,才能最大程度发挥作用。     

Diagnostics and differential diagnostics of the chronic obstructive pulmonary disease

The author builds upon present definition of chronic obstructive pulmonary disease (COPD) and states that diagnosis of COPD is based on history of risk factors and on presence of bronchial obstruction which is not entirely reversible. The main examination method for diagnosing and confirmation of COPD is spirometry. Differential diagnostics is necessary for identifying other diseases with similar symptoms: bronchial asthma, congestive heart failure, lung carcinoma, bronchiectasia, pulmonary tuberculosis, bronchitis obliterans, interstitial pulmonary processes. The author presents a list of symptoms and findings which help to distinguish these diseases from COPD.     

Comparison of FEV6 and FVC for detection of airway obstruction in a community hospital pulmonary function laboratory

The National Lung Health Education Program recommends that primary care providers perform spirometry tests on cigarette smoking patients 45 years or older in order to detect airways obstruction and aid smoking cessation efforts [Ferguson GT, Enright Pl, Buist AS, et al. Office spirometry for lung health assessment in adults: a consensus statement from the national lung education program. Chest 2000; 117: 1146-61]. An abbreviated forced expiratory maneuver that requires exhalation for 6s (FEV6) has recently been proposed as a substitute for forced vital capacity (FVC) to facilitate performance of such spirometry. We set out to assess the accuracy of diagnosis of obstruction and abnormal pulmonary function using FEV6 in comparison to FVC in a community hospital population. One hundred pulmonary function tests performed at a community hospital were randomly selected and retrospectively analyzed. Sixty-three of the 100 tests had satisfactory 6-s expiration and were subject to further analysis. We compared the spirometric interpretation using Morris predictive equations for FEV1/FVC and Hankison predictive equations for FEV1/FVC and FEV1/FEV6. The Hankison set of equations is the only published reference formulas for prediction of FEV6. We found that versus our Morris gold standard, Hankison based FEV1/FVC interpretation was 100% sensitive and 67% specific for the diagnosis of obstruction and 100% sensitive and 65% specific for the diagnosis of any abnormality. The Hankison based FEV1/FEV6 interpretation was 97% sensitive and 47% specific for diagnosing obstruction and 100% sensitive and 50% specific for identifying any abnormality versus the Morris FVC based gold standard. In conclusion, in our hospital based pulmonary function laboratory, FEV6 based interpretation has excellent sensitivity for detection of spirometric abnormalities. However, its moderate specificity may hinder its utility as a screening test. Further testing is necessary to determine its reliability in different patient populations with less highly trained operators.     

Lung function, bronchial responsiveness, and asthma in a community cohort of 6-year-old children

Children as young as 6 years old can perform spirometry, yet the relationship between current asthma, lung function, and bronchial responsiveness has not been described at this age; 2,537 children from a community-based birth cohort were assessed at 6 years of age, with history (n = 2,141), physical examination (n = 1,995), standard spirometry (n = 1,735), and a random sample (n = 711) offered methacholine challenge. Males had greater values of FVC and FEV(1) but not of mean forced expiratory flow during the middle half of the FVC or FEV(1)/FVC than females. The greatest influences on lung function at 6 years were height, sex, birth weight, and wheezing in the first year of life. Children with current asthma had small but significant deficits in lung function and were more sensitive to methacholine. The optimal cutpoint for determining heightened bronchial responsiveness was found to be a 15% fall in FEV(1) at a dose of 1.8 mg/ml. A negative test could be useful in excluding a diagnosis of asthma (negative predictive value of 92%). Lung function testing, including methacholine challenge, is feasible in 5- to 7-year-old children and has the potential to contribute to the clinical management of children with asthma.Keywords:     

Feasibility of spirometry and reversibility testing for the identification of patients with chronic obstructive pulmonary disease on asthma registers in general practice

There is renewed interest in the diagnosis of chronic obstructive pulmonary disease (COPD) within primary care. Primary care physicians have difficulty distinguishing asthma from COPD. We tested the feasibility of using spirometry and if appropriate, reversibility testing, to identify patients with COPD on asthma registers in primary care. We carried out a cross-sectional study in three inner-city group practices in east London. Three hundred and twenty-eight patients aged 50 years and over on practice asthma registers were invited to attend for spirometry and, if appropriate, a trial of oral corticosteroids. The main outcome measures were: feasibility of carrying out spirometry; lung function; severity of COPD; prior diagnosis of COPD; response to a corticosteroid trial; quality of life. One hundred and sixty-eight of 328 (51%) patients attended for spirometry. According to British Thoracic Society criteria, 58 (34%) patients had normal spirometry at the time of assessment; 40 (24%) had active asthma and 57 (34%) had COPD. Thirteen patients (8%) were unable to perform spirometry. Of 57 patients with COPD 30 (53%) had mild, 15 (26%) had moderate and 12 (21%) had severe disease. Twenty-three of 57 (40%) patients with COPD on spirometry had this diagnosis recorded prior to the study. New diagnoses of COPD were more likely in those with mild or moderate disease (P<0.05). Twenty-three of 57 (40%) patients with COPD completed a corticosteroid trial: one showed significant reversibility of lung function. Spirometry was feasible and helped identify patients with COPD on asthma registers in these inner-city practices. Patients aged 50 years and over on asthma registers had a wide spectrum of lung function with considerable diagnostic misclassification. Some patients with normal lung function when tested may have had well controlled asthma. New diagnoses of COPD were mainly in those with mild or moderate disease.     

Contents of chemical mediators in sputum in a case of mycoplasma pneumoniae bronchiolitis resembling bronchial asthma]

A case of Mycoplasma pneumoniae bronchiolitis with hypoxemia is presented. A 41-year-old man was admitted to hospital because of fever, productive cough and dyspnea with wheezing of one month duration. On admission, bronchial asthma was suspected on the basis of reversible airflow obstruction and sputum eosinophilia. However, despite treatment with bronchodilators, his condition did not improve. Chest film and computed tomogram revealed small nodular shadows and tramlines in the bilateral lower lung fields, and pulmonary function tests indicated peripheral airway obstruction. Serologic titer for Mycoplasma pneumoniae was 1:160. A diagnosis of bronchiolitis due to Mycoplasma pneumoniae was made. Improvement of lung function and roentgenographic findings was observed following administration of erythromycin and doxycycline. The concentrations of prostanoids in sputum were markedly higher than in cases of bronchial asthma, and decreased as he improved. These observations suggest that Mycoplasma bronchiolitis should be considered in the differential diagnosis of wheezing, and that measurement of prostanoids in sputum may be useful in the differentiation of infective bronchiolitis and bronchial asthma.     

Value of bronchial reversibility to salbutamol,exhaled nitric oxide and responsiveness to methacholine to corroborate the diagnosis of asthma in children

Introduction and ObjectivesFunctional and inflammatory measures have been recommended to corroborate asthma diagnosis in schoolchildren, but the evidence in this regard is conflicting. We aimed to determine, in real-life clinical situation, the value of spirometry, spirometric bronchial reversibility to salbutamol (BDR), bronchial responsiveness to methacholine (MCT) and fractional exhaled nitric oxide (FENO), to corroborate the diagnosis of asthma in children on regular inhaled corticosteroids (ICS) referred from primary care.MethodsOne hundred and seventy-seven schoolchildren with mild-moderate persistent asthma, on treatment with regular ICS, participated in the study. Abnormal tests were defined as FENO ≥ 27 ppb, BDR (FEV1 ≥ 12%) and methacholine PC20 ≤ 4 mg/mL.ResultsThe proportions of positive BDR, FENO and MCT, were 16.4%, 33.3%, and 87.0%, respectively. MCT was associated with FENO (p < 0.03) and BDR (p = 0.001); FENO was associated with BDR (p = 0.045), family history of asthma (p = 0.003) and use of asthma medication in the first two years of life (p = 0.004). BDR was significantly related with passive tobacco exposure (p = 0.003).ConclusionsSpirometry, BDR and BDR had a poor performance for corroborating diagnosis in our asthmatic children on ICS treatment; on the contrary, MCT was positive in most of them, which agrees with previous reports. Although asthma tests are useful to corroborate asthma when positive, clinical diagnosis remains the best current approach for asthma diagnosis, at least while better objective and feasible measurements at the daily practice are available. At present, these tests may have a better role for assessing the management and progression of the condition.     

Prevalence and manifestations of obstructive lung disease in the city of Oslo

A stratified random sample of 1209 subjects aged 16--69 was examined in Oslo, Norway in 1973--74 by a team of 11 chest physicians. They used information from a standardized interview and clinical examination, radiographs and ventilatory function tests to make a diagnostic decision. The within-observer agreement for the diagnosis bronchial asthma and the composite group obstructive lung disease (OLD) was 87% and 80%, respectively. More than 80% of maximal between-observer agreement was observed for these two entities. The point prevalence estimate of chest physicians' diagnosis of obstructive lung disease (OLD) was 5.5%, comprising bronchial asthma 1.4% and chronic obstructive lung disease (COLD) 4.1%. The prevalence of COLD increased with age, and it was four times more frequent in smokers/ex-smokers than in non-smokers. The prevalence of bronchial asthma showed no relation to age or smoking. Individuals aged 20--69 years with bronchial asthma, COLD and OLD, had 1 sec forced expiratory volumes of 83%, 71% and 74% of predicted values, respectively. A previous history of hay fever was reported five times more frequently by those with bronchial asthma than in the survey population. Disability pension was received by 15% of those with OLD.     

Spirometry in primary care

Canadian Thoracic Society (CTS) clinical guidelines for asthma and chronic obstructive pulmonary disease (COPD) specify that spirometry should be used to diagnose these diseases. Given the burden of asthma and COPD, most people with these diseases will be diagnosed in the primary care setting. The present CTS position statement was developed to provide guidance on key factors affecting the quality of spirometry testing in the primary care setting. The present statement may also be used to inform and guide the accreditation process for spirometry in each province.Although many of the principles discussed are equally applicable to pulmonary function laboratories and interpretation of tests by respirologists, they are held to a higher standard and are outside the scope of the present statement.