Tables
- Table 1—
Requirements of markers in chronic obstructive pulmonary disease for different groups, some of which, but not all, are shared
Group Key requirements Family physicians Simplicity Specificity Reliability Clarity Hospital specialists Sensitivity Specificity Reliability Clinical utility Payers Cost-effective Clarity Pharmaceutical industry Practicality Sensitivity Generalisability Reliability Simplicity Regulatory authorities Sensitivity Specificity Reliability Clarity Clinical utility Generalisability Scientists Reliability Sensitivity Specificity Biological credibility Patients Clarity Simplicity - Table 2—
Phases of marker validation process for therapeutic trials(modelled on 35)
Classification Description Validation Phase 1 Natural history marker Demonstration of relationship between frequency/magnitude of marker and clinical outcomes Reflect underlying disease mechanisms Predict clinical outcomes independent of treatment Phase 2 Biological activity marker Phase I/II trials demonstrating appropriate effects on the marker with therapeutic intervention Responds to therapy Change in frequency/magnitude of marker corresponds with therapeutic potency Dose-dependent effects of treatment on the marker Phase 3 Marker of therapeutic efficacy Demonstration that the marker predicts clinical outcomes and responds to therapy in outcome trials An early change in the marker predicts clinical outcome in the context of active therapy Ideally, marker could be used as a surrogate endpoint for clinical outcomes Validation should establish whether the marker is applicable to all disease stages and all interventions - Table 3—
Potential markers for the assessment of chronic obstructive pulmonary disease
Biological markers Physiological markers Symptomatic markers Expectorated cellular markers of inflammation Markers of lung function Symptoms Neutrophils, macrophages, Inspiratory capacity, DL,CO MRC Respiratory Questionnaire eosinophils, mast cells, Physiological tests of small airway obstruction Breathlessness lymphocytes Lung hyperinflation MRC Dyspnoea scale, Borg Expectorated soluble markers of inflammation Rate of decline of lung function scale, BDI/TDI, UCSD TNF-α, IL-8, ECP, MPO Exercise testing dyspnoea scale Expired gases 6-min walk test Disease-specific health status (health- NO, CO, H2O2 Bronchial hyperreactivity related quality of life) Expired air condensate Skeletal muscle function CRDQ, SGRQ, BPQ, PFSDQ, LTB4, cytokines, aldehydes Lean body mass PFSS, CCQ Peripheral blood markers Imaging Generic health status Activated neutrophils, TNF-α, CT scan, PET, hyperpolarised SF-36, NHP, EQ-5D soluble TNF receptors, IL-6, gas MR Cognitive function IL-8, CRP Exacerbations Sputum protease/anti-protease levels Rate HNE, MMPs, α1-AT, SLPI, Type TIMPs Quantification of luminal airway mucus EGF levels in sputum Measures of pulmonary hypertension Urine markers Markers of matrix degradation, e.g. desmosine TNF-α: tumour necrosis factor-α; IL: interleukin; ECP: eosinophilic cationic protein; MPO: myeloperoxidase; NO: nitric oxide; CO: carbon monoxide; H2O2: hydrogen peroxide; LTB4: leukotriene B4; CRP: C-reactive protein; HNE: human neutrophil elastase; MMPs: matrix metalloproteinases; α1-AT: α1-antitrypsin; SLPI: secretory leukocyte protease inhibitor; TIMPs: tissue inhibitors of matrix metalloproteinases; EGF: epidermal growth factor; DL,CO: diffusing capacity of the lung for carbon monoxide; CT: computed tomograpy; PET: positron emission tomography; MR: magnetic resonance; MRC: Medical Research Council; BDI/TDI: baseline and transition dyspnoea index; UCSD: University of California, San Diego; CRDQ: Chronic Respiratory Disease Questionnaire; SGRQ: St. George's Respiratory Questionnaire; BPQ: Breathing Problems Questionnaire; PFSDQ: Pulmonary Function Status & Dyspnoea Questionnaire; PFSS: Pulmonary Function Status Scale; CCQ: Clinical COPD Questionnaire; SF-36: Short Form-36; NHP: Nottingham Health Profile; EQ-5D: EuroQol 5D.
