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Table 5 Elements of construct validity

From: Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol

Grouping Recommendations from guidelinesa Specific application to PAH Justification
Animal subjects Model matches age of patients to clinical setting Adult animals included Typical onset of PAH occurs in adulthood [31, 32]
  Characterization of animal properties at baseline RVSP or mPAP assessed at baseline Confirmation that the model successfully establishes PAH
  Matching model to sex of patients in clinical setting Both male and female animal included Prevalence of PAH occurs in female versus males is 2:1 [31, 32]
Outcome measurements Matching of measure to clinical outcome Clinically relevant outcome reported (e.g., pulmonary hemodynamics, RV remodeling, cardiac function, mortality) Clinically relevant outcomes may increase potential generalizability to clinical setting
   Long-term follow-up (>3 weeks post-intervention) PAH is a chronic disease; long-term assessment increases reliability of findings
   Pulmonary hemodynamics assessed by direct catheterization Right heart catheterization is the gold standard for diagnosing PAH
  Assessment of multiple manifestations of disease phenotype Study reports ≥2 types of outcome measurements (pulmonary hemodynamics, RV remodeling, cardiac function, mortality, histopathological assessment of vascular lesions) Efficacy in multiple manifestations of PAH may increase reliability of findings
Modeling of disease Matching model to human manifestation Criteria for PAH are met in disease control (mPAP >25 mmHg; RVSP >35 mmHg [12, 33]) PAH is induced successfully in the model
  Treatment response along mechanistic pathway A molecular or cellular mechanism of treatment is measured and reported Ensures therapy is producing a biological effect; ensures negative effects cannot be ascribed to a lack of biological activity
Administration of intervention Matching timing of treatment delivery to clinical setting Intervention is given after PAH is established (>2 weeks in animal models) PAH usually present with symptoms before diagnosis
  Matching the duration/exposure of treatment to clinical setting Evidence of cell persistence in any animal organ Ensures presence of cells during course of treatment
  Matching model to co-interventions in clinical setting Animals are on background medical therapy for PAH (e.g., Prostacyclins endothelin receptor antagonists, PDE5 inhibitors, calcium channel blockers) PAH patients would be on conventional pharmacotherapy
Environment Address confounders associated with setting, experimental setting General anesthetic is not used during outcome measurements Anesthetics may exert effects on cardiovascular system; patients undergo right heart catheterization under local anesthetic, echocardiography performed without anesthetics in patients
  1. aRecommendations to reduce threats to construct validity were identified by [20]