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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]