Table 3 Biomarker example types organized by biological level and compared for pathophysiologic level

Genetic marker

1° Cause

Presence of a gene mutation

CF mutations

Measure presence of gene

Not a function

RNA/gene expression

1° pathophysiologic

Expression of aberrant RNA

Friedrich’s ataxia

Direct impact on gene expression

Unclear about downstream effect

RNA splicing error

Fragile X

Presence of new gene expression

Enzyme or protein level

1° pathophysiologic

Enzyme activity in tissue

Alpha-1-antitrypsin

Direct measure of active compound

Difficult to verify tissue effect

Protein in circulation

Biochemical

1° pathophysiologic

Blood level of an accumulating metabolite due to a 1° block

Phenylalanine in PKU

Directly toxic compound or active compound

Not a measure of tissue effect

Decrease in level of critical needed biochemical

BH4 in BH4 deficiency

Secondary Biochemical

2° pathophysiologic

Increase in secondary metabolite that is toxic or part of pathophysiology but not from original defect

Succinyl-lactone in tyrosinemia I

Directly measure of toxic effector

Cannot always measure downstream toxicity

Homogentisic acid in alkaptonuria

Biopsy

2° pathophysiologic

Presence of abnormal cells or marker

GL3 granules in Fabry

Direct measure of disease or absence of protein

Variability of biopsies, representative sampling, variable assay methods

Pathological change in structure

Dystrophin in Duchenne

Ex vivo explant

2° pathophysiologic

Evaluate a cell removed from the patient for a phenotype or function

CGD/y-interferon

None

Failed : questionable validity of an ex vivo assessment

X-ray/Imaging

2° pathophysiologic

Bone structure

X-ray ricket score

Bone structure is nature of disease

X-ray does not show function exactly

Presence of abnormal lesions

Change in size

Visual appearance like fundoscopy

Clinical Physiology tests

1° clinical effect

Tests used in clinical evaluations of clinical conditions dependent primarily on a single tissue/organ

FVC in CF

Measure of a physical function that is directly relevant

Not strictly a clinical outcome and hard to gauge size of effect with clinical outcome

EMG, EKG, NCV, BAER, hand held dynamometry

Muscle strength in DMD or HIBM

Clinical function

2° clinical effect or intermediate clinical measure

Tests that study integrated multiple body systems/organs, Pulmonary function tests, sleep apnea, muscle function

6 min walk test

Measure of a patient’s function

Need to interpret magnitude of change for relevance to patient

Walking speed