SMELL-S and SMELL-R: Olfactory tests not influenced by odor-specific insensitivity or prior olfactory experience

Significance Currently available smell testing methods can be confounded by the lack of prior experience or insensitivity to the odorants used in the test. This introduces a source of bias into clinical tests aimed at detecting patients with olfactory dysfunction. We have developed smell tests that use mixtures of 30 molecules that average out the variability in sensitivity to individual molecules. Because these mixtures have an unfamiliar smell and the tests are nonsemantic, their use eliminates differences in test performance due to familiarity with the smells or the words used to describe them. SMELL-S and SMELL-R facilitate smell testing in different populations, without the need to adapt test stimuli to account for differences in familiarity with the test odors. Smell dysfunction is a common and underdiagnosed medical condition that can have serious consequences. It is also an early biomarker of neurodegenerative diseases, including Alzheimer’s disease, where olfactory deficits precede detectable memory loss. Clinical tests that evaluate the sense of smell face two major challenges. First, human sensitivity to individual odorants varies significantly, so test results may be unreliable in people with low sensitivity to a test odorant but an otherwise normal sense of smell. Second, prior familiarity with odor stimuli can bias smell test performance. We have developed nonsemantic tests for olfactory sensitivity (SMELL-S) and olfactory resolution (SMELL-R) that use mixtures of odorants that have unfamiliar smells. The tests can be self-administered by healthy individuals with minimal training and show high test–retest reliability. Because SMELL-S uses odor mixtures rather than a single molecule, odor-specific insensitivity is averaged out, and the test accurately distinguished people with normal and dysfunctional smell. SMELL-R is a discrimination test in which the difference between two stimulus mixtures can be altered stepwise. This is an advance over current discrimination tests, which ask subjects to discriminate monomolecular odorants whose difference in odor cannot be quantified. SMELL-R showed significantly less bias in scores between North American and Taiwanese subjects than conventional semantically based smell tests that need to be adapted to different languages and cultures. Based on these proof-of-principle results in healthy individuals, we predict that SMELL-S and SMELL-R will be broadly effective in diagnosing smell dysfunction.