Chem. Senses 28: 423-432,
2003
© Oxford University Press 2003
The Prevalence of Androstenone Anosmia
1 Helen Wills Neuroscience Institute, University of California at Berkeley, Berkeley, CA 94720, USA 2 Department of Psychology, University of California at Berkeley, Berkeley, CA 94720, USA
Correspondence to be sent to: Noam Sobel, 3210 Tolman Hall, MC 1650, University of California at Berkeley, Berkeley, CA 94720, USA. e-mail: nsobel{at}socrates.berkeley.edu
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Abstract |
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It has been estimated that
30% of the population is unable to detect
the odor of androstenone. These estimates, however, were made using tests and
criteria optimized for identifying detection. Such criteria favor Type II over
Type I errors—that is, they are excellent at identifying true detectors
at the cost of erroneously labeling some detectors as non-detectors. Because
these criteria were used to identify non-detectors, it is possible that the
rate of non-detection may have been overestimated. To test this we screened 55
subjects for non-detection employing previously used methods. This screen
yielded nine putative non-detectors, a 16.3% putative non-detection rate. We
then retested these putative non-detectors using a forced choice
(yes–no) paradigm to obtain a precise measure of their sensitivity. We
found that this group of putative non-detectors was significantly above chance
at detecting androstenone (P < 0.001), despite very low
self-confidence in their performance. Based on the results of the signal
detection analysis in this sample, we estimate the rate of actual androstenone
non-detection in young healthy adults is between 1.8 and 5.96%, which is
significantly lower than previously estimated. This finding is significant
considering the implications of specific anosmias on the understanding of odor
discrimination.
Key words: androstenone, odor detection, specific anosmia
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Androstenone (5-androst-16-en-3-one) is a steroid considered a pheromone in boars (Patterson, 1968
;
Melrose et al.,
1971), that is also present in human secretions such as saliva
(Bird and Gower, 1983), sweat
(Brooksbank et al.,
1974; Claus and Alsing,
1976), and urine (Brooksbank
and Haslewood, 1961). Although perceptual descriptions of
androstenone odor range from `sweaty' and `urinous', to `floral' and `sweet'
(Beets and Theimer, 1970;
Van Toller et al.,
1983), some individuals fail to report any olfactory percept
following exposure to androstenone. Specific androstenone-anosmia, a condition
where a person of otherwise normal olfactory acuity is unable to detect
androstenone, has been reported at a prevalence ranging from 11 to 75% in
adults (mean of men and women combined 27.5%,
Table 1).
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Some studies suggest a sex difference whereby androstenone anosmia is
between two (Dorries et al.,
1989) and six times (Griffiths
and Patterson, 1970) more prevalent in men than in women. Such
findings suggest that sex hormones may specifically influence detection rates
of biologically sourced odors such as androstenone
(Le Magnen, 1952), and similar
odorants belonging to what Amoore and colleagues referred to as the urinous
and musky primary odors (Amoore,
1977b). Also supporting a sex hormone influence on androstenone
perception is the finding that the hedonics of androstenone fluctuate with the
menstrual cycle. Androstenone is perceived as more unpleasant at the beginning
and end of the menstrual cycle, but less unpleasant near ovulation
(Hummel et al.,
1991). However, a sex difference in androstenone detection remains
controversial, as other studies reported no sex differences in detection of
androstenone and related odorants (Beets
and Theimer, 1970;
Whissell-Buechy and Amoore,
1973; Amoore et al.,
1975).
In turn, androstenone anosmia may have a genetic basis
(Beets and Theimer, 1970;
Polak, 1973;
Amoore, 1977a;
Wysocki and Beauchamp, 1984;
Lancet, 1986;
Gross-Isseroff et al.,
1992; Lancet et al.,
1993a,b).
The ability of one monozygotic twin to detect androstenone is highly
predictive of the same ability in the second twin, but this is not true for
dizygotic twins (Wysocki and Beauchamp,
1984). This familial profile is in line with the theory that
androstenone anosmia may be related to the expression of one or more genes
encoding either a specific olfactory receptor for androstenone, or a receptor
involved in a multi-receptor response to androstenone.
The estimated rate of a specific anosmia reflects a combination of the
interpretation one gives to the term `anosmia' and the statistical method used
when screening for it. Here we use the term anosmia as an indication of
complete inability to detect the odorant
(Henkin, 1966). Screening
methods widely used for identifying non-detectors of androstenone have been
those designed to identify odorant thresholds in detectors. The criterion in
these tests is set to favor Type II over Type I errors—that is, they are
excellent at identifying true detectors at the cost of erroneously labeling
some detectors as non-detectors (Figure
1a). However, when seeking to identify non-detectors, one would
want to err in the opposite direction, or in other words, to accurately
identify true non-detectors of androstenone at the cost of erroneously
labeling some non-detectors as detectors. Because the criterion for
identifying detectors has been used to identify non-detectors, we predict that
the rate of non-detection may have been overestimated. To test this prediction
we screened for non-detectors using a 74-repetition yes–no forced choice
paradigm to obtain more precise measurements of detection.
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Methods |
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Overview
In order to identify putative non-detectors of androstenone, subjects were
screened using a standard four-trial three-alternative forced-choice paradigm.
Considering that a more concentrated head-space may be obtained over undiluted
crystal rather than over diluted androstenone, screening was performed twice,
once with concentrated diluted, and once with undiluted androstenone. An
additional screening protocol was performed with pyridine to assure that
complete anosmics were not included in the study. Although pyridine is also
trigeminal, it was used in this context in order to maintain consistency with
previous studies on androstenone anosmia
(Wysocki et al.,
1989). Subjects identified as putative non-detectors of both
diluted and undiluted androstenone at screening were subsequently invited to
complete a 74-trial yes–no forced-choice detection task analyzed
according to signal detection theory. As a control, a sample of subjects
identified as detectors at the screening were also tested on the forced choice
(yes–no) task.
Subjects
We studied 55 subjects (33 men, 22 women) ranging in age from 18 to 30 (mean = 20.5). Exclusion criteria included smoking, history of nasal or head trauma or surgery, chronic disease including allergies, current use of medication, and nasal congestion. All subjects gave informed consent to procedures approved by the UC Berkeley Committee for the Protection of Human Subjects.
Stimuli
Odorants were presented in 60 ml glass weighing jars. The undiluted
stimulus consisted of 5 mg crystal androstenone (5
-androst-16-en-3-one,
Steraloids Inc., Newport, RI), and the diluted stimulus consisted of 30 ml of
7.34 x 10-3 M androstenone in white light mineral oil
(Sigma-Aldrich). Androstenone purity was verified with GC-MS run at a
detection level of 0.5 ng contaminant/µg androstenone. The control stimulus
consisted of 30 ml of 1:60 (v:v) pyridine (99%, Sigma-Aldrich) in white light
mineral oil. Foils consisted of 30 ml of mineral oil for the diluted stimuli,
and an empty jar for the undiluted stimulus. All jars were presented at room
temperature.
Screening
Subjects were blindfolded during the task. Each trial consisted of three randomly ordered presentations, one target and two foils, such that chance performance in this task was 33% accuracy. A computer-controlled voice recording advised the participant to prepare to sniff at the tone. The computer then initiated a countdown of 3–2–1, followed by a tone. Subjects were instructed to sniff at the time of the tone, at which point they were presented with either the odorant or a foil. Following three successive presentations with an inter-stimulus interval (ISI) of 7 s, subjects were prompted by the computer to identify which jar had contained the odorant (a, b or c), and to specify their confidence in their response on a scale of 1–10, with 1 being a guess and 10 being most certain. Following their answer, subjects were given computer-generated feedback that indicated whether they were correct or not and informed them which jar had in fact contained the odorant. There was a 45 s inter-trial interval (ITI) in order to minimize adaptation effects. The above combination of blindfolding and computer–subject interactions was designed to prevent any experimenter-generated cues as to presentation content.
Subjects completed four trials per odorant. Strict criteria were used to define putative androstenone non-detectors. Subjects that were correct on three or more trials of either diluted or undiluted androstenone were considered detectors and excluded. Subjects were considered putative non-detectors if they were wrong on three or more trials of both diluted and undiluted androstenone (25% accuracy or less). Those subjects who were correct on two trials of either diluted or undiluted androstenone were given two extra trials, bringing the total trials in that screen to six. If they were wrong on both additional trials (33% accuracy, which is chance), they were included, but if they were correct on either additional trial they were defined as detectors and excluded.
Yes–no forced-choice detection
Subjects deemed putative non-detectors by the screening task were entered
into the yes–no forced-choice detection task. The task was performed
with undiluted androstenone. Methods were identical to those at screening,
except that instead of three alternatives, trials consisted of one
presentation of either androstenone or a foil presented in a random order (ISI
= ITI = 45 s) such that chance performance on this task was 50% accuracy. The
subject indicated whether the odor was present (yes) or not (no), but did not
receive any feedback. The task consisted of 74 such trials. In addition to
percentage accuracy, a signal detection analysis was performed on the results
of the yes–no forced-choice detection task, computing d',
a measure of sensitivity, and ß, a measure of bias
(Green and Swets, 1966).
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Results |
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Screening
All subjects accurately detected all trials of pyridine. Of the 55 subjects screened, 46 were determined to be detectors of androstenone, having successfully detected diluted androstenone, undiluted androstenone, or both. Detection was better for undiluted versus diluted androstenone. Of the 46 detectors, 12 failed to detect androstenone diluted in mineral oil despite detection of undiluted androstenone, but only two failed to detect undiluted androstenone despite detection of diluted androstenone. A total of nine subjects (six men, three women) failed to detect both diluted and undiluted androstenone, and were considered putative non-detectors to be entered into the yes–no forced-choice study. Of these nine putative non-detectors, six failed three of the four trials, and three initially failed two of four trials, but also failed the two additional verification trials (i.e. failed four of six trials in total). The 16.3% non-detection rate obtained here was lower than values previously reported in the literature (Table 1), indicating that we were relatively strict in our criteria. These putative non-detectors formed 18.1% of the men and 13.6% of the women that participated in the study, suggesting no significant sex difference in the current results (Z = 0.457, P = 0.65).
Analysis of confidence ratings showed that whereas detectors reported higher confidence ratings following correct versus incorrect detection of undiluted androstenone [mean correct = 7.19, mean incorrect = 3.65; t(45) = 8.82, P < 0.001], putative non-detectors were equally confident whether they were correct or incorrect [mean correct = 4.17, mean incorrect = 3.46; t(8) = 1.04, P = 0.32]. Two-factor analysis of variance (ANOVA) was conducted on the confidence ratings for the diluted and the undiluted androstenone using type of subject (detectors versus putative non-detectors) and trial type (correct versus incorrect) as factors. Significant interaction terms were obtained for both the undiluted [F(1,242) = 10.32, P < 0.0016] and diluted [F(1,252) = 7.98, P < 0.0052] androstenone. Figure 2 shows the means and standard errors for the interaction. Post hoc t-tests revealed that detectors reported higher confidence following correct detection [mean correct = 7.19, mean incorrect = 3.65; t(45) = 8.82, P < 0.001], putative non-detectors were equally confident whether they were correct or incorrect [mean correct = 4.17, mean incorrect = 3.46; t(8) = 1.04, P = 0.32)]. The same pattern was observed with the undiluted androstenone so that putative non-detectors were significantly less confident than detectors following correct trials [mean non-detectors = 4.17, mean detectors = 7.19; t(52) = 4.65, P < 0.001)], but equally confident following incorrect trials [mean non-detectors = 3.46, mean detectors = 3.65; t(52) = 0.42, P = 0.68]. These results are robust using a Bonferroni correction which for four tests sets the per test level of significance at 0.013 for an overall 0.05 level of significance.
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Yes–no forced-choice task
One subject discontinued participation due to increasing nasal congestion during task performance. Mean accuracy for the remaining eight subjects was 57.5 ± 2.4% (Table 2). This group deviation from chance was significant as evidenced in the overall positive d' (mean d' = 0.42 (±0.13), t(7) = 3.17; P < 0.016). An alternative, non-parametric sign test on the percent correct values confirms this result. Under the null hypothesis non-detectors should be at chance (50%) on average and equally likely to have a percent correct score higher or lower than chance. Only one subject (SD028) obtained a percent correct score below chance on the extended yes–no forced choice task, indicating that the putative non-detectors tended to score significantly better than chance (binomial P < 0.036). In other words, the results of the comprehensive task analyzed by measures of signal detection were very different from the results of the screen, and suggested that the group of putative non-detectors were in fact detectors (Figure 3). It is important to note that these tests allow us to conclude that the group of putative non-detectors as a whole perform better than chance, but do not allow us to determine how much each individual within this group differs from chance. To answer this question with sufficient power would require a large number of simple forced choice (yes–no) trials and was beyond the scope of the present study.
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To test for a difference in bias between detectors and putative non-detectors, one would need to compare ß scores for these populations. To this end we administered the 74-trial yes–no forced-choice task to 20 subjects randomly selected from those deemed detectors at screening. The distribution of scores for this group was bimodal with 11 subjects never missing a single trial over 74 presentations (hyperosmics), and the remaining subjects clustering around a d' of 1.93 [osmics, difference from chance, t(8) = 6.99, P < 0.001]. There was a weak trend towards lower ß scores in putative non-detectors [mean non-detectors = 1, mean detectors = 2.5, t(15) = 1.96, P = 0.068] indicating a trend for non-detectors to be more tolerant of false alarms than were detectors.
To estimate the rate of androstenone non-detection in the general population we examined the make up of our entire sample of 55 subjects that clustered into four groups: anosmics—the one subject with a negative d', hyposmics—subjects who were slightly but significantly above chance, osmics—subjects robustly above chance, and hyperosmics—subjects that essentially never fail to detect androstenone (Figure 4). We treated osmics and hyposmics as derived from a single underlying distribution of sensitivity so that we could estimate the rate of non-detection in the overall population. The mean d' of this distribution was 1.216 (SD = 1.01). Based on a normal distribution with this mean and standard deviation, one would expect a non-detection rate (d' < 0) of 11.43% among osmics and hyposmics. As this group comprises 52% of the sample, we would expect a 5.96% non-detection rate in the overall population. This analysis did not consider the hyperosmics because d' is undefined in cases where subjects made no errors. A second estimate of the overall rate of non-detection that considers the hyperosmics as well is obtained by abandoning the assumption of a normal distribution, and observing that only one of the 55 subjects had a d' score less than zero. This ratio predicts a 1.8% non-detection rate in the general population. Thus we predict a population non-detection rate between 1.8 and 5.96%.
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Discussion |
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The current findings suggest that the prevalence of androstenone anosmia is significantly lower than previously estimated. Several statistical methods have been employed to characterize olfactory detection and threshold (Cometto-Muniz and Cain, 1990
,
1998;
Kurtz et al., 1999;
Linschoten et al.,
2001; Cometto-Muniz et
al., 2002) that could also be used to identify non-detection
as long as the correct criterion is applied. Here we used such a test and
criterion and found that definite non-detection of androstenone is in fact
quite rare. The current results do not point to a sex difference in
androstenone anosmia, but considering that this study was not designed to
specifically address that question, we do not consider this null finding
conclusive. A concern in the design of this study was that if we were lenient
in comparison to previous studies at defining putative non-detectors at
screening, it would be no surprise that a stricter test would later reveal
they were in fact detectors. This concern was addressed by screening with
feedback for both diluted and undiluted androstenone, and by ruling on the
statistically strict side of employing the commonly used three-alternative
forced-choice task at screening. This combination yielded a 16.3% putative
non-detection rate. This rate is lower than the commonly reported rate
(Table 1), making it safe to
predict that subjects labeled here as putative non-detectors at screening were
highly likely to have received the label of non-detector in previous studies.
Nevertheless, these putative non-detectors could detect androstenone at above
chance level as indicated by the signal detection analysis (P <
0.001).
In graphing the distribution of androstenone detection thresholds, Labows
and Wysocki (Labows and Wysocki,
1984) depicted three clusters that overlap with four clusters seen
here. One cluster, hyperosmics, scored 12 and higher on their binary dilution
scale. This cluster corresponds to a group consisting of 46.1% of the current
sample that was at 100% accuracy on the yes–no task (undefined
d'), i.e. never failed to detect a single trial over 74
repetitions. A second group, osmics, scored 8 on their binary dilution
scale. This cluster corresponds to a group consisting of 37.6% of the current
sample that were at 80% accuracy and had d' scores near two. A
third group, specific hyposmics, scored 2 on their binary dilution scale.
This cluster corresponds to a group consisting of 14.5% of the current sample
that were at 59% accuracy and had d' scores that were only
slightly but significantly above zero. Finally, here we used signal detection
to also isolate the fourth and very small group of true specific anosmics
consisting of 1.8% of the sample (one subject) that was at 47% accuracy and
had a negative d' score
(Figure 4).
The rarity of specific anosmia to androstenone is significant in light of
the implications of specific anosmias on the understanding of odor
discrimination (Guillot, 1948;
Amoore, 1967;
Wysocki et al., 1977;
Lancet et al.,
1993a,b;
Griff and Reed, 1995;
Zhang and Firestein, 2002).
Models of odor discrimination that take specific anosmias into account mostly
suggest that these anosmias are related to a specific make-up of genes
encoding for specific olfactory receptors. In the simplest form, one may
suggest that a person selectively anosmic to androstenone may be missing a
putative androstenone receptor. Based on this assumption of genetic
polymorphism one may aim to isolate the putative androstenone receptor gene by
screening for androstenone anosmia and comparing gene expression between
osmics and anosmics. The current findings, however, suggest that most subjects
considered specific anosmics may in fact be specific hyposmics. Thus,
hypotheses derived under the assumptions of complete non-detection or anosmia
may be misleading. The current results, however, do not rule out specific
androstenone hyposmia as a helpful key toward elucidating the genetic basis of
odor discrimination. Even under the assumption that most seemingly anosmics
are in fact hyposmics, one may suggest that such hyposmia reflects a specific
genetic make up. Under the assumption of a single putative androstenone
receptor, one may suggest that at exceedingly high concentrations such as
those used here, androstenone will saturate and activate other receptors that
would ordinarily not respond to androstenone at lower concentrations. Thus,
androstenone hyposmia may still reflect complete lack of a putative
androstenone receptor. In turn, under the assumption of a multi-receptor
response to androstenone, androstenone hyposmia may reflect a missing
component of a complex response, and may therefore contain helpful cues
towards understanding the genetics of olfactory perception.
Hyposmia as a clue to the genetics of odor discrimination inherently
assumes that hyposmia is related to peripheral mechanisms, namely total lack
of, or a reduced number/density of particular olfactory receptors. An
alternative view is that specific hyposmia is the result of a central
mechanism. In other words, that the input from the nose to the brain may be
similar across osmics and hyposmics, but hyposmics fail to process this signal
as an olfactory percept. This distinction may be related to that made between
an early preconscious stimulus decoding phase, and a later phase reflecting
conscious stimulus evaluation, as evidenced in temporally distinct olfactory
event-related potentials (Pause et
al., 1999). There are several lines of evidence pointing to a
peripheral odor response that does not always translate into odor awareness, a
phenomenon described as `blindsmell'
(Sobel et al., 1999)
[not to be confused with `odor blindness', a term coined by Amoore et
al. (Amoore et al.,
1968) to describe specific anosmia]. For example, conditioning
with undetected odors can induce negative mood
(Kirk-Smith et al.,
1983), and undetected odors can affect patterns of EEG
(Lorig et al., 1990;
Schwartz et al.,
1994), galvanic skin response
(Van Toller et al.,
1983), and brain activation as measured with both functional
magnetic resonance imaging (Sobel et
al., 1999) and positron emission tomography
(Jacob et al., 2001).
In the current study, although hyposmics had no percept of the odorant
(Figure 2), they could detect
its presence at above chance levels (Table
2). Finally, Schiffman reported that hypnosis can induce detection
at levels not obtained in the normal wake state
(Schiffman, 1979). Considering
it is unlikely that hypnosis alters gene expression at the olfactory
epithelium, this finding further implicates a central mechanism that blocks
conscious olfactory detection. Although we favor the hypothesis that
implicates the central late rather than peripheral early processing phase for
selective androstenone hyposmia, the current data do not preferentially
support the peripheral or central hypothesis. Furthermore, the reasons for
androstenone hyposmia may be different from those for complete androstenone
anosmia, and whereas a central mechanism may be responsible for the former, a
peripheral mechanism may be responsible for the latter. The contribution of
the current study is in pointing to the rarity of such complete androstenone
anosmia. Finally, a word of caution may be merited as to the pathway by which
the hyposmics here detected androstenone. Although we know of no evidence for
trigeminal responses to this compound, this alternative is not ruled out.
Thus, trigeminal responses to androstenone may complicate even further any
deduction from the olfactory phenotype to genotype.
An additional question is how our findings impact on the interpretation of
androstenone learning studies. Wysocki et al.
(Wysocki et al.,
1989) first described this phenomenon wherein individuals unable
to detect androstenone acquire the ability to detect it following systematic
exposure. This phenomenon has been replicated in an animal model
(Wang et al., 1993)
and in humans (Stevens and O'Connell,
1995; Moller et al.,
1999; Pause et al.,
1999), as well as with other odorants
(Dalton et al., 2002;
Cain and Schmidt, 2002), and
may be considered a model for adult neural plasticity. Regardless of whether
the underlying plasticity is central
(Brennan and Keverne, 1997;
Mainland et al.,
2002) or peripheral (Wang
et al., 1993; Yee and
Wysocki, 2001), the current findings imply a slight reframing of
this result. Whereas previously it was thought that androstenone exposure led
to a shift from complete non-detection to detection, our findings imply the
shift may have been from poor detection to better detection. Furthermore, not
all subjects become sensitized in androstenone learning studies. It is
tempting, therefore, to speculate that hyposmics (those that appear
non-detectors at a standard screen, but are above chance at signal detection)
can develop sensitivity, but absolute anosmics can not. (Testing this
hypothesis, however, is a daunting task. Considering that true anosmics may
constitute only 1.8% of the population, one would have to screen 1111 subjects
to obtain a sample of 20 true androstenone anosmics.) Regardless, however, of
whether the shift in previous studies was from non-detection to detection, or
poor detection to better detection, this phenomenon remains equally worthy and
intriguing as a model for plasticity in the adult human olfactory system.
Determining that the group of putative non-detectors obtained at screening was comprised primarily of hyposmics who were significantly above chance was straightforward. In turn, there are several avenues by which one may estimate the rate of non-detection in the general population based on these results. Taking a nonparametric approach and directly extrapolating from the current d' scores to the general population, one would estimate a 1.8% rate of non-detection. In turn, if one were to assume that these d' scores reflected a normal distribution of d' scores in the general population, none would estimate a 5.96% overall rate of non-detection. Although we find the former, lower of these two values, to be the appropriate estimate, we venture on the conservative side of concluding that the prevalence of androstenone non-detection (complete specific anosmia) in young healthy adults is between 1.8 and 5.96%.
Finally, one may ask what method should be used to screen for
non-detectors. As a rule, longer tests containing increased sampling promise
higher accuracy (Doty et al.,
1995). The 74-trial yes–no forced-choice task with a 45 s
ISI that we used here is robust at identifying true non-detectors, but takes
nearly 90 min to complete, and is thus not well suited for scenarios where one
needs a quick screen for non-detection. As a compromise, based on the
distribution of d' scores in this study, we conclude in
recommending an 18-trial three-alternative forced choice paradigm with a 45 s
ISI that takes 20 min to conduct. Chance at this screen is six correct.
If a particular study calls for strict criteria of non-detection, we recommend
identifying as non-detectors those who score between two and five correct,
thus accepting only a 6.75% chance of erroneously including hyposmics at the
cost of a 58.3% chance of erroneously rejecting anosmics
(Figure 1b). In cases where one
can afford more lenient criteria that will combine ansomics and hyposmics, we
recommend selecting those who score between two and nine correct, thus
accepting a 65.78% chance of erroneously including hyposmics at the cost of a
4.78% chance of erroneously rejecting anosmics.
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Acknowledgments |
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This work was supported by the NIH NIDCD, the Searle Foundation and the Hellman Family Fund. We thank Arak Elite.
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Accepted April 30, 2003
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