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Optimizing Odor Identification
Testing as Quick and
Accurate Diagnostic Tool for
Parkinson’s Disease
Philipp Mahlknecht, MD, PhD,
1,2
Raimund Pechlaner, MD, PhD,
1
Sanne Boesveldt, PhD,
3,4
Dieter Volc, MD,
5
Bernardette Pinter, MD,
1
Eva Reiter, MD,
1
Christoph M€
uller, MD,
1
Florian Krismer, MD,
1
Henk W. Berendse, MD, PhD,
3
Jacobus J. van Hilten, MD, PhD,
6
Albert Wuschitz, MD,
5
Wolfgang Schimetta, PhD,
7
Birgit H€
ogl, MD,
1
Atbin Djamshidian, MD, PhD,
1
Michael Nocker, MD,
1
Georg G€
obel, PhD,
8
Arno Gasperi, MD,
9
Stefan Kiechl, MD,
1
Johann Willeit, MD,
1
Werner Poewe, MD,
1
and
Klaus Seppi, MD
1
*
1
Department of Neurology, Medical University Innsbruck, Innsbruck,
Austria
2
Sobell Department of Motor Neuroscience and Movement
Disorders, UCL Institute of Neurology, London, United Kingdom
3
Department of Neurology, Neuroscience Campus Amsterdam, VU
University Medical Centre, Amsterdam, The Netherlands
4
Divisions
of Human Nutrition, Wageningen University, Wageningen, The
Netherlands
5
Study Center Confraternitaet-PKJ Vienna, Vienna,
Austria
6
Department of Neurology, Leiden University Medical Centre,
Leiden, The Netherlands
7
Department of Applied Systems Research
and Statistics, Johannes Kepler University Linz, Linz, Austria
8
Department of Medical Statistics, Informatics and Health
Economics, Medical University Innsbruck, Innsbruck, Austria
9
Department of Neurology, Hospital of Bruneck, Bruneck, Italy
ABSTRACT
Introduction: The aim of this study was to evaluate
odor identification testing as a quick, cheap, and reli-
able tool to identify PD.
Methods: Odor identification with the 16-item Sniffin’
Sticks test (SS-16) was assessed in a total of 646 PD
patients and 606 controls from three European centers
(A, B, and C), as well as 75 patients with atypical par-
kinsonism or essential tremor and in a prospective
cohort of 24 patients with idiopathic rapid eye move-
ment sleep behavior disorder (center A). Reduced odor
sets most discriminative for PD were determined in a
discovery cohort derived from a random split of PD
patients and controls from center A using L1-
regularized logistic regression. Diagnostic accuracy
was assessed in the rest of the patients/controls as
validation cohorts.
Results: Olfactory performance was lower in PD
patients compared with controls and non-PD patients
in all cohorts (each P<0.001). Both the full SS-16 and
a subscore of the top eight discriminating odors (SS-8)
were associated with an excellent discrimination of PD
from controls (areas under the curve 0.90; sensitiv-
ities 83.3%; specificities 82.0%) and from non-PD
patients (areas under the curve 0.91; sensitivities
84.1%; specificities 84.0%) in all cohorts. This
remained unchanged when patients with >3 years of
disease duration were excluded from analysis. All 8
incident PD cases among patients with idiopathic rapid
eye movement sleep behavior disorder were predicted
with the SS-16 and the SS-8 (sensitivity, 100%; posi-
tive predictive value, 61.5%).
Conclusions: Odor identification testing provides
excellent diagnostic accuracy in the distinction of PD
patients from controls and diagnostic mimics. A
reduced set of eight odors could be used as a quick
tool in the workup of patients presenting with parkin-
sonism and for PD risk indication. V
C2016 The Authors.
Movement Disorders published by Wiley Periodicals,
Inc. on behalf of International Parkinson and Move-
ment Disorder Society
Key Words: Parkinson’s disease; parkinsonism;
tremor; diagnosis; olfactory dysfunction
Olfactory deficits affect 75% to 90% of patients
with Parkinson’s disease (PD), and olfactory testing
may also represent a sensitive screening test for indi-
viduals at risk of developing PD,
1-4
whereas olfactory
function is normal or only mildly impaired in other
forms of degenerative parkinsonism or essential
------------------------------------------------------------------------------------------------------------------------------
This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
*Correspondence to: Dr. Klaus Seppi, Department of Neurology, Univer-
sity of Innsbruck, A-6020 Innsbruck, Anichstraße 35, Innsbruck, Austria;
E-mail: klaus.seppi@uki.at
Funding agencies: The assessment of the patients enrolled in Inns-
bruck, Austria, took place as part of studies supported by funds of the
Austrian Science Fund (FWF KLI82-B00), the Medical University Inns-
bruck (MFI 6169), and the Oesterreichische Nationalbank (Austrian Fed-
eral Bank, Anniversary Fund, project no.: 14174). The Bruneck Study
was supported by the “Pustertaler Verein zur Praeavention von Herz-und
Hirngefaesserkrankungen,” the Gesundheitsbezirk Bruneck;, the mayor
of Bruneck, and the “Assessorat fuer Gesundheit”, Province of Bolzano,
Italy.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online ver-
sion of this article.
Received: 8 January 2016; Revised: 10 February 2016; Accepted: 29
February 2016
Published online 00 Month 2016 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26637
BRIEF REPORT
Movement Disorders, Vol. 00, No. 00, 2016 1
tremor (ET).
2,5
Olfactory testing has recently been
incorporated in the newly established International
Parkinson and Movement Disorder Society criteria for
PD
6
and prodromal PD.
7
To test for olfactory performance in PD, most stud-
ies have focused on odor identification using the dis-
posable University of Pennsylvania Smell Identification
Test (UPSIT) or the reusable Sniffin’ Sticks test battery
assessing olfactory threshold and odor discrimination
in addition to odor identification.
2,8
Both tests are
time-consuming, and olfactory testing is rarely per-
formed in clinical routine. Most of existing shortened
versions of odor identification tests were not specifi-
cally developed for PD patients, nor were any of these
tests properly validated.
9-13
Hence, we sought to assess the diagnostic value of
the 16-item Sniffin’ Sticks identification subtest (SS-16)
as an easy-to-use, inexpensive tool. We also aimed to
shorten and optimize it to identify both established
and early/prodromal PD using a discovery cohort and
different validation cohorts.
Patients and Methods
For the present study, data from a total of 134 PD
patients and 46 patients with atypical parkinsonism (23
multiple system atrophy [MSA], 23 progressive supra-
nuclear palsy [PSP]), who participated in three inde-
pendent prospective, cross-sectional clinical studies at
the Department of Neurology, Innsbruck Medical Uni-
versity (Innsbruck, Austria)
14,15
and from 336 age-
matched healthy controls (HCs) and 29 subjects with
ET from the prospective population-based Bruneck
Study
16,17
were analyzed (center A). Patients were regu-
larly followed over at least 24 months to reassess their
clinical diagnosis, and 4 cases were reclassified as MSA
(n 51) or PSP (n 53) during clinical follow-up. PD
patients and HCs from center A were randomly split
into approximately equal parts. Patients with MSA,
PSP, and ET were subsumed as differential diagnoses
(DDs) in the validation cohort only (Supporting Fig. 1).
Two independent sets of PD patients and HCs were
used as additional validation cohorts; 400 PD patients
and 150 HCs from the Departments of Neurology of
the VU University Medical Centre (Amsterdam, The
Netherlands) and the Leiden University Medical Centre
(Leiden, The Netherlands) (center B);
18
and 112 consec-
utive PD patients and 120 controls recruited by general
neurologists in Vienna, Austria (center C). Last, we
used a previously described prospective cohort of 24
patients with polysomnography-confirmed idiopathic
rapid eye movement sleep behavior disorder (iRBD),
19
consecutively recruited at center A. iRBD patients were
tested for olfactory function at baseline and followed
up for a mean of 6 years in order to detect incident neu-
rodegenerative diseases, in particular, PD. Studies were
approved by the local ethics committees. All partici-
pants gave written informed consent according to the
Declaration of Helsinki.
Olfactory testing was performed with the SS-16 (Bur-
ghart Medizintechnik, Germany) as described elsewhere.
20
In center C, the Sniffn’ Sticks 12-item odor identification
test (SS-12),
21
a commercially available, shorter version of
the SS-16 test, was used. Subscores of reduced sets of odors
were derived for the present analyses.
Group comparisons between PD patients and con-
trols or DDs were performed with appropriate tests
(see table legends). Odor sets predictive of PD were
determined in the discovery cohort by L1-regularized
logistic regression implementing the least absolute
shrinkage and selection operator (the LASSO)
22
using
the glmnet R package. The performance of full and
reduced odor sets in discriminating PD from controls
or DDs was gauged using area under the receiver
operating characteristic curve (AUC) with respective
95% confidence intervals (95% CI). Performance of
full and reduced odor sets is given by conventional
measures of diagnostic accuracy. To adjust for the
bias in prevalence of PD versus DDs in our pooled
cohort from center A, positive predictive values (PPVs)
and negative predictive values (NPVs) were modeled
for two additional scenarios using published data on
the relative prevalence of PD versus DDs (1) as
reported in general neurological services and (2) as
assumed in specialized movement disorder services.
23
Furthermore, we evaluated the accuracy of the SS-16
and its subscores in (1) identifying PD in cohort A
after excluding patients with >3 years of disease dura-
tion and (2) predicting incident PD among the 24 idio-
pathic RBD patients. SPSS (version 22.0; IBM Corp.,
Armonk, NY) and R software (version 3.2.2; R Foun-
dation for Statistical Computing, Vienna, Austria)
were used for statistical analyses. The local signifi-
cance level was set at P<0.05. Full methods can be
found in the Supporting Appendix.
Results
Characteristics of the patients and controls in the
different cohorts are shown in Table 1A and in the
Supporting Information. Figure 1A and Supporting
Table 1 depict differences in identifying individual
odors in the study groups.
An increasing discriminatory power in the distinction
of PD patient versus HC, as demonstrated in AUCs,
was achieved with an increasing number of odor items
used in the discovery cohort (Fig. 1B). This could be
reproduced in the validation sets, reaching the 95%
confidence interval (CI) of AUCs achieved with the
entire Sniffin Sticks tests (SS-16 and SS-12; upper and
lower row in Fig. 1B, respectively) when using only six
sticks and the optimum when using eight (SS-8). We
assessed diagnostic accuracy of the SS-16 and SS-8 in
identifying PD patients (Table 1B). Of note, all 4
MAHLKNECHT ET AL
2Movement Disorders, Vol. 00, No. 00, 2016
TABLE 1.
A: Characteristics of the groups
Center A
(Innsbruck and Bruneck)
Centre B
(Leiden)
Centre C
(Vienna)
HCs 5336 PD 5134 DDs 575 MSA 523 PSP 523 ET 529 iRBD 524 HCs 5150 PD 5400
Controls 5
120 PD 5112
Age
a
68.8 68.3
P50.99
68.0 68.8 68.8 69.7
P50.99
63.3 68.9
P50.090
67.2 66.2
P50.99
74.5 69.8
P50.012
66.0 65.0 59.2 67.4
P50.022
61.4 69.9 67.4 610.4
P50.54
69.2 68.6
Female (%)
b
53.6
P50.003
37.3 48.0
P50.35
52.2
P50.75
30.4
P50.99
58.6
P50.17
12.5 42.0
P50.38
37.5 58.3
P50.24
50.0
Disease dura-
tion (yr)
a
NA 6.2 64.8 8.0 614.1
P50.99
4.2 63.2
P50.081
3.1 62.0
P50.006
18.7 618.0
P<0.001
0.8 61.3 NA 11.4 66.3 NA 6.8 65.4
H&Y
a
NA 2.4 60.9 3.2 60.7
P<0.001
3.3 60.9
P<0.001
3.0 60.7
P50.002
NA NA NA 2.6 60.8 NA 2.0 60.7
UPDRS-III
a
NA 31.3 615.1 36.9 611.5
P50.002
43.0 69.2
P<0.001
30.9 610.4
P50.99
NA 2.7 62.9
MMSE
a
28.5 61.5
P50.99
28.8 61.3 27.7 62.2
P50.018
27.2 62.4
P50.60
27.0 62.1
P50.003
28.6 61.7
P50.99
27.4 62.6
SS-12 Sum
a
9.8 62.1
P<0.001
5.4 62.5 9.1 61.9
P<0.001
9.1 61.6
P<0.001
8.4 62.1
P<0.001
9.5 61.9
P<0.001
10.3 61.9
p<0.001
6.5 62.7
SS-16 Sum
a
12.7 62.7
P<0.001
6.8 63.1 11.8 62.4
P<0.001
11.7 62.1
P<0.001
10.9 62.6
P<0.001
12.6 63.7
P<0.001
9.9 64.4 12.6 62.3
P<0.001
7.4 63.0
B: Diagnostic accuracy of the SS-16 and the SS-8 in the identification of PD in the various cohorts
Set of
Odors
AUC
(95% CI) Cutoff
Sensitivity
(95% CI)
Specificity
(95% CI)
Specificity
vs. MSA
Specificity
vs. PSP
Specificity vs.
ET
Accuracy
(95% CI)
Discovery:
PD vs. HC
(center A)
SS-16 0.91 (0.87–0.95) 10 85.9% (75.8–92.4) 86.1% (80.1–90.6) 86.1% (81.1–89.9)
SS-8 0.91 (0.87–0.95) 5 88.7% (79.1–94.4) 84.4% (78.2–89.1) 85.7% (80.7–89.5)
Validation:
PD vs. HC
(center A)
SS-16 0.93 (0.90–0.97) 10 92.1% (82.3–97.0) 86.5% (80.3–91.0) 88.5% (83.1–91.7)
SS-8 0.94 (0.91–0.97) 5 93.7% (84.3–98.0) 84.0% (77.6–88.9) 86.7% (81.6–90.6)
Validation:
PD vs. DD
(center A)
SS-16 0.92 (0.87–0.96) 10 92.1% (82.3–97.0) 76.0% (65.1–84.3) 78.3% (57.7–90.8) 65.2% (44.8–81.3) 82.8% (65.0–92.9) 83.3% (76.2–88.7)
9
c
84.1% (73.0–91.3) 84.0% (73.9–90.8) 87.0% (67.0–96.3) 73.9% (53.2–87.7) 89.7% (72.8–97.2) 84.1% (77.0–89.3)
SS-8 0.91 (0.85–0.96) 5 93.7% (84.3–98.0) 72.0% (60.9–81.0) 69.6% (48.9–84.6) 69.6% (48.9–84.6) 75.9% (57.6–88.1) 81.9% (74.6–87.5)
4
c
84.1% (73.0–91.3) 88.0% (78.5–93.8) 91.3% (72.0–98.8) 78.3% (57.7–90.8) 93.1% (77.0–99.2) 86.2% (79.4–91.1)
Validation:
PD vs. HC
(center B)
SS-16 0.91 (0.88–0.93) 10 83.3% (79.3–86.6) 82.0% (75.0–87.4) 82.6% (79.1–85.5)
SS-8 0.90 (0.88–0.93 5 85.3% (81.4–88.4) 83.3% (76.5–88.5) 84.7% (81.5–87.5)
Part A of the table: Pvalues report significances of comparisons of values in respective columns/groups versus PD within centers (A, B, and C) and are post hoc Bonferroni corrected for center A. Part B of the
table: Preferred cutoffs of predictive scores were determined by Youden’s index in the discovery cohort and, in a subgroup analysis, did not differ between sexes. SS-8 5subscore of the eight best-discriminating
odors (licorice, anise, mint, cinnamon, banana, pineapple, rose, and coffee).
a
Results represent means 6standard deviation; Pvalues calculated using Mann-Whitney’s U test.
b
Pvalue calculated using chi-square test.
c
Additional lower cutoffs were applied in the distinction versus DDs because a mildly decreased sense of smell had been reported in MSA, PSP, and ET patients
2,5
and our model was established in a comparison
of PD patients with HCs (discovery cohort).
MMSE, Mini–Mental State Examination; NA, not applicable.
ODOR IDENTIFICATION IN PD
Movement Disorders, Vol. 00, No. 00, 2016 3
patients who were reclassified (MSA, 1 case; PSP, 3
cases) during clinical follow-up had a normal olfactory
function at baseline according to the SS-16 and SS-8. In
a modeled general neurological service (PD prevalence:
91.8%), both the SS-16 and the SS-8 would yield PPVs
of >97%. In a specialized outpatient clinic (lower PD
prevalence 69.0% because of higher proportion of non-
PD parkinsonism), PPVs of around 90% would be
achieved (Supporting Table 2). To test the usefulness of
the SS-16 and the SS-8 as a screening method for early/
prodromal PD, we repeated the diagnostic accuracy
analyses after excluding patients with >3 years of dis-
ease duration, which did not alter the results (Supporting
Table 3). Furthermore, the 8 incident PD cases among
iRBD patients were predicted with the SS-16 and the SS-
8 with the same sensitivity of 100.0% (95% CI: 62.8–
100.0), specificity of 68.8% (95% CI: 44.2–86.1), PPV
of 61.5% (95% CI: 35.4–82.4), and NPV of 100.0%
(95% CI: 70.0–100.0).
Discussion
We found excellent diagnostic accuracy for the SS-
16 and a shortened test, the SS-8, in the distinction of
FIG. 1. Identification of individual odors in the study groups in the three different centers (A). Gray horizontal line indicates the probability of correctly
guessing an odor in the employed forced choice test. AUCs with 95% CIs as a function of combination of odors best predicting PD according to
the LASSO analysis in the various cohorts (B). The three horizontal lines in each graph represent the AUCs with 95% CIs of the full test used (SS-16
for the upper row and SS-12 for the lower row). The best eight discriminating odors derived from the full SS-16 were used for the SS-8 subscore
(licorice, anise, mint, cinnamon, banana, pineapple, rose, and coffee).
MAHLKNECHT ET AL
4Movement Disorders, Vol. 00, No. 00, 2016
PD not only from controls, but also from non-PD
tremor or atypical parkinsonism.
To the best of our knowledge, our study is the larg-
est study of olfactory testing ever performed in
patients with PD, related disorders, and controls com-
prising a total of 1,351 individuals. We employed a
sophisticated logistic regression analysis to determine
reduced sets of odors along the LASSO regularization
path in a discovery cohort. This variable selection
algorithm considers the statistical dependencies among
odor-specific olfactory impairments and minimizes
redundancy. Whereas the diagnostic performance in
identifying PD of the three, four, or five best-
discriminating odors was inferior to the whole SS-16,
the six best discriminating odors achieved accuracy
within the 95% CI of the AUCs of the entire set,
which was further improved by using a combination
of eight odors (but not beyond).
Short tests such as the SS-8 might be particularly
appealing for two purposes: First, in a clinical setting,
they might serve as an additional quick (approxi-
mately 3 minutes) and handy tool in the workup of
patients presenting with parkinsonism where clinicians
want to identify true PD cases with a high specificity
and predictivity. In our sample, the specificity for PD
was high (84% with the SS-16 and 88% with the SS-
8) combined with a high sensitivity (84%). When
modeling prevalences in a general neurological service
and a specialized movement disorders outpatient
clinic, the PPVs were high at 98% and 94%, respec-
tively. The usefulness of the SS-16 and SS-8 for ruling
out DDs is further supported by the analysis in par-
kinsonian patients with less than 3 years of disease
duration yielding a similar diagnostic accuracy as in
the whole sets. Indeed, all 4 patients in whom an ini-
tial diagnosis of PD was later changed to MSA or PSP
during follow-up had a normal olfactory function.
Second, a short olfactory test could be useful as a
highly sensitive screening tool in population-based
studies seeking to define cohorts at high risk for
PD.
3,24
Along these lines, we found a high sensitivity
of the SS-16 and SS-8 in identifying PD versus HCs in
the center A (92% and 94%) and center B (83% and
85%) validation cohorts combined with a good speci-
ficity of 82%. This excellent diagnostic accuracy
remained unchanged when only PD patients with less
than 3 years of disease duration were included. Fur-
thermore, the SS-16 and SS-8 accurately identified 8
incident PD cases from a previously described cohort
of 24 iRBD patients clinically followed for 6 years.
Whereas previous studies focused on even shorter
sets of three odors in the Sniffin’ Sticks or UPSIT,
9-13
in our analysis six to eight odors emerged as the
smallest number with equal performance as the entire
set. In line with previous evidence,
25
this argues
against the concept of selective anosmia in PD.
13
Also,
one must take into account that the nature of the Snif-
fin’ Sticks (and the UPSIT) as a forced-choice test bear-
ing an inherent 25% likelihood of a correct answer,
which limits the options of setting cutoffs in reduced
odor sets, possibly resulting in unsatisfactory specificity
and/or sensitivity. It should be noted that none of the
previous studies used independent validation samples,
which is a particular strength of our study.
However, there are limitations. Diagnoses of PD
and DDs were made according to clinical criteria
without pathological confirmation. Therefore, mis-
diagnosis cannot be ruled out. However, in center A,
patients with parkinsonism were followed up for at
least 2 years in order to reduce likelihood of misdiag-
noses. Furthermore, cultural differences may impact
on short olfactory tests to a greater extent compared
to longer sets, where a greater variety of odors might
balance such effects.
26
Nevertheless, given the repro-
ducibility shown in the external validation samples, it
is likely that diagnostic accuracy in other samples will
be similar.
To conclude, our analysis confirms that odor identi-
fication testing with the SS-16 is associated with excel-
lent accuracy in diagnosing PD and shows that it can
be shortened considerably without losing diagnostic
power. A shortened test of eight odors may be of sub-
stantial value in both a clinical setting assisting in the
distinction from frequent diagnostic mimics and in a
population-based setting for PD risk evaluation.
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Supporting Data
Additional Supporting Information may be found in
the online version of this article at the publisher’s
web-site.
MAHLKNECHT ET AL
6Movement Disorders, Vol. 00, No. 00, 2016