Veterinary Therapeutics • Vol. 4, No. 1, Spring 2003
Use of Client-Specific Outcome Measures to Assess
Treatment Effects in Geriatric, Arthritic Dogs:
Controlled Clinical Evaluation of a Nutraceutical*
Daniel A. Gingerich, DVM, MS
Janna D. Strobel, PhD
Stolle Milk Biologics
6954 Cornell Road, Suite 400
Cincinnati, OH 45242
■ ABSTRACT
A questionnaire method was designed for
dog owners to monitor the orthopedic disabilities of their pets for evaluation of a nutraceutical with joint health claims. Fifty large-breed
dogs, 7 to 12 years of age, presenting with signs
of osteoarthritis, were randomly allocated to
placebo and active treatment groups. Degree of
disability was assessed by physical examination,
a standard questionnaire on daily activities,
and a case-specific questionnaire that monitored specific impairments of each dog. The
test product was a special milk protein concentrate (SMPC) from hyperimmunized cows,
previously shown to express antiinflammatory
and antiarthritic activity in humans. After a 1week run-in period of dosing with placebo,
each dog was randomly assigned to a treatment
and given gelatin capsules containing either
SMPC or a placebo twice daily for 8 weeks.
Overall improvement was noted in 68% and
35% of the SMPC and placebo groups, respectively. Significant (P < .05) improvement in
mean standardized and patient-specific questionnaire scores and in owner global assessments was detected in the SMPC group but
*Funding for this study was provided by the
Veterinary Products Laboratories Division of
Farnam, Phoenix, AZ.
56
not in the placebo group. Compared with the
placebo group, the treatment response was significantly better in the SMPC group with regard to case-specific scores (P < .001) and owner global assessments (P = .004). The product
was well tolerated and serum chemistry findings remained within normal limits.
■ INTRODUCTION
Objective assessment of clinical outcome is a
continuing challenge in veterinary therapeutics. This is particularly true in conditions such
as osteoarthritis1 for which there are few universally accepted biochemical markers2,3 or
other objective measurements of severity or response to therapy. Force plate evaluations in
horses4 and dogs5,6 provide objective clinical
data but require resources unavailable to most
veterinary practitioners. For drugs such as
NSAIDs with known structure and biologic
targets, pharmacokinetic/pharmacodynamic
analyses are universally accepted approaches.7,8
However, nutraceuticals such as glucosamine
and chondroitin products with poorly defined
mechanisms of action cannot be readily evaluated by traditional approaches. For this reason,
subjective questionnaires have been developed
and validated in human patients with arthritis
and utilized in clinical evaluation of nutraceu-
D. A. Gingerich and J. D. Strobel
ticals.9 In veterinary medicine, evaluation of
nutraceuticals represents similar challenges.10,11
In humans, the Western Ontario McMaster
Universities Osteoarthritis Index (WOMAC),12
which monitors the degree of difficulty performing daily activities, has become the standard for osteoarthritis trials. The sensitivity of
standard questionnaires was increased in patients with rheumatoid arthritis by the McMaster-Toronto Arthritis (MACTAR)13 approach, which tracks the specific functions of
concern to a particular patient. Although questionnaire-based outcome measures have been
refined over the years, applied to conditions
other than rheumatic diseases,14,15 and are as effective as any available clinical measure, including laboratory tests and radiographs, to
measure functional disability,16 they have not
been as widely utilized in veterinary medicine.
A questionnaire-based method has been developed that combines both the WOMAC
(standardized) and MACTAR (patient-specific) approaches for evaluation of musculoskeletal disabilities in dogs, and a clinical trial was
designed to evaluate a dietary supplement with
joint health claims.17 This supplement was a
special milk protein concentrate (SMPC) prepared from the milk of hyperimmunized cows
that has antiinflammatory activity and suppresses autoimmune disease in laboratory animals.18
Milk contains a number of bioactive components, including immunoglobulins, cytokines,
enzymes, hormones, and growth factors. The
recognition of antiinflammatory properties of
human breast milk19 and milk from hyperimmunized cows20,21 suggests that dairy ingredients
may also be of therapeutic value in orthopedic
conditions. SMPC has no demonstrable cyclooxygenase- or lipoxygenase-inhibiting activity and therefore does not belong in the traditional NSAID class of agents. It is speculated
that SMPC contains natural factors that inhibit
inflammation by suppressing neutrophil emi-
gration from the vascular space, possibly by restricting extravasation through tight junctions.22
The purpose of this study was to determine
whether the antiarthritic effects of this nutraceutical supplement as described in human
patients23,24 would be applicable to dogs. The
trial was designed not only to test the product
but also to evaluate and compare a standardized disability questionnaire with a case-specific questionnaire designed specifically for dogs,
which came to be known as the “Cincinnati
Orthopedic Disability Index” (CODI).
■ MATERIALS AND METHODS
Test Population
Five companion animal veterinary practices
in the Cincinnati area participated in the randomized, parallel, double-blind, placebo-controlled trial that included outpatient dogs with
musculoskeletal impairments. Fifty older, largebreed dogs of either sex were recruited based on
the presence of disabilities observed by the owners. Physical examinations were performed by
an attending veterinarian to rule out nonmusculoskeletal causes. Dogs with concomitant diseases that required treatment with drugs with
overlapping effects (such as corticosteroids,
NSAIDs, or analgesics) and dogs that were
overly obese (in the opinion of the veterinarian)
were excluded. To be eligible, the dogs had to
be cared for by attentive owners who gave informed consent and agreed to treat and observe
their dogs over a 9-week period (including a
1-week placebo run-in period designed to assess
the level of compliance by the owners before the
actual test materials were allocated).
Treatments
At the end of the placebo run-in period, treatments were assigned based on computer-generated random codes. Test and control articles
were supplied in identical, coded plastic bottles.
The test article was an SMPC powder (Micro-
57
Veterinary Therapeutics • Vol. 4, No. 1, Spring 2003
Lactin, SMBI), described elsewhere,18,23,24 supplied in gelatin capsules each containing 500 mg
SMPC. The placebo was rice flour, an inert ingredient identical in appearance to the test powder, supplied in identical capsules. Each dog was
given two capsules twice daily (2 g/day) for a total of 8 weeks. The first week of treatment after
the run-in placebo period was designated Week
0. Neither the veterinarian nor the owner had
knowledge of group assignments.
Evaluations
Blood samples were drawn at Week 0 and at
the final visit and submitted for hematology and
standard clinical chemistry profiles. Veterinary
clinical evaluation consisted of history, medication review, and physical evaluation of lameness,
weight bearing, joint mobility, and pain on manipulation according to published criteria.5
Clinical outcomes were based on physical examination, a standardized questionnaire on physical activities, a case-specific questionnaire developed with each owner (CODI), and owner and
veterinarian global assessments of overall response to therapy (worse, no change, slight,
good, excellent). Follow-up visits to the veterinary clinic were required at 4 and 8 weeks. To
construct the CODI questionnaire, each owner
was interviewed by the veterinarian or registered
technician to determine the activities of the dog
that appeared to be restricted by the musculoskeletal condition (Figure 1). Up to five
observable activities were selected and then
assessed by each owner biweekly throughout the
study. If owners suggested more than five, they
were asked to prioritize them and select the five
activity restriction most egregious to either the
owner or the dog. In addition to the CODI
form, owners completed a standardized activity
questionnaire biweekly (Figure 1).
At each visit, the owners were questioned
about adverse events; study criteria and treatment records were reviewed; and unused cap-
58
sules were counted as a compliance check. The
owners were asked whether, in their opinion,
the condition had improved (owner global assessment). At the final visit (Week 8), the above
procedures were repeated and the final veterinary physical examination, veterinary global assessment, and laboratory tests were repeated.
Statistical Evaluation
The answers on the physical, standardized,
and CODI forms were assigned numerical values 0 through 4 (normal to severe) and transformed to a scale (0 to 100), which has been
used frequently in human orthopedics, using
the following equation25:
Actual raw
score
× 100
Transformed scale = 100 –
Possible raw score
Owner and veterinarian global assessments
were assigned numerical values of –1 (worse)
to +3 (excellent). The data were analyzed using
commercially available statistical software26 at
the nominal .05 level of significance. The significance of any interaction between treatment
and any particular clinic was tested by two-way
analysis of variance (ANOVA) for the change
from baseline for each outcome variable. Questionnaire data are ordinal rather than continuous, which implies nonparametric statistical
treatment. The statistical significance of the
changes in physical examination scores within
each group was tested by the Wilcoxon signed
rank test. Within group responses in standardized and case-specific disability scores and
owners’ globalassessments were tested by a
Friedman repeated measures ANOVA on ranks
test (a nonparametric equivalent to one-way
ANOVA). Comparisons of responses between
treatment and placebo groups were made by
two-way repeated measures ANOVA with
treatment and time as grouping variables. The
strength of association (correlation) between
D. A. Gingerich and J. D. Strobel
Cincinnati Orthopedic Disability Index (CODI)
Please tell us what activities seem to be difficult for your dog.
Now tell us which of these activities are most troublesome to you or your dog.
Changes or problems related to
arthritis in your dog:
no problem
a little
quite a bit
severe
impossible
a little
quite a bit
severe
impossible
1
2
3
4
5
Standard Orthopedic Questionnaire
How difficult are these
activities for your dog?
no problem
Walking
Running
Jumping
Getting up
Lying down
Climbing stairs
Descending stairs
Figure 1. Owner questionnaire used to assess degree of disability in dogs with musculoskeletal impairments.
59
Veterinary Therapeutics • Vol. 4, No. 1, Spring 2003
TABLE 1. Sex, Age, and Body Weight Distribution for Arthritic Dogs Treated
with Placebo or Special Milk Protein Concentrate (SMPC)
Number
Group
Dogs
Males
Placebo
17
7
SMPC
18
8
Females
Age (yr) [Range]
Body Weight (kg) [Range]
10
9.9 + 1.2 [8–12]
32.4 + 6.2 [19–41]
10
9.1 + 1.7 [7–12]
32.2 + 7.7 [20–48]
Age and weight data are expressed as mean + SD.
outcome variables was tested by the Spearman
rank order correlation method applied to data
from all 35 dogs that completed the study. Finally, the effect size (d ), defined as the difference between the mean value in the test and
placebo groups at the end of the trial divided
by the standard deviation of the placebo outcome at trial end9,27 was computed for each
outcome variable as follows:
Change in mean Change in mean
– placebo score
Effect size = treatment score
SD change in placebo score
■ RESULTS
Fifty dogs were enrolled, 35 of which completed the entire study. Of the 15 dogs that
were removed from the study, six had been randomized into the SMPC group and nine were
in the placebo group. Dropouts were due to
various reasons, including perceived lack of efficacy, lost to follow up, or eliminated due to
unrelated conditions such as fractures or noncompliance. Several common large breeds
(e.g., shepherds, retrievers, boxers, Dobermans) were represented in the study, and both
groups were similar in age, sex, and body
weight distribution (Table 1). Each clinic contributed between five and 10 completed cases
consisting of at least two dogs treated with
placebo and two treated with SMPC. Because
there was no significant treatment × clinic or
treatment × sex interaction with regard to any
outcome variable, the data were pooled for fur-
60
ther analysis. Data obtained from questionnaires completed by owners for Weeks 2 and 6
were disregarded because some owners created
new disabilities on their own or failed to score
previously defined activities during those periods. No dogs were eliminated from the analysis based on these deviations. For the scoring
systems to work properly, disabilities had to be
present (acknowledged and recorded) at the
start of the trial and monitored according to the
given schedule.
Both treatments were well tolerated by the
dogs with the exception of one placebo-treated
and one SMPC-treated dog, each of which
vomited within 30 minutes of each dosage and
had to be withdrawn from the study. Hematology and serum chemistry results were essentially unchanged in both groups, with the exception of serum cholesterol, which decreased
from a mean of 295 to 234 mg/dl in the
SMPC group (P = .003) but did not change in
the placebo group.
Global assessment of overall improvement was
reported by owners in 12 of 18 dogs (66.7%) in
the SMPC group and six of 17 dogs (35.3%) in
the placebo group. The global assessments by
veterinarians were in agreement with those of the
owners for all dogs in the placebo group and in
all but one dog in the SMPC group.
Numeric results of physical examinations,
questionnaires, and owner and veterinarian global assessments are summarized in Table 2. At
baseline, there were no significant differences be-
D. A. Gingerich and J. D. Strobel
TABLE 2. Physical Examination, Disability, and Global Response Scores for Arthritic
Dogs Before and After Treatment with Placebo or Special Milk Protein Concentrate (SMPC)
Transformed Scale (0–100)
Global
(–1 Worse to +3 Excellent)
Group
Week
Physical Exam
Standardized
Case-Specific
Client
Veterinarian
Placebo
(n = 17)
0
4
8
49.3 + 5.4
64.1 + 4.8
69.6 + 4.1
67.4 + 3.7
NS
56.2 + 3.7
61.8 + 4.1
59.6 + 4.5
NS
0.4 + 0.1
0.4 + 0.2
NS
0.6 + 0.2
64.2 + 3.4
72.0 + 3.6
76.3 + 4.3
.009
48.5 + 4.2
69.1 + 4.7
74.0 + 5.2†
<.001
1.2 + 0.3†
1.3 + 0.3†
.002
1.3 + 0.2
P value*
SMPC
(n = 18)
P value*
0
4
8
62.5 + 6.6
.021
47.6 + 4.1
61.4 + 5.3
.009
NS = not significantly different.
Data are expressed as mean + SEM.
*Significance of change from baseline†
†Significantly different from placebo value at the same evaluation.
al assessments improved significantly (P < .01) in the test group but not
Case-specific
Standardized
in
placebo controls. Comparisons
24
Placebo
between groups revealed that mean
20
responses in the SMPC group were
16
significantly (P < .05) greater than in
the placebo group with regard to
12
CODI scores and owner global
8
assessments, whereas physical
4
examination and standardized questionnaire results and veterinarian
0
global assessments did not differ sta-4
tistically between groups.
4
8
0
Week
The most frequent case-specific
impairments identified and moniFigure 2. Changes (mean ± SEM) in standardized versus case-specific tored were long walks, difficulty on
disability scores reported by owners of dogs treated with special milk slippery floors, getting in and out
protein concentrate (SMPC) compared with changes for controls treated
of the car, apparent pain and stiffwith placebo.
ness during defecation, jumping
onto furniture, retrieving toys, and playing
tween treatment groups with regard to physical
with other animals. The standardized questionor questionnaire findings. Physical examination
naire results, which captured disabilities related
scores improved slightly (but significantly, P <
to daily activities common to all dogs, were nu.05) in both groups during the treatment period.
merically higher than CODI disability parameStandardized and CODI scores and owner globChange in Score
28
61
Veterinary Therapeutics • Vol. 4, No. 1, Spring 2003
dogs in the SMPC group at the final evaluation time were numerically similar to thoseof owners but not
P = .004
Not significant
P = .012
significantly different from placebo
1.2
controls, as illustrated in Figure 3.
SMPC
Global assessments were signifi(n=18)
0.8
cantly (P < .001) correlated with
Placebo
changes in physical examination
(n=17)
and questionnaire scores, and all
0.4
outcome variables were significantly correlated(P < .001) with each oth0.0
er (Table 3).
Owner at
Veterinarian
Owner at
8 weeks
at 8 weeks
4 weeks
The effect sizes were 0.03, 0.62,
1.61, 0.90, and 0.65 for physical
Figure 3. Overall global response (mean ± SEM) for arthritic dogs to examination, standardized, casetreatment with special milk protein concentrate (SMPC) or placebo specific, client global, and veteriaccording to owners and veterinarians. Each dog was scored on a scale of narian global outcome variables,
–1 to 3 (worse to excellent).
respectively. According to published orthopedic standards,9 these
findings indicate that treatment
1.6
had a large effect on case-specific
1.4
and owner global responses, an
intermediate effect on standardized
1.2
and veterinarian global responses,
1.0
"Large"
and a negligible effect on the physical
0.8
effect
examination responses (Figure 4).
0.6
Effect Size
Worse to Excellent
1.6
0.4
■ DISCUSSION
This prospective, randomized
0.0
study
was designed to examine the
Physical Standard
CaseOwner Veterinarian
effect of a dietary nutraceutical
examination score
specific
global
global
supplement on disabilities of musFigure 4. Comparison of effect size ([treatment response – placebo culoskeletal origin that were of
concern to the dog owner rather
response]/SD placebo response).
than to examine its effects on osters monitored by the owners (Table 2) and did
teoarthritis per se. The hypothesis was that the
not show as much improvement, as illustrated
attentive dog owner is capable of assessing treatin Figure 2.
ment effects in conditions for which there are
Owner global assessments of overall response
no consistent objective outcome markers. To
to treatment were significantly higher in the
simplify the study, the dose of SMPC was exSMPC than in the placebo group at both the
trapolated from results of laboratory animal
4- and 8-week evaluation times (Table 2). Vetstudies and clinical findings in humans, and
erinarian global assessments of responses in
the population of dogs was restricted in body
0.2
62
"Small"
effect
D. A. Gingerich and J. D. Strobel
TABLE 3. Spearman Rank Order Correlation Coefficients in 35 Arthritic Dogs. All Outcome Variables are Highly Significantly Correlated (P < .001)
Physical examination
Standard
Case-specific
Client global
Standard
Case-Specific
Client Global
Veterinarian Global
0.579
0.533
0.599
0.716
0.601
0.725
0.742
0.547
0.589
0.839
weight and age. In particular, dogs with a degree of obesity that could have compromised
musculoskeletal evaluations were excluded.
The use of a 1-week placebo run-in period was
based on two considerations: First, owners
would have to prove to themselves and to the
veterinarian that they were motivated enough
to give their dog two large capsules orally twice
daily. Second, the owners would have an opportunity to observe the dog’s behavior in the
context of filling out score sheets and to rethink the case-specific disabilities to be monitored. Because the study was completely blinded, neither the owner nor the attending
veterinarian was aware that only placebo capsules
were given during that first week. The physical
examination and questionnaire scores from
Week 0 were used as baseline data.
The 35% placebo effect based on both owner
and veterinarian global assessment of overall
response appears high but is within the range
of 25% to 38% placebo response reported in
larger trials on the NSAID carprofen in dogs
with osteoarthritis.5,28 Placebo effects must be
attributed largely to owner or veterinarian
expectations rather than to psychological effects on the canine patient. The finding that
physical examination scores improved in both
placebo and active groups is difficult to
explain. Moreover, although physical findings
did not differ, the veterinarian global assessments were higher for the test group than for
controls, suggesting that veterinarians based
their evaluations on factors other than changes
in physical examination findings and were
influenced in some manner by the owners.
Numerically, the perceived difference in response between test product and placebo was
greater for the owners than for the veterinarians (Figure 3), a finding consistent with results
of other trials.5,29–31
Owner assessment of treatment outcome in
orthopedics has been used successfully by other
researchers to evaluate drugs and surgical procedures5,29,30,32,33 but has been less successful in
evaluating nutraceuticals.34 Validated, questionnaire-based outcome measures consisting
of 20 or more questions grouped into categories such as pain, stiffness, and activities of
daily living have been used for some years in
human arthritis trials.12,13,16,25 Dogs, however,
cannot fill out questionnaires or be interviewed, and only seven activities could be identified that most dogs do on a daily basis for
inclusion in the standardized questionnaire
(the WOMAC approach). There was no attempt to categorize these questions, although
others have monitored subcategories such as the
dog’s quality of life, activity, lameness, disability,
stiffness, ability to jump, and effect of cold,
damp weather.26,30,32 Instead, a case-specific
method was devised similar to the MACTAR
approach proposed for human patients with
rheumatoid arthritis13 (the CODI approach).
In this initial trial, the specific disabilities were
not ranked or weighted as is done in the original
MACTAR approach, although this may have
further improved sensitivity. The standardized
63
Veterinary Therapeutics • Vol. 4, No. 1, Spring 2003
scores were invariably higher at baseline than
the CODI scores because some of the individual
standardized variables, such as walking and
running, were often completely normal. For
example, although a dog may not have difficulty walking or running, he may be unwilling
to go for long walks, retrieve toys, or play with
other animals. By capturing these details in
case-specific questionnaires, the sensitivity of
detecting owners’ perceptions of treatment
effects is greatly enhanced. Although the
CODI approach greatly improved sensitivity
compared with the standardized approach in
this study (Figure 3), both outcome measures
were highly significantly correlated (P < .001)
with owners’ global assessment scores.
There are several advantages to transforming
subjective, ordinal data to the scale of 0 to 100,
which is common in orthopedics,25 and broader
utilization of this technique in veterinary trials
is advocated by the authors. First, the transformed data often satisfy the criteria of normal
distribution and equal variance that arguably
justify the more-familiar, parametric statistical
treatment. Second, the data from any subjective
scoring system, regardless of the scale, can be
similarly transformed and grouped into clinically meaningful categories such as stiffness,
lameness, or activity. Well-defined scoring systems both in orthopedics35 and in other areas
such as atopic dermatitis in dogs36 have been
developed, and the data from these could easily
be transformed to permit comparisons among
treatment groups and various subgroups in
similar terms. Third, use of the transformed
scale establishes the custom of expressing clinical
improvement in terms of increasing scores and
enables calculation of percentage improvement
by simple subtraction.
The concept of “effect size,” a unitless measure
of the degree to which the apparent treatment
effect exceeds the placebo effect, has not been
widely reported in veterinary trials. Originally
64
developed for the behavioral sciences,29 an effect
size of 0.2 or below is considered a “small” effect,
and 0.8 or higher is a “large” effect.9 According
to this convention, the effect sizes on the CODI
scale and the owner global assessment were
large; the standardized scale and veterinarian
global assessment were intermediate; and the
physical examination outcome was negligible
(Figure 4) in this study. It is also noted that the
effect size on the CODI scale was markedly
greater than on the other outcome measures.
Calculation and reporting of effect size in veterinary trials is advocated as a convenient construct for comparing the magnitude of outcomes within and among trials.
In this first trial, it was anticipated that owners
would be able to identify five or more disabilities
unique to their pet. In fact, most owners only
identified two or three concerns, and some of
these were the same as those on the standardized
form. It appears that more extensive owner
interviews using probing questions such as
“does your dog like to chase things?” or “do
you take your dog on walks or outings?” would
be more productive. Furthermore, it was
concluded that the ability of the client and his
or her rapport with both the dog and the veterinarian (or technician) are the most important aspects of case selection in such trials.
Owners sometimes failed to list and score the
same disabilities on follow-up forms or to list
different ones as they were observed throughout
the study. This was often true on home followup forms for Weeks 2 and 6, causing data from
those times to be unreliable and therefore
dropped from the study evaluation. To avoid
this pitfall, it is important to write down the disabilities identified at baseline on all follow-up
forms in advance. Forms for each evaluation period were deliberately issued separately in this
study to encourage the owners and veterinarians
to record the scores independent of previous ratings. Despite the shortcomings, the present
D. A. Gingerich and J. D. Strobel
CODI methodology was of sufficient sensitivity
to detect treatment effects, with adequate statistical power, in a relatively small study.
The paucity of adverse effects and lack of
changes in clinical chemistry findings over the
8-week treatment period is noteworthy (but
not unexpected) because the test substance is a
naturally derived nutritional product, not an
NSAID. The apparent serum cholesterol-lowering effect of the test product is of interest,
not for its clinical relevance in dogs but rather
because it is consistent with similar findings in
human patients with hypercholesterolemia.37,38
In summary, this study describes the development of a scoring system for controlled clinical
trials in dogs that is based on owner evaluation
and permits the reduction of data derived in this
manner to quantitative terms. Furthermore, the
study demonstrated the value of the 0 to 100
transformed scale and the calculation and reporting of effect size in randomized, controlled
trials in veterinary medicine. Results of the present trial using this methodology support the
conclusion that the milk-derived SMPC ingredient has therapeutic value in dogs, and it provided benefits similar to those observed clinically in human patients using the same ingredient
and similar methodology.23,24 Because the product does not share the mechanism or potential
toxicity of NSAIDs,39 it appears to provide the
veterinarian with a safe alternative for long-term
management of musculoskeletal disabilities in
aging pets. The results of this study are encouraging and provide justification for larger controlled trials in more diverse populations as well
as trials to validate the present methodology
against accepted objective standards.
■ ACKNOWLEDGMENTS
The authors thank the following Cincinnati area practitioners and their technicians for contributing clinical cases: Dr. Larry Smith, Salt Run Veterinary Clinic; Drs. Gary
Schroeder, Mary Kelley, and Deborah McArthur, Peach
Grove Animal Hospital; Drs. Richard Seaman and Lisa
McMahan, Madeira Veterinary Hospital; Drs. Gary Smith,
Robert Outzs, Pamela Sawyer, and Jack Walkenhorst,
County Animal Hospital; Drs. Kevin Ketring, Terri McCarty, and Joseph Stratman, College Hill Pet Clinic. The
authors also thank Dr. William Rogers, Veterinary Internal
Medicine, for assistance in the original design of the study.
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