Clinical Criteria for the Diagnosis of Salivary Gland Hypofunction M. NAVAZESH2, C. CHRISTENSEN1, and V. BRIGHTMAN University ofPennsylvania School of Dental Medicine, General Clinical Research Center, and The Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104 There is considerable difficulty in the making of initial clinical decisions as to whether a given patient has salivary gland hypofunction, and hence requires additional salivary gland evaluation. This study identified a set of four clinical measures that, together, successfully predicted the presence or absence of salivary gland hypofunction. The four measures were: dryness of lips, dryness of buccal mucosa, absence of saliva produced by gland palpation, and total DMFT; they were derived from discriminant analysis of data collected from 71 individuals with normal and low salivary flow rates. These measures are proposed as criteria for clinical decision-making, as well as for classification of patients in studies of salivary gland dysfunction syndromes. This study also identified unstimulated whole salivary flow rates of 0.12-0.16 mL/ min as the critical range separating individuals with salivary gland hypofunction from those with normal gland function. J Dent Res 71(7):1363-1369, July, 1992
Introduction. While several methods (sialometry, sialochemistry, retrograde sialography, salivary scintigraphy, and biopsy) are available for evaluation of salivary gland dysfunction, each method requires either specially trained personnel and/or equipment not generally available in a dental office. Among the set of measures more readily obtained in a clinical setting, there are no commonly accepted criteria for diagnosis of salivary gland hypofunction. "Salivary gland hypofunction" is used here to describe any objectively demonstrable reduction in either whole and/or individual salivary gland flow rates. This term is preferred to "xerostomia" and "dry mouth syndrome", because these latter terms have been used to describe symptoms of dry mouth with or without confirmatory salivary flow rate measurements (Fox, 1989). A variety of oral changes has been associated with salivary gland hypofunction, including increased dental caries and periodontal disease, mucositis and angular cheilitis, disturbed oral sensation, and altered taste (Bahn, 1972; Conger, 1973; Henkin et al., 1972; Dreisen et al., 1977; Navazesh and Ship, 1983; Weiffenbach et al., 1986; Sreebny and Broich, 1989; Handel, 1989; Wolff et al., 1990). Most efforts to diagnose salivary gland hypofunction have included measures of salivary flow rate. Following the original descriptions of the conditions referred to as "dry mouth" and "xerostomia" by Bartley (1868) and Hutchinson (1889), several methods for the evaluation of salivary gland dysfunction were introduced in the latter 19th and first half of the 20th centuries; standardized methods for the diagnosis of salivary gland dysfunction were not described until 1967. Bertram (1967) identified symptoms of dryness, decreased unstimulated whole (UW) salivary flow rate, and changes in the oral hard and soft tissues as important for the diagnosis of "xerostomia"; and based on a sample of 50 patients with symptoms of oral dryness (40% with Sjogren's syndrome), he associated "xerostomia" with UW < 0.20 mL/15 min, and "hyposalivation" with UW> 0.20 but 0.20 mL/min) were recruited from among patients and staff of the School of Dental Medicine; also, these individuals were chosen to match closely the age and gender distribution of the lowflow group. Both types of subjects were excluded if they had any current infectious disease, bleeding disorder, history of major salivary gland extirpation, or radiation-induced salivary gland hypofunction. A total of 168 subjects was screened, and 71 subjects 1363
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TABLE 1 PEARSON CORRELATIONS AMONG SALIVARY FLOW RATE MEASURES
Collection Method
Test/Re-test' Reliability
Unstimulated Whole (UW)
+0.84
Stimulated Whole (Chewing) (SW)
+0.87
Right Acid-stimulated Parotid (RASP)
+0.63
Right Candy-stimulated Parotid (RCSP)
+0.72
Left Acid-stimulated Parotid (LASP) Left Candy-stimulated Parotid (LCSP)
+0.72 +0.66
Comparison of Different Collection Methods2 UW-SW
Relatedness of Salivary Measures +0.63
SW-RCSP
+0.40
SW-LCSP
+0.54
salivary gland hypofunction were described in detail. Not described in this paper are the methods and results for measurement of salivary pH, urea, calcium, sodium, potassium, and chloride, and the methods for assessment of oral Candida (detailed methods can be obtained upon request from the authors). Clinical examination.-Scores for the following were obtained in the order listed, so that standard measures ofthe oral hard and soft tissues would be provided. All the clinical evaluations were performed by the principal author (MN). (i) Lip dryness.-Dryness and cracking of the corners and/or the vermillion borders of the lips were scored as 0 (normal), 1 (dry vermillion border), 2 (dry, chapped and/or fissured tissue), or 3 (angular cheilitis, redness or fissuring at the commissure, with lesions of traumatic origin excluded). The dryness and fissuring were scored as present even if observed unilaterally. (ii) Buccal mucosa dryness.-Dry tongue blades were used for retraction of the buccal mucosa bilaterally, and the mucosa was scored as: 0 (normal), 1 (looks dry, but tissue does not stick to the tongue blade), 2 (looks dry, and tissue sticks to the tongue blade), or 3 (looks dry, tissue sticks to the tongue blade, and the location of one or both parotid ducts is not apparent). Scored positive for "sticking" if either or both cheeks stuck to the tongue blade. (iii) Salivary pool. -Saliva which had accumulated on the floor of the mouth at this point in the examination was referred to as the salivary pool and was scored as: 0 (present or normal), or 1 (absent).
Majorsalivaryglandpalpation.-Evidence ofmajorgland swelling, tenderness upon palpation, or failure ofsaliva to be elicited from either Wharton's or Stensen's ducts was scored. If flow was limited RASP- LASP +0.61 to one or two drops or was viscous or contaminated with blood or pus, it was scored as having no saliva. Scores were recorded as 0 (absence UW-ASP3 +0.57 of any of the abovementioned symptoms, or 1 (symptoms present). (i) Tongue mucosa.-Changes in the tongue dorsal mucosa were +0.44 UW-CSP3 'For repeat determinations with a single collection method; all scored on the four-point scale devised by Bertram (1967). (ii) Periodontium. -A plaque index and modified gingival index correlations are significant at p < 0.001. were determined according to the methods of Loe (1967). Probing 2UW, SW, RCSP, LCSP, RASP, and LASP are the averaged depth was recorded to the nearest mm. Subgingival bacterial values for the second and third visits. plaque was collected from the six deepest pockets, and examined by 3ASP and CSP are the averaged values from the left and right dark-field microscopy (Listgarten et al., 1984). parotid glands for the second and third visits. (iii) Total DMFT. -The numbers of decayed, missing, and filled teeth were scored and summed to provide total DMFT (Cormier and successfully completed all phases of this project. This group con- Levy, 1981). sisted of 48 women and 23 men who ranged in age from 19 to 82 Saliva collections.-Unstimulated and stimulated whole saliva and stimulated parotid gland saliva specimens were collected on years, with a mean age of 52 years. Test schedule.-Subjects were tested three times in consecutive three separate occasions. Flow rate was calculated as g/min, which weekly visits at the School of Dental Medicine GCRC. Testing was is nearly equivalent to mL/min (Navazesh and Christensen, 1982). performed between 9:00 a.m. and 3:00 p.m., so that circadian Whole saliva was collected in pre-weighed test tubes fitted with influences would be minimized (Dawes, 1974). Subjects were funnels. Before salivary collections began, each subject rinsed instructed to refrain from food or beverages, water excepted, for two thoroughly several times with de-ionized water and rested for five h before each test session and to discontinue all medications eight min. After a one-minute practice collection that was discarded, h before a session. unstimulated whole saliva (UW) was collected over a single fiveAt the first visit, the subject was familiarized with the testing minute period by means of a draining method (Navazesh and protocol, and informed consent was obtained. The Cornell Medical Christensen, 1982). Stimulated whole saliva (SW) was collected in Index and an oral sensory questionnaire were administered, and a similar manner, with moderate stimulation produced by having UW was collected and used for tentative classification of subjects as subjects chew an inert gum base at 45 chews/min, paced with a normal or abnormal. During the second visit, information was metronome. The first two-minute collection was discarded. obtained on the nature, frequency, and duration of any oral comStimulated parotid saliva was collected sequentially from each plaints, including oral dryness or soreness, bad breath, and changes gland for five min by means ofa modified Carlson-Crittendon device in taste. Information was also obtained on the subject's frequency (H&I Instrumentation, Teaneck, NJ 07666). Parotid saliva was of dental visits, smoking habits, current health status, and history collected after collection of whole saliva. Both acid-stimulated (ASP) of medication usage (within past two yr). Subjects then received a and candy-stimulated (CSP) parotid saliva specimens were collected. head-and-neck clinical examination, a rinse was collected for a For acid stimulation, the dorsal surface of the tongue was stroked measure of oral Candida, and a series of salivary collections was every 30 s with a cotton roll soaked with 0.15 mol/L citric acid; for performed. During the third visit, the series of salivary collections candy stimulation, sour candy (Lemon Stix Kisses, Jolly Rancher, and the oral rinse for Candida were repeated. Division of Beatrice Foods Co., Wheatridge, CO 80033) was used, Clinical and salivary measures.-A comprehensive set of 64 with sucking rate paced by a metronome set at 45 beats/min. measures was obtained from each subject. Only those measures Statistical analysis.-The reliability of multiple measures of that were ultimately important to the definition or prediction of salivary flow and composition was assessed with Pearson correlaRCSP-LCSP
+0.63
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TABLE 2 THE FOUR DISCRIMINANT FUNCTION VARIABLES THAT BEST DISCRIMINATED BETWEEN CLEARLY ABNORMAL AND NORMAL FLOW RATE GROUPS Variable Description LD1
TDMFT2 BMD3
MSGP4
Score 0-3 (normal-severe) 0 -28 (low-high) 0-3 (normal-severe) 0= normal 1 = abnormal
Abnormal (n = 15) x ± S.D. 1.3± 1.1
Normal (n = 13) x ± S.D. 0.2 ± 0.6
22.3 ± 5.4
15.3 ± 5.9
1.8± 5.4
0.1 ± 0.3
abnormal (12/15)
abnormal (2/13)
'LD = Lip Dryness. 2TDMFT = Total decayed, missing, and filled teeth. 3BMD = Buccal mucosa dryness. 4MSGP = Ductal expulsion of saliva by major salivary gland palpation. tions. Because correlations were high, we werejustified in combining subject in a private operatory, and there was no communication the multiple salivary measures, and a mean score was used. Pearson during the test between the dental evaluators. On average, each correlations were also performed between different salivary flow rate subject was seen by six dentists, whereas each dentist saw five methods so that their interrelatedness could be assessed. Then, t subjects. tests were used for comparison of the normal and low salivary flow groups on the entire set ofclinical and salivary measures. A step-wise (Wilks' lambda) discriminant analysis program with Results. default selection criteria (SPSS Inc., 1986) was used for classifica- Relationship between salivary measures.-Salivary flow rate is the tion of subjects participating in the study into either Normal or most critical measure for definition (classification) of an individual Abnormal salivary flow rate groups, based on their clinical and with salivary gland hypofunction. Thus, we utilized a variety of salivary chemistry measures. The statistical program consisted of methods for collecting salivary flow rate measures and tested each two parts: For the first part, we chose a subgroup ofthe total subject of these measures for reliability and the degree of interrelatedness. pool who could unquestionably be identified by salivary flow rate measures as having either normal or abnormally low salivary flow TABLE 3 rates. For this subgroup, measures from the clinical examination DISCRIMINANT FORMULA FOR CLASSIFICAANALYSIS flow rate and salivary composition analysis (excluding salivary measures) were entered into the discriminant program for the TION INTO NORMAL OR ABNORMAL FLOW RATE GROUPS purpose of selecting that subset of linearly combined measures that = -0.345 (LD Score) + 0.267 (TDMFT Score) best discriminated between the two groups of subjects. All mea- Flow Rate sures (except total DMFT) used in the discriminant program were + 2.242 (BMD score) + 4.426 (MSGP) - 8.891 first normalized by conversion to z scores. In the second part ofthe discriminant analysis program, the remaining subjects were in- A positive score = Abnormal flow classification cluded, and classified by the program into Normal or Abnormal flow rate groups based on each subject's values for the set of measures A negative score = Normal flow classification chosen by the discriminant analysis. The success of this classificaAn Example: tion was determined by comparison of the discriminant classification of every subject with the classification based on multiple Assume scores for a hypothetical patient of salivary flow measures obtained from subjects. = 1 Subsequent validation of the classification method.-A strin- LD gent test of the validity of the clinical measures was performed after TDMFT = 22 the completion of the present study described here. The logic of the BMD = 2 validation was to examine the objectivity ofthe clinical measures by 1 having dentists naive to the nature of this salivary research also MSGP = score a series of patients. Twenty-five volunteer adult dental patients were included in this phase of the study. Subjects received salivary flow rate Then apply the formula: measurements and head-and-neck clinical evaluation. The exam-0.345 (1) + 0.267 (22) Classification Score iners included 24 dentists, all general practitioners. The examiners were provided with a brief written protocol to follow the scoring + 2.242 (2) + 4.426 (1) 8.891 method described earlier in the "Materials and methods" section for 5.548 Classification Score each clinical variable. The examiners were given no verbal instructions or assistance. The above patient would be classified as having salivary gland A subject was first seen by the principal author (MN) and then by a small number of dentist-examiners. Each dentist evaluated the hypofunction because the score is positive. =
-
=
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TABLE 4 COMPARISON OF THE DISCRIMINANT CLASSIFICATION OF NORMAL AND ABNORMAL FLOW RATE GROUPS WITH ACTUAL SALIVARY FLOW RATES
Flow Rate Classification Classification by UW Low flow rate (< 0.16 mL/min)
(n = 30)
Normal flow rate
(n = 35)
Discriminant Analysis Classification Abnormal Normal 26 (87%) 4 (13%) True positives 2 (6%)
33 (94%) True negatives
Abnormal
Classification by ASP Low flow rate (< 0.30 mL/min) Normal flow rate (> 0.30 mL/min)
(n = 22)
14 (64%)
(n = 42)
True positives 14 (33%)
The reliability (reproducibility) of each type of salivary measure was determined by calculation of Pearson correlations between individual flow rate measures obtained during the second and third visits. Relatively high test/re-test reliabilities for salivary flow rate (r = 0.63-0.87) were found for all of the collection methods (Table 1); however, whole saliva measures were generally more reliable than parotid measures. Correlations between flow rates obtained by different salivary collection methods were generally not as high as those for repeat determinations of flow rate with a single collection method (see Table 1). All the correlations between collection methods were significantly and positively related to each other, indicating that unstimulated and stimulated measures as well as whole and parotid measures shared some commonality. However, since the values were lower than those obtained from repeat measures of a single method, the different measures were also testing different aspects of salivary flow rate. Additionally, whole salivary flow rate measures were better correlated with each other (r = 0.63) than with parotid measures (r = 0.44-0.57) and vice versa. Before the discriminant analysis was performed, the salivary flow rate measures were combined by the averaging of multiple collections (second and third visits) and, for parotid collections, by combination of left- and right-gland measures. This procedure was justified by the high correlations between these variables. Thus, these combined measures were used for subsequent analysis: unstimulated whole (UW), chewing-stimulated whole (SW), acidstimulated parotid (ASP), and candy-stimulated parotid (CSP). Classification of normal and abnormal salivary flow groups by discriminant analysis.-Before the discriminant analysis could be performed, it was necessary for subjects with unquestionably either
Normal 8 (36%) 28 (67%) True negatives
normal or abnormally low salivary flow rates to be identified. Fifteen subjects were classified as the Abnormal group by means of the multiple criteria that UW be < 0.06 mLlmin (lowest 10% of a large sample of healthy adults; Christensen, 1986), and that ASP be < 0.40 mL/min (Daniels, 1984). (When a lower parotid flow rate criterion, < 0.25 mL/min, was used, the sample of subjects fitting this more restrictive definition of salivary hypofunction was too small for use in the discriminant analysis.) The 15 subjects in this abnormal flow rate group had an average UW (i ± SD) of 0.01 + 0.02 mLlmin and an average ASP of 0.19 ± 0.16 mL/min (K ± SD). The group classified as Normal consisted of 13 subjects, also chosen on the basis of both whole and parotid flow rate measures. This group was defined by a UW >0.34 mL/min (the mean flow rate in a healthy adult population; Christensen, 1986); subjects who had unusually high flow rates (. 0.80 mL/min) were excluded from this group. A criterion of . 0.50 mL/min was initially chosen for the normal ASP, equivalent to the figure quoted by Mason et al. (1967) for lemonjuice-stimulated parotid flow rate in 83 normal subjects. The 13 subjects in this normal flow rate group had an average UW (x ± SD) of 0.51 ± 0.13 mL/min and an average ASP of 0.78 ± 0.27 mL/min. Criteria were also established for the clinical and salivary composition variables to be used in the discriminant analysis. A chosen variable had to have few missing values among the entire subject pool, and had to be significantly correlated with at least two of the four salivary flow rate measures (r > 0.30). The final list of variables used in the discriminant program included 14 measures. These included: (1) the four measures that were ultimately chosen as best discriminating two groups-lip dryness (LD), buccal mucosa dryness (BMD), ductal expulsion of saliva by major salivary gland palpation (MSGP), and total DMFT (TDMFT); and (2) ten other
TABLE 5
SUBSEQUENT VALIDATION: DISCRIMINANT CLASSIFICATION OF NORMAL AND ABNORMAL FLOW RATE GROUPS WITH A NEW GROUP OF PATIENTS AND DENTISTS Flow Rate Classification (UW) Low flow rate (n = 15) (< 0.16 mL/min) Normal flow rate (n = 10) (> 0.16 mL/min)
Discriminant Analysis Classification By Principal Author (MN) By Other Dentists Abnormal Normal Abnormal Normal 80% 20% 77% 23% True positives True positives 0% 100% 0% 100% True negatives True negatives
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TABLE 6 DEMOGRAPHIC AND CLINICAL HISTORY MEASURES FOR SUBJECTS WITH LOW AND NORMAL SALIVARY FLOW RATES Demographic/Historical Measures Gender (percent female)
Low Flow (< 0.16 mLimin UW)
Normal Flow (> 0.16 mLimin UW)
88.0%
49.0%
Frequency of Dental Check-ups (>2/year)
73.5%
48.6%
Symptomatic Dryness/Soreness of Mouth/Tongue
64.0%
27.0%
Medications likely to inhibit salivary flow * No. of medications used (mean) * Duration of use (mean) History of: * Sjbgren's Syndrome * Polyarthritis * Cardiovascular Disease * Emotional Disorder
1.4
0.2 1.8 yr
5.5 yr 26.5% 35.3% 32.4% 32.4%
measures-salivary pool, tongue mucosal changes, percentage of cervical caries, percentage of spirochetes in the plaque analysis, oral Candida count, acid-stimulated parotid salivary calcium concentration, and stimulated whole salivary pH, and sodium, potassium, and urea concentrations. Derivation of a formula for classification of subjects as Normal or Abnormal. -In the first stage of the analysis, the program selected the subset of variables that maximally discriminated the specially selected Abnormal (n = 15) and Normal (n = 13) groups of subjects. Since the sample size was small, given the number of discriminant variables being tested, several step-wise discriminant analyses were run with all and then subsequently several subsets of the 15item discriminant variable set listed above. This was done for determination of whether the subset of variables chosen by the program would emerge when embedded in several different partial sets of variables. In all cases, the same four measures from the 15item set were always selected by the program as the set of variables that best discriminated Abnormal and Normal flow rate groups.
2.7% 2.7% 8.1% 8.1%
These four measures were: LD, BMD, MSGP, and TDMFT. Listed in Table 2 are the means and standard deviations for the four "discriminant" variables among the subset of subjects used for derivation of the discriminant formula. Use ofthe discriminant formula for classification of all subjects as Normal orAbnormal.-Table 3 depicts the discriminant formula that allows assignment ofindividuals as havingabnormal or normal flow rates based on their scores for the four clinical measures. This formula was used for classification ofall the subjects in the study (n = 71, both the identified subgroups and the remaining subject pool) as having normal and abnormal flow rate groups based on their values for the four discriminant variables (the clinical variables of LD, TDMFT, BMD, and MSGP). The classification scheme successfully categorized 12 of the 13 subjects (92.3%) originally identified as having normal flow rates and 14 of the 15 subjects (93.3% originally identified as having abnormal flow rates. This successful categorization suggests that the discriminant formula is valid because it classifies "known"members ofnormal and abnormal flow
TABLE 7 ORAL CLINICAL MEASURES FOR SUBJECTS WITH LOW AND NORMAL SALIVARY FLOW RATES Low Flow (< 0.16 mLimin UW) 1.2 ± 1.1
Normal Flow (> 0.16 mL/min UW) 0.2 ± 0.5
Major Salivary Gland Palpation*
abnormal 27/35
abnormal 5/36
Salivary Pool*
abnormal 2/35
abnormal 1/36
Buccal Mucosa Dryness*
1.4 ± 1.1
0.1 ± 0.4
Tongue Mucosal Changes*
0.7 ± 0.8
0.1 ± 0.3
Candida Count**
1.3 ± 0.9
0.8 ± 0.8
Clinical Measure Lip Dryness*
0.8 ± 0.4 0.6 ± 0.3 Gingival Index** Total DMFT** 21.1 ± 5.9 17.5 ± 6.6 * t test; minimally, p < 0.005; more stringent p value reflecting multiple comparisons. **Approached statistical significance. Values are mean standard deviation, except where fractions are expressed. See scoring system in "Materials and methods" section. Downloaded from jdr.sagepub.com at University of Manitoba Libraries on June 5, 2015 For personal use only. No other uses without permission.
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rate groups. Based on this successful classification of "known" members ofthe group, it is assumed that most other subjects in the study were also successfully classified as having either normal or abnormally low salivary flow. Relationship
between actual
salivary flow
rate
measures
and the
flow rate classification score. -The actual salivary flow rates
of the two classified groups were compared for identification ofthe values most closely related to the classification by discriminant analysis. UW and ASP values for each subject were compared with the subject's classification as abnormal or normal, as provided by the discriminant program. The discriminant analysis was most successful in separating groups when UW between 0.12 and 0.16 mL/ min was used as the salivarybasis for classification of salivary gland
hypofunction. Table 4 shows the results for the discriminant program when UW < 0. 16 mL/min was used for definition of salivary gland hypofunction. Table 4 displays the same type ofresult when ASP
Introduction. While several methods (sialometry, sialochemistry, retrograde sialography, salivary scintigraphy, and biopsy) are available for evaluation of salivary gland dysfunction, each method requires either specially trained personnel and/or equipment not generally available in a dental office. Among the set of measures more readily obtained in a clinical setting, there are no commonly accepted criteria for diagnosis of salivary gland hypofunction. "Salivary gland hypofunction" is used here to describe any objectively demonstrable reduction in either whole and/or individual salivary gland flow rates. This term is preferred to "xerostomia" and "dry mouth syndrome", because these latter terms have been used to describe symptoms of dry mouth with or without confirmatory salivary flow rate measurements (Fox, 1989). A variety of oral changes has been associated with salivary gland hypofunction, including increased dental caries and periodontal disease, mucositis and angular cheilitis, disturbed oral sensation, and altered taste (Bahn, 1972; Conger, 1973; Henkin et al., 1972; Dreisen et al., 1977; Navazesh and Ship, 1983; Weiffenbach et al., 1986; Sreebny and Broich, 1989; Handel, 1989; Wolff et al., 1990). Most efforts to diagnose salivary gland hypofunction have included measures of salivary flow rate. Following the original descriptions of the conditions referred to as "dry mouth" and "xerostomia" by Bartley (1868) and Hutchinson (1889), several methods for the evaluation of salivary gland dysfunction were introduced in the latter 19th and first half of the 20th centuries; standardized methods for the diagnosis of salivary gland dysfunction were not described until 1967. Bertram (1967) identified symptoms of dryness, decreased unstimulated whole (UW) salivary flow rate, and changes in the oral hard and soft tissues as important for the diagnosis of "xerostomia"; and based on a sample of 50 patients with symptoms of oral dryness (40% with Sjogren's syndrome), he associated "xerostomia" with UW < 0.20 mL/15 min, and "hyposalivation" with UW> 0.20 but 0.20 mL/min) were recruited from among patients and staff of the School of Dental Medicine; also, these individuals were chosen to match closely the age and gender distribution of the lowflow group. Both types of subjects were excluded if they had any current infectious disease, bleeding disorder, history of major salivary gland extirpation, or radiation-induced salivary gland hypofunction. A total of 168 subjects was screened, and 71 subjects 1363
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1364
NAVAZESH et al.
J Dent Res July 1992
TABLE 1 PEARSON CORRELATIONS AMONG SALIVARY FLOW RATE MEASURES
Collection Method
Test/Re-test' Reliability
Unstimulated Whole (UW)
+0.84
Stimulated Whole (Chewing) (SW)
+0.87
Right Acid-stimulated Parotid (RASP)
+0.63
Right Candy-stimulated Parotid (RCSP)
+0.72
Left Acid-stimulated Parotid (LASP) Left Candy-stimulated Parotid (LCSP)
+0.72 +0.66
Comparison of Different Collection Methods2 UW-SW
Relatedness of Salivary Measures +0.63
SW-RCSP
+0.40
SW-LCSP
+0.54
salivary gland hypofunction were described in detail. Not described in this paper are the methods and results for measurement of salivary pH, urea, calcium, sodium, potassium, and chloride, and the methods for assessment of oral Candida (detailed methods can be obtained upon request from the authors). Clinical examination.-Scores for the following were obtained in the order listed, so that standard measures ofthe oral hard and soft tissues would be provided. All the clinical evaluations were performed by the principal author (MN). (i) Lip dryness.-Dryness and cracking of the corners and/or the vermillion borders of the lips were scored as 0 (normal), 1 (dry vermillion border), 2 (dry, chapped and/or fissured tissue), or 3 (angular cheilitis, redness or fissuring at the commissure, with lesions of traumatic origin excluded). The dryness and fissuring were scored as present even if observed unilaterally. (ii) Buccal mucosa dryness.-Dry tongue blades were used for retraction of the buccal mucosa bilaterally, and the mucosa was scored as: 0 (normal), 1 (looks dry, but tissue does not stick to the tongue blade), 2 (looks dry, and tissue sticks to the tongue blade), or 3 (looks dry, tissue sticks to the tongue blade, and the location of one or both parotid ducts is not apparent). Scored positive for "sticking" if either or both cheeks stuck to the tongue blade. (iii) Salivary pool. -Saliva which had accumulated on the floor of the mouth at this point in the examination was referred to as the salivary pool and was scored as: 0 (present or normal), or 1 (absent).
Majorsalivaryglandpalpation.-Evidence ofmajorgland swelling, tenderness upon palpation, or failure ofsaliva to be elicited from either Wharton's or Stensen's ducts was scored. If flow was limited RASP- LASP +0.61 to one or two drops or was viscous or contaminated with blood or pus, it was scored as having no saliva. Scores were recorded as 0 (absence UW-ASP3 +0.57 of any of the abovementioned symptoms, or 1 (symptoms present). (i) Tongue mucosa.-Changes in the tongue dorsal mucosa were +0.44 UW-CSP3 'For repeat determinations with a single collection method; all scored on the four-point scale devised by Bertram (1967). (ii) Periodontium. -A plaque index and modified gingival index correlations are significant at p < 0.001. were determined according to the methods of Loe (1967). Probing 2UW, SW, RCSP, LCSP, RASP, and LASP are the averaged depth was recorded to the nearest mm. Subgingival bacterial values for the second and third visits. plaque was collected from the six deepest pockets, and examined by 3ASP and CSP are the averaged values from the left and right dark-field microscopy (Listgarten et al., 1984). parotid glands for the second and third visits. (iii) Total DMFT. -The numbers of decayed, missing, and filled teeth were scored and summed to provide total DMFT (Cormier and successfully completed all phases of this project. This group con- Levy, 1981). sisted of 48 women and 23 men who ranged in age from 19 to 82 Saliva collections.-Unstimulated and stimulated whole saliva and stimulated parotid gland saliva specimens were collected on years, with a mean age of 52 years. Test schedule.-Subjects were tested three times in consecutive three separate occasions. Flow rate was calculated as g/min, which weekly visits at the School of Dental Medicine GCRC. Testing was is nearly equivalent to mL/min (Navazesh and Christensen, 1982). performed between 9:00 a.m. and 3:00 p.m., so that circadian Whole saliva was collected in pre-weighed test tubes fitted with influences would be minimized (Dawes, 1974). Subjects were funnels. Before salivary collections began, each subject rinsed instructed to refrain from food or beverages, water excepted, for two thoroughly several times with de-ionized water and rested for five h before each test session and to discontinue all medications eight min. After a one-minute practice collection that was discarded, h before a session. unstimulated whole saliva (UW) was collected over a single fiveAt the first visit, the subject was familiarized with the testing minute period by means of a draining method (Navazesh and protocol, and informed consent was obtained. The Cornell Medical Christensen, 1982). Stimulated whole saliva (SW) was collected in Index and an oral sensory questionnaire were administered, and a similar manner, with moderate stimulation produced by having UW was collected and used for tentative classification of subjects as subjects chew an inert gum base at 45 chews/min, paced with a normal or abnormal. During the second visit, information was metronome. The first two-minute collection was discarded. obtained on the nature, frequency, and duration of any oral comStimulated parotid saliva was collected sequentially from each plaints, including oral dryness or soreness, bad breath, and changes gland for five min by means ofa modified Carlson-Crittendon device in taste. Information was also obtained on the subject's frequency (H&I Instrumentation, Teaneck, NJ 07666). Parotid saliva was of dental visits, smoking habits, current health status, and history collected after collection of whole saliva. Both acid-stimulated (ASP) of medication usage (within past two yr). Subjects then received a and candy-stimulated (CSP) parotid saliva specimens were collected. head-and-neck clinical examination, a rinse was collected for a For acid stimulation, the dorsal surface of the tongue was stroked measure of oral Candida, and a series of salivary collections was every 30 s with a cotton roll soaked with 0.15 mol/L citric acid; for performed. During the third visit, the series of salivary collections candy stimulation, sour candy (Lemon Stix Kisses, Jolly Rancher, and the oral rinse for Candida were repeated. Division of Beatrice Foods Co., Wheatridge, CO 80033) was used, Clinical and salivary measures.-A comprehensive set of 64 with sucking rate paced by a metronome set at 45 beats/min. measures was obtained from each subject. Only those measures Statistical analysis.-The reliability of multiple measures of that were ultimately important to the definition or prediction of salivary flow and composition was assessed with Pearson correlaRCSP-LCSP
+0.63
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TABLE 2 THE FOUR DISCRIMINANT FUNCTION VARIABLES THAT BEST DISCRIMINATED BETWEEN CLEARLY ABNORMAL AND NORMAL FLOW RATE GROUPS Variable Description LD1
TDMFT2 BMD3
MSGP4
Score 0-3 (normal-severe) 0 -28 (low-high) 0-3 (normal-severe) 0= normal 1 = abnormal
Abnormal (n = 15) x ± S.D. 1.3± 1.1
Normal (n = 13) x ± S.D. 0.2 ± 0.6
22.3 ± 5.4
15.3 ± 5.9
1.8± 5.4
0.1 ± 0.3
abnormal (12/15)
abnormal (2/13)
'LD = Lip Dryness. 2TDMFT = Total decayed, missing, and filled teeth. 3BMD = Buccal mucosa dryness. 4MSGP = Ductal expulsion of saliva by major salivary gland palpation. tions. Because correlations were high, we werejustified in combining subject in a private operatory, and there was no communication the multiple salivary measures, and a mean score was used. Pearson during the test between the dental evaluators. On average, each correlations were also performed between different salivary flow rate subject was seen by six dentists, whereas each dentist saw five methods so that their interrelatedness could be assessed. Then, t subjects. tests were used for comparison of the normal and low salivary flow groups on the entire set ofclinical and salivary measures. A step-wise (Wilks' lambda) discriminant analysis program with Results. default selection criteria (SPSS Inc., 1986) was used for classifica- Relationship between salivary measures.-Salivary flow rate is the tion of subjects participating in the study into either Normal or most critical measure for definition (classification) of an individual Abnormal salivary flow rate groups, based on their clinical and with salivary gland hypofunction. Thus, we utilized a variety of salivary chemistry measures. The statistical program consisted of methods for collecting salivary flow rate measures and tested each two parts: For the first part, we chose a subgroup ofthe total subject of these measures for reliability and the degree of interrelatedness. pool who could unquestionably be identified by salivary flow rate measures as having either normal or abnormally low salivary flow TABLE 3 rates. For this subgroup, measures from the clinical examination DISCRIMINANT FORMULA FOR CLASSIFICAANALYSIS flow rate and salivary composition analysis (excluding salivary measures) were entered into the discriminant program for the TION INTO NORMAL OR ABNORMAL FLOW RATE GROUPS purpose of selecting that subset of linearly combined measures that = -0.345 (LD Score) + 0.267 (TDMFT Score) best discriminated between the two groups of subjects. All mea- Flow Rate sures (except total DMFT) used in the discriminant program were + 2.242 (BMD score) + 4.426 (MSGP) - 8.891 first normalized by conversion to z scores. In the second part ofthe discriminant analysis program, the remaining subjects were in- A positive score = Abnormal flow classification cluded, and classified by the program into Normal or Abnormal flow rate groups based on each subject's values for the set of measures A negative score = Normal flow classification chosen by the discriminant analysis. The success of this classificaAn Example: tion was determined by comparison of the discriminant classification of every subject with the classification based on multiple Assume scores for a hypothetical patient of salivary flow measures obtained from subjects. = 1 Subsequent validation of the classification method.-A strin- LD gent test of the validity of the clinical measures was performed after TDMFT = 22 the completion of the present study described here. The logic of the BMD = 2 validation was to examine the objectivity ofthe clinical measures by 1 having dentists naive to the nature of this salivary research also MSGP = score a series of patients. Twenty-five volunteer adult dental patients were included in this phase of the study. Subjects received salivary flow rate Then apply the formula: measurements and head-and-neck clinical evaluation. The exam-0.345 (1) + 0.267 (22) Classification Score iners included 24 dentists, all general practitioners. The examiners were provided with a brief written protocol to follow the scoring + 2.242 (2) + 4.426 (1) 8.891 method described earlier in the "Materials and methods" section for 5.548 Classification Score each clinical variable. The examiners were given no verbal instructions or assistance. The above patient would be classified as having salivary gland A subject was first seen by the principal author (MN) and then by a small number of dentist-examiners. Each dentist evaluated the hypofunction because the score is positive. =
-
=
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TABLE 4 COMPARISON OF THE DISCRIMINANT CLASSIFICATION OF NORMAL AND ABNORMAL FLOW RATE GROUPS WITH ACTUAL SALIVARY FLOW RATES
Flow Rate Classification Classification by UW Low flow rate (< 0.16 mL/min)
(n = 30)
Normal flow rate
(n = 35)
Discriminant Analysis Classification Abnormal Normal 26 (87%) 4 (13%) True positives 2 (6%)
33 (94%) True negatives
Abnormal
Classification by ASP Low flow rate (< 0.30 mL/min) Normal flow rate (> 0.30 mL/min)
(n = 22)
14 (64%)
(n = 42)
True positives 14 (33%)
The reliability (reproducibility) of each type of salivary measure was determined by calculation of Pearson correlations between individual flow rate measures obtained during the second and third visits. Relatively high test/re-test reliabilities for salivary flow rate (r = 0.63-0.87) were found for all of the collection methods (Table 1); however, whole saliva measures were generally more reliable than parotid measures. Correlations between flow rates obtained by different salivary collection methods were generally not as high as those for repeat determinations of flow rate with a single collection method (see Table 1). All the correlations between collection methods were significantly and positively related to each other, indicating that unstimulated and stimulated measures as well as whole and parotid measures shared some commonality. However, since the values were lower than those obtained from repeat measures of a single method, the different measures were also testing different aspects of salivary flow rate. Additionally, whole salivary flow rate measures were better correlated with each other (r = 0.63) than with parotid measures (r = 0.44-0.57) and vice versa. Before the discriminant analysis was performed, the salivary flow rate measures were combined by the averaging of multiple collections (second and third visits) and, for parotid collections, by combination of left- and right-gland measures. This procedure was justified by the high correlations between these variables. Thus, these combined measures were used for subsequent analysis: unstimulated whole (UW), chewing-stimulated whole (SW), acidstimulated parotid (ASP), and candy-stimulated parotid (CSP). Classification of normal and abnormal salivary flow groups by discriminant analysis.-Before the discriminant analysis could be performed, it was necessary for subjects with unquestionably either
Normal 8 (36%) 28 (67%) True negatives
normal or abnormally low salivary flow rates to be identified. Fifteen subjects were classified as the Abnormal group by means of the multiple criteria that UW be < 0.06 mLlmin (lowest 10% of a large sample of healthy adults; Christensen, 1986), and that ASP be < 0.40 mL/min (Daniels, 1984). (When a lower parotid flow rate criterion, < 0.25 mL/min, was used, the sample of subjects fitting this more restrictive definition of salivary hypofunction was too small for use in the discriminant analysis.) The 15 subjects in this abnormal flow rate group had an average UW (i ± SD) of 0.01 + 0.02 mLlmin and an average ASP of 0.19 ± 0.16 mL/min (K ± SD). The group classified as Normal consisted of 13 subjects, also chosen on the basis of both whole and parotid flow rate measures. This group was defined by a UW >0.34 mL/min (the mean flow rate in a healthy adult population; Christensen, 1986); subjects who had unusually high flow rates (. 0.80 mL/min) were excluded from this group. A criterion of . 0.50 mL/min was initially chosen for the normal ASP, equivalent to the figure quoted by Mason et al. (1967) for lemonjuice-stimulated parotid flow rate in 83 normal subjects. The 13 subjects in this normal flow rate group had an average UW (x ± SD) of 0.51 ± 0.13 mL/min and an average ASP of 0.78 ± 0.27 mL/min. Criteria were also established for the clinical and salivary composition variables to be used in the discriminant analysis. A chosen variable had to have few missing values among the entire subject pool, and had to be significantly correlated with at least two of the four salivary flow rate measures (r > 0.30). The final list of variables used in the discriminant program included 14 measures. These included: (1) the four measures that were ultimately chosen as best discriminating two groups-lip dryness (LD), buccal mucosa dryness (BMD), ductal expulsion of saliva by major salivary gland palpation (MSGP), and total DMFT (TDMFT); and (2) ten other
TABLE 5
SUBSEQUENT VALIDATION: DISCRIMINANT CLASSIFICATION OF NORMAL AND ABNORMAL FLOW RATE GROUPS WITH A NEW GROUP OF PATIENTS AND DENTISTS Flow Rate Classification (UW) Low flow rate (n = 15) (< 0.16 mL/min) Normal flow rate (n = 10) (> 0.16 mL/min)
Discriminant Analysis Classification By Principal Author (MN) By Other Dentists Abnormal Normal Abnormal Normal 80% 20% 77% 23% True positives True positives 0% 100% 0% 100% True negatives True negatives
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Vol. 71 No. 7
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TABLE 6 DEMOGRAPHIC AND CLINICAL HISTORY MEASURES FOR SUBJECTS WITH LOW AND NORMAL SALIVARY FLOW RATES Demographic/Historical Measures Gender (percent female)
Low Flow (< 0.16 mLimin UW)
Normal Flow (> 0.16 mLimin UW)
88.0%
49.0%
Frequency of Dental Check-ups (>2/year)
73.5%
48.6%
Symptomatic Dryness/Soreness of Mouth/Tongue
64.0%
27.0%
Medications likely to inhibit salivary flow * No. of medications used (mean) * Duration of use (mean) History of: * Sjbgren's Syndrome * Polyarthritis * Cardiovascular Disease * Emotional Disorder
1.4
0.2 1.8 yr
5.5 yr 26.5% 35.3% 32.4% 32.4%
measures-salivary pool, tongue mucosal changes, percentage of cervical caries, percentage of spirochetes in the plaque analysis, oral Candida count, acid-stimulated parotid salivary calcium concentration, and stimulated whole salivary pH, and sodium, potassium, and urea concentrations. Derivation of a formula for classification of subjects as Normal or Abnormal. -In the first stage of the analysis, the program selected the subset of variables that maximally discriminated the specially selected Abnormal (n = 15) and Normal (n = 13) groups of subjects. Since the sample size was small, given the number of discriminant variables being tested, several step-wise discriminant analyses were run with all and then subsequently several subsets of the 15item discriminant variable set listed above. This was done for determination of whether the subset of variables chosen by the program would emerge when embedded in several different partial sets of variables. In all cases, the same four measures from the 15item set were always selected by the program as the set of variables that best discriminated Abnormal and Normal flow rate groups.
2.7% 2.7% 8.1% 8.1%
These four measures were: LD, BMD, MSGP, and TDMFT. Listed in Table 2 are the means and standard deviations for the four "discriminant" variables among the subset of subjects used for derivation of the discriminant formula. Use ofthe discriminant formula for classification of all subjects as Normal orAbnormal.-Table 3 depicts the discriminant formula that allows assignment ofindividuals as havingabnormal or normal flow rates based on their scores for the four clinical measures. This formula was used for classification ofall the subjects in the study (n = 71, both the identified subgroups and the remaining subject pool) as having normal and abnormal flow rate groups based on their values for the four discriminant variables (the clinical variables of LD, TDMFT, BMD, and MSGP). The classification scheme successfully categorized 12 of the 13 subjects (92.3%) originally identified as having normal flow rates and 14 of the 15 subjects (93.3% originally identified as having abnormal flow rates. This successful categorization suggests that the discriminant formula is valid because it classifies "known"members ofnormal and abnormal flow
TABLE 7 ORAL CLINICAL MEASURES FOR SUBJECTS WITH LOW AND NORMAL SALIVARY FLOW RATES Low Flow (< 0.16 mLimin UW) 1.2 ± 1.1
Normal Flow (> 0.16 mL/min UW) 0.2 ± 0.5
Major Salivary Gland Palpation*
abnormal 27/35
abnormal 5/36
Salivary Pool*
abnormal 2/35
abnormal 1/36
Buccal Mucosa Dryness*
1.4 ± 1.1
0.1 ± 0.4
Tongue Mucosal Changes*
0.7 ± 0.8
0.1 ± 0.3
Candida Count**
1.3 ± 0.9
0.8 ± 0.8
Clinical Measure Lip Dryness*
0.8 ± 0.4 0.6 ± 0.3 Gingival Index** Total DMFT** 21.1 ± 5.9 17.5 ± 6.6 * t test; minimally, p < 0.005; more stringent p value reflecting multiple comparisons. **Approached statistical significance. Values are mean standard deviation, except where fractions are expressed. See scoring system in "Materials and methods" section. Downloaded from jdr.sagepub.com at University of Manitoba Libraries on June 5, 2015 For personal use only. No other uses without permission.
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rate groups. Based on this successful classification of "known" members ofthe group, it is assumed that most other subjects in the study were also successfully classified as having either normal or abnormally low salivary flow. Relationship
between actual
salivary flow
rate
measures
and the
flow rate classification score. -The actual salivary flow rates
of the two classified groups were compared for identification ofthe values most closely related to the classification by discriminant analysis. UW and ASP values for each subject were compared with the subject's classification as abnormal or normal, as provided by the discriminant program. The discriminant analysis was most successful in separating groups when UW between 0.12 and 0.16 mL/ min was used as the salivarybasis for classification of salivary gland
hypofunction. Table 4 shows the results for the discriminant program when UW < 0. 16 mL/min was used for definition of salivary gland hypofunction. Table 4 displays the same type ofresult when ASP
