The Cost-effectiveness of Three Thyroid Function Testing Strategies for Suspicion of Hypothyroidism in a Primary Care Setting JOEL M. $CHECTMAN, MD, MPH, L. GREGORYPAWLSON, MD, MPH Objective: To determine the sensitivity and specificity o f thyroxine (T~) and the cost-effectiveness o f three t e s t i n g strategies in the d i a g n o s i s o f h y p o t h y r o i d i s m in a p r i m a r y care setting. Design: 1) A retrospective c h a r t review to d e t e r m i n e sensitzMity a n d specificity o f T4 i n d i a g n o s i n g hypothyroidism; a c o s t - e f f e c t i v e n e s s analysis c o m p a r i n g o r d e r i n g a n initial T4 test alone, a n initial thyroid-stimulating h o r m o n e (TSH) test alone, a n d T4 a n d TSH tests together in diagnosi n g hypothyroidism; a sensitivity a n a l y s i s w a s p e r f o r m e d o n critical assumptions. Setting: P r / m a r y care adult p r a c t i c e o f a health mainten a n c e organization. Patients: Eight h u n d r e d sixteen consecutive p a t i e n t s susp e c t e d o f h a v i n g h y p o t h y r o i d i s m w h o h a d both T4 a n d TSH tests performed. I n t e r v e n t i o n s : None. Results: The sensitivity o f a T4 cut-off o f 7 I l g / d l (90.3 n m o l / L ) i n d i a g n o s i n g p r i m a r y h y p o t h y r o i d i s m was 93 % (95% confidence i n t e r v a l = 8 5 - 1 0 0 % ) a n d the specificity w a s 68% (95% confidence i n t e r v a l = 6 5 - 71%). The c o s t effectiveness ratios o f u s i n g a n initial T4 o r TSH test w e r e a b o u t the s a m e across a w i d e r a n g e o f test characteristics a n d disease p r e v a l e n c e estimates. As the ratio o f T 4 to TSH test charges declines f r o m 0.6 to 0.2, the m a r g i n a l cost o f the TSH-first m e t h o d inereases f r o m $3,500 to $18,000 f o r each a d d i t i o n a l h y p o t h y r o i d p a t i e n t identified. O r d e r i n g both tests together w a s very costly c o m p a r e d with the single test methods ($125,000 f o r each a d d i t i o n a l case diagn o s e d ) a n d r e m a i n e d so u n d e r a wide r a n g e o f assumptions. C o n c l u s i o n s : When h y p o t h y r o i d i s m is suspected, a TSHf i r s t testing a p p r o a c h is generally p r e f e r a b l e d u e to its g r e a t e r sensitivity and, u n d e r m o s t assumptions, o n l y small i n c r e m e n t in average o r m a r g i n a l c o s t p e r case comp a r e d with a T4-first method. Key words: hypothyroidism; cost-effectiveness; t h y r o i d f u n c t i o n testing. J GEN INTERN MED 1990; 5:9--15.
sitive and specific for p r i m a r y hypothyroidism, is supp o r t e d b y s o m e , 37 w h i l e others favor a s e r u m thyroxine (T4) determination as the less costly initial test o f choice.2, S-ll However, in actual clinical practice, ordering the tests together (and often others as well) appears to b e the most c o m m o n strategy b y far. 2, t2 T w o studies have addressed the c o s t - e f f e c tiveness ratios of thyroid function testing strategies w h e n hypothyroidism is suspected. 2, 13 In one study, two strategies w e r e compared: ordering an initial TSH versus ordering an initial T4 f o l l o w e d b y a TSH only if the T4 w e r e b e l o w a certain cut-off level. The authors f o u n d that laboratory savings of 30% c o u l d b e achieved w i t h o u t a substantial sacrifice of diagnostic effectiveness b y using the T4-first strategy. 2 However, this savings estimate d e p e n d s on their specific assumptions regarding cost and test characteristics, as a sensitivity analysis was not reported. The second study c o m p a r e d the c o s t - e f f e c t i v e n e s s of an initial T 4 w i t h that of an initial TSH and c o n c l u d e d that "TSH may be most costeffective w h e n hypothyroidism is suspected. ''t3 However, evidence to s u p p o r t this statement was not provided. This r e p o r t first analyzes the sensitivity and specificity ofT4 in the diagnosis of hypothyroidism, and then incorporates this information into a c o s t - effectiveness analysis. Three diagnostic strategies for suspicion o f h y p o t h y r o i d i s m are c o m p a r e d : T4-first, TSH-first, and b o t h tests together. A sensitivity analysis on critical ass u m p t i o n s and estimates is also reported.
METHODS SYMPTOMS SUGGESTIVEof hypothyroidism are c o m m o n in p r i m a r y care practice and f r e q u e n t l y trigger thyroid function testing. Previous reports indicate that the yield of disease identification from such testing is l o w (in the range of 1 - 4%). 1. z Given the high f r e q u e n c y o f such s y m p t o m s and the l o w yield, a better understanding of the c o s t - e f f e c t i v e n e s s ratios of different diagnostic a p p r o a c h e s w o u l d be useful. The use of o n l y a thyroid-stimulating h o r m o n e (TSH) test, w h i c h is senReceived from the Department of Health Care Sciences, George Washington University Medical Center, Washington, DC. Presented in part at the 1 lth annual meeting of the Society of General Internal Medicine, April 29, 1988, Arlington, Virginia. Address correspondence and reprint requests to Dr. Schectman: Department of Health Care Sciences, George Washington University Medical Center, Washington, DC 20037.
Receiver Operating Characteristics The sensitivity and specificity of T4 w e r e determ i n e d using data collected f r o m a chart audit of consecutive patients for w h o m b o t h TSH and T4 determinations w e r e o r d e r e d for the suspicion of hypothyroidism b e t w e e n January 1985 and February 1987. To increase the sample size of patients w i t h elevated TSH (and thus the precision of the sensitivity estimates for T4), the record r e v i e w was e x t e n d e d to March 1988 for patients s u s p e c t e d of having hypothyroidism w h o w e r e f o u n d to have elevated TSH. Patients w h o had k n o w n histories of thyroid disease or w e r e taking medications k n o w n to affect thyroid function tests w e r e excluded. All patients w e r e p r i m a r y care patients from the adult practice of the D e p a r t m e n t of Health Care Sciences of George 9
10
SchectTnan. Paw/son. COST-EFFECTIVENESSOF TESTING FOR HYPOTHYROIDISM
Washington University, and nearly all w e r e enrolled in its staff m o d e l health m a i n t e n a n c e organization. For p u r p o s e s of calculating the sensitivity of 3"4 in the diagnosis of hypothyroidism, patients w e r e considered h y p o t h y r o i d if the TSH level was > 5 m U / L a b o v e the u p p e r normal limit. This cut-off was chosen as the " g o l d standard" because, in a p r i o r study, t 73% of patients w i t h only b o r d e r l i n e TSH elevations of 0 - 5 m U / L above normal w e r e found to have normal TSH levels w h e n tests w e r e s u b s e q u e n t l y r e p e a t e d (and the patients w e r e not felt to b e h y p o t h y r o i d b y their physicians). No patient w i t h a TSH above this cut-off had a normal repeat level and all w e r e clinically considered to be hypothyroid. Furthermore, other studies suggest that the majority of patients with a TSH above this or a similar cut-off go on to d e v e l o p overt h y p o t h y r o i d i s m within several years, even w h e n they are a s y m p t o m a t i c initially. 14-t6 The gold standard for the absence of hypothyroidism was a TSH level within normal limits. This is a w e l l - a c c e p t e d standard in regard to p r i m a r y hypothyroidismtT-2t; central hypothyroidism is so rare 22 that it is unlikely to affect this analysis. We identified a total of 31 patients w h o had simultaneous T 4 and TSH determinations w i t h the TSH > 5 m U / L above normal. These 3"4 TSH pairs w e r e used to calculate the sensitivities of various levels of T4 in the diagnosis of hypothyroidism. A total of 785 patients had simultaneous T4 and TSH determinations in w h i c h the TSH level was within normal limits. These T4/TSH pairs w e r e used to calculate the specificities of various T 4 levels in the diagnosis of hypothyroidism. Ninety-five p e r c e n t confidence intervals (CI) for the sensitivity and specificity estimates w e r e calculated using standard m e t h o d s for a binomial distribution.
Cost- Effectiveness Analysis MODEL
The three strategies c o m p a r e d were: ordering a T4 test first, ordering a TSH test first, and ordering these tests together. In o u r model, e a c h test result was initially categorized as normal or abnormal. W h e n o n l y one test was done initially, any a b n o r m a l result triggered the p e r f o r m a n c e of the o t h e r thyroid function test (i.e., if T4 w e r e b e l o w the specified diagnostic cutoff, a TSH test w o u l d automatically be done w i t h o u t requiring an additional patient visit). Each strategy's estimated sensitivity and specificity w e r e used to calculate its true/false-positive and true/false-negative rates. The strategy of initially obtaining b o t h T4 and TSH determinations was assigned 100% sensitivity and 100% specificity in order to bias the analysis in favor o f this m o r e conservative and p o p u l a r a p p r o a c h . Costs w e r e measured in dollars spent on the thyroid function tests alone, although additional costs w e r e considered in the sensitivity analysis. Effective-
ness was m e a s u r e d in terms of the n u m b e r o f hypothyroid cases identified. Decision-Maker 6.0 (© Pratt Associates) was used to p e r f o r m this analysis. The results of the c o s t - e f f e c t i v e n e s s analysis are r e p o r t e d in terms o f b o t h average and marginal c o s t effectiveness ratios. Average c o s t - e f f e c t i v e n e s s refers to the total costs divided b y the total effectiveness (as defined above) of a strategy. It thus represents the casefinding laboratory cost for hypothyroidism. Marginal c o s t - effectiveness c o m p a r e s one strategy w i t h another and represents the difference in costs divided b y the difference in effectivenesses of the two strategies." It thus represents the extra cost incurred to identify an additional case b y the m o r e sensitive b u t m o r e costly strategy. ASSUMPTIONS (TABLE 1)
TSH T e s t C h a r a c t e r i s t i c s . In the c o s t effectiveness analysis, a TSH level is considered abnormal w h e n it is above the u p p e r limit of normal o f the clinical laboratory. Using this criterion, the sensitivity of a TSH test in identifying s y m p t o m a t i c patients w i t h p r i m a r y hypothyroidism a p p r o a c h e s 100%, tT-2t w h i l e the p r o p o r t i o n of patients w i t h primary as o p p o s e d to central hypothyroidism has b e e n estimated to be greater than 99.9%. 22 In the c o s t - e f f e c t i v e n e s s analysis, the base estimate for TSH sensitivity is 99%, w i t h a range of 97% to 99.5% used in the sensitivity analysis. The base estimate for TSH specificity is 98%, similar to that o b t a i n e d in prior studies t, 23-25and consistent with standard laboratory test characteristics derived from " r e f e r e n c e " samples. However, d u e to a larger p r o p o r t i o n of borderline abnormal results, the specificity of this TSH cut-off m a y b e m u c h l o w e r in an exclu"in this analysis the T4-flrststrategy serves as a baseline with the marginal cost-effectiveness of the TSH-firststrategy calculated by comparison with it. The marginal cost-effectiveness of ordering both tests is calculated by comparison with the TSH-firststrategy. TABLE 1
Summary of Assumptions Baseline
Range
Test characteristic
T. Sensitivity Specificity TSH Sensitivity Specificity 3"4-I- TSH Sensitivity Specificity
0.93 0.68
0.80-0.95
0.99 0.98
0.97-0.995 0.93-0.98
1.00 1.00
Cost 1"4 TSH Additional
$26 $46 $0
Prevalenceof disease
2%
(0.2-0.6) X TSHcost
$40-$60 $0-$100
1%-5q,~
JOURNALOF GENERALINTERNALMEDICINE, VolumeS (January/February), 1990
11
Receiver Operator Characteristics
1.00
.....----------0 8 m
7
0.8O -
FIGURE 1. Thyroxine (1"4) test sensitivity versus ( 1 -specificity) in the diagnosis of hypothyroidism for T 4 cut-offs (listed in graph) between 4 and 8 /lg/dl (51.6 and 103.2 nmol/I).
0.60 > ~o tO 09
0.4O - 4
0.20-
0.00 0.00
I
I
0.20
I
I
I
0.40
I
0.60
I
I
0.80
I
1.00
1-Specificity
sively elderly population, w i t h estimates ranging from 80% to 99%. 14, 15, 26-28~. Therefore, TSH specificity was varied from 93% to 98% in the analysis to a c c o m m o d a t e varying p r o p o r t i o n s of elderly patients in a test p r i m a r y care population. 2:4 Test Characteristics. The characteristics of a T 4 test in identifying s y m p t o m a t i c hypothyroidism dep e n d on the diagnostic cut-off used. Goldstein and Mushlin 2 r e p o r t e d a sensitivity of 93% and a specificity of 81% using a cut-off of 7 g g / d l (90.3 nmol/1). The results of o u r receiver operating characteristic analysis revealed a similar sensitivity (93%) for this 374 cut-off, but a substantially l o w e r specificity of 68% + 3% (95% CI). This result is similar to the 69% specificity rep o r t e d to us b y Ciba-Corning (personal c o m m u n i c a tion) for the T4-radioimmunoassay utilized in this study. In this analysis, a T4 level of 7 ]/g/dl (90.3 n m o l / l ) was used as the cut-off for considering a patient to be potentially hypothyroid. The specificity of this T 4 cutoff, as indicated above, is estimated to b e 68%. The base estimate for sensitivity is 93%, b u t it was varied bet w e e n 80% and 95% in o u r sensitivity analysis. This range was used because o u r baseline estimate c a m e f r o m two studies w i t h very small sample sizes. This base estimate of 93% may be high due to the higher TSH threshold used as a gold standard in o u r study as w e l l as T4 results potentially biasing diagnostic categorization -~This tremendous variability may be due to differences in the age, sex, ethnicity, and health of the populations; the definition of and inquiry for symptoms; whether any follow-up was undertaken; and assay performance.
in the other study. 2 Test Costs. Charges for 374 and TSH determinations (not laboratory costs) w e r e obtained f r o m eight clinical laboratories in the m e t r o p o l i t a n Washington, D.C., area. Wide variations w e r e found, w i t h T4 charges ranging from $10 to $51 ( m e a n $26) and TSH charges f r o m $25 to $62 ( m e a n $46). In this analysis, the base estimates for T4 and TSH charges w e r e $26 and $46, r e s p e c t i v e l y (the m e a n charges in o u r area survey). In a sensitivity analysis, TSH charges w e r e varied f r o m $40 to $60 w h i l e T4 charges w e r e varied f r o m 20 to 60% of the charges for TSH (i.e., w h e n TSH charge = $40, T4 was varied f r o m $8 to $24). Additional Costs. Additional costs r e p r e s e n t miscellaneous costs for any additional tests and services (exclusive of thyroid function tests) d e e m e d necessary given the p a t i e n t ' s nonspecific symptoms. These costs w e r e assumed to b e the same regardless of w h i c h thyroid function test was ordered. They w e r e varied bet w e e n $ 0 (thereby isolating the cost of thyroid function tests alone) and $100 (incorporating o t h e r laboratory a n d / o r visit charges generated in the diagnostic process). A baseline estimate of $0 is used, thus including the thyroid function test costs alone in the analysis. Prevalence o f Hypothyroidism. Yields of hypothyroidism identifications in s y m p t o m a t i c adult prim a r y care patients s u s p e c t e d of this condition w e r e 2% in a p r i o r study ~ and 4% in a previous and smaller study. 2 In this analysis, the p r e v a l e n c e o f disease in the tested p o p u l a t i o n was varied b e t w e e n 1% and 5%, w i t h a base estimate of 2%.
12
SchectTnan, Paw/son, COST-EFFECTIVENESS
OF T E S T I N G
FOR HYPOTHYROIDISM
TABLE 2
Cost- Effectiveness Ratios of Three Tests Strategies for Hypothyroidism Under BaselineAssumptions Average Cost Per Patient Tested
Average Cost-Effectiveness Per Patient Tested
Average Cost-Effectiveness
T4-first
$41.28
0.0186
$2,219
$2,219
TSH-first
$47.02
0.0198
$2.375
$4,786
Both tests
$72.00
0.0200
$3,600
$124,878
Strategy
RESULTS Receiver Operating Characteristics Figure 1 displays the true-positive-versus-falsepositive rates of several T4 cut-offs in the diagnosis of
$50001
$4000] E O0)
c¢> $ > ~o -
both tests
$3000 t
Cost- Effectiveness Analysis
\
/ T4-first strategy
8
o
$1000-
$o .80
hypothyroidism, using a TSH > 5 mU/L above normal as the gold standard. The T4 cut-off of 7 gg/dl (90.3 nmol/1) is 93% sensitive (95% CI = 8 5 - 1 0 0 % ) and 68% specific (95% CI = 6 5 - 7 1 % ) in diagnosing the disease. Higher T4 levels are much less specific, while lower ones are substantially less sensitive. Varying the T4 cut-off utilized in the cost-effectiveness analysis (with resultant changes in test sensitivity and specificity as depicted in Figure 1) revealed that the chosen cut-off of 7 gg/dl (90.3 nmol/l) optimized c o s t effectiveness of the T4-first strategy.
TSH-fitst stralegy
$2000-
Marginal Cost-Effectiveness
I
I
I
I
I
.83
.86
.89
.92
.95
T4 Sensitivity
Table 2 compares the average and marginal c o s t effectiveness ratios of the three test strategies under baseline assumptions. The average cost-effectiveness of the TSH-first strategy is only $155 per case more than that of the T4-first approach. Therefore, using the T4first strategy would result in a savings of only 6.5%. The marginal cost- effectiveness of the TSH-first strategy is $4,786, or roughly $2,500 more than the average cost per case of the T4-first approach ($2,219).
FIGURE 2. Averagecost - effectivenessratios of three strategies as a function of thyroxine (T4) test sensitivity. TSH = thyroid-stimulating hormone.
$5000 ~~,~~... $4000==
$5000-
$4000
both tests
-
u) ¢/) ~) c-
O
o
< w
/
$3000-
Q) E
TSH-first strategy
/
T4-fL~st st ra~egy
O (O
TSH-first~/
both tests
T4-.~t
O
c)
$1000
.970
~
>..~-
\
$2000-
$3000-
strategy
$1000I
I
I
I
I
.975
.980
.985
.990
.995
TSH Sensitivity FIGURE 3. Averagecost- effectivenessratios ofthree strategies as a function of thyroid-stimulating hormone (TSH) test sensitivity. T4 = thyroxine.
$0 .01
I
I
I
I
.02
.03
.04
.05
Prevalence FIGURE 4. Averagecost - effectivenessratios of three strategies as a function of prevalenceof hypothyroidism among those tested. TSH = thyroid-stimulating hormone; T4 = thyroxine.
13
JOURNALOFGENERALINTERNALMEDICINE,Volume S (January/February), 1990
TABLE 3 Cost- Effectiveness Ratios of Three Test Strategies with Various Ratios of T4 to TSH Charges
Strategy
Ratio*
Cost
Effectiveness
Average Cost- Effectiveness
Marginal Cost- Effectiveness
T4-first TSH-first Both tests
0.2 0.2 0.2
$24.48 $46.36 $55.20
0.0186 0.0198 0.0200
$1,316 $2,342 $2,760
$1,316 $18,234 $44,188
T4-first TSH-first Both tests
0.4 0.4 0.4
$33.68 $46.73 $64.40
0.0186 0.0198 0.0200
$1,811 $2,360 $3,220
$1,811 $10,870 $88,375
T4-first TSH-first Both tests
0.6 0.6 0.6
$42.88 $47.09 $73.60
0.0186 0.0198 0.0200
$2,305 $2,378 $3,680
$2,305 $3,505 $132,563
*This represents the ratio of T 4 tO TSH chargesand represents a variation in T 4 charge between $9.20 and 27.60 (ratio of 0.2-0.6) with a TSH charge = $46 (other assumptions remain at baseline).
The average cost-effectiveness of using the tests together is $1,225 per case (or 52%) more than that of the TSH-first strategy. Since the increase in case-finding effectiveness by ordering both tests is small (sensitivity increases from 0.99 to 1.0 u n d e r base assumptions), the marginal cost is very high ( $ 1 2 5 , 0 0 0 ) to detect each additional case. The marginal cost-effectiveness of ordering both tests remains high (minimum---$ 4 0 , 0 0 0 ) across the entire range of values tested in the sensitivity analysis. As the sensitivities of the two testing methods and the prevalence o f disease are varied (Figs. 2 - 4 ) , the T4-first strategy varies from 8% less costly per case diagnosed to 8% more costly per case than the TSH-first approach to testing. Reducing the TSH specificity from 98% to 93% increases the per-case savings achieved by the T4-first strategy only to 9% (from the 6.5% at baseline). Varying the test charges results in large changes in the relative c o s t - effectiveness ratios of the two testing approaches. At the base estimate of $46 for TSH charge, as T4 charge declines from 60% ( $ 2 7 . 6 0 ) to 20% that of TSH ($ 9.20), the average c o s t - effectiveness of the T4first strategy changes from 3% to 44% less costly than the TSH-first testing strategy per case of hypothyroidism diagnosed (Table 3). Across the same range of T4 charges ( $ 2 7 . 6 0 to $9.20), the marginal c o s t effectiveness of the TSH-first strategy increases from $3,500 to $18,000 per additional hypothyroid case discovered. As shown in Figure 5, w h e n TSH charge is varied from $40 to $60, the marginal cost-effectiveness ratios of the TSH-first and T4-first strategies are similar at a T~ charge of 60% that of TSH, but the TSH-first marginal cost-effectiveness increases linearly as the ratio ofT4 to TSH test charges decreases. At a test charge ratio of 20% (i.e., T4 charges, $ 8 - $12; TSH, $ 4 0 - $60), the marginal cost-effectiveness of the TSH-first strategy varies from $16,000 to $24,000.
$25,000- -- TSH charge $40 TSH charge $60
$20,000o) c
.~
~
TSH-first strategy
$15,000$10,000-
0
o
$5,000$0 0.2
!
013
o14
I
0.5
o;
Ratio T4/TSH Cost FIGURE 5. Marginal cost-effectiveness of thyroid-stimulating hormone (TSH)-first strategy versus thyroxine (T4)-first strategy as a function of the ratio of T4 charge to TSH charge for fixed TSH chargesof $40 and $60 (other base assumptions unchanged).
Table 4 illustrates the effects of including miscellaneous additional costs among the case-finding costs. As such costs increase equally for all strategies, the differences in cost b e t w e e n the T~-first and TSH-first strategies remain constant at $ 5.74 u n d e r our baseline assumptions. However, the ratio of total T4-first costs to TSH-first costs approaches the ratio of T4-first effectiveness to TSH-first effectiveness w h e n additional costs equal about $50. At the point w h e r e the ratio of total costs equals the ratio o f effectiveness of the two strategies, the methods are o f equal c o s t - effectiveness.
DISCUSSION This analysis reveals that the c o m m o n clinical practice of ordering both a T4 test and a TSH test as o p p o s e d to a single test w h e n hypothyroidism is susp e c t e d results in a high marginal cost for each of the few additional hypothyroid patients thus identified.
14
Schectman. Paw~son, CoST-EFFECTIVENESSOF TESTING FOR HYFOTHYROIDISM TABLE 4
Cost- EffectivenessRatios of Three Test Strategies with VariousAdditionalCosts
Strategy
Other Charges*
Cost
Effectiveness
Average Cost- Effectiveness
Marginal Cost- Effectiveness
T4-first TSH-flrst Both~sts
$0 $0 $0
$41.28 $47.02 $72.00
0.0186 0.0198 0.0200
$2,219 $2.375 $3.600
$2.219 $4,786 $124.878
T4-first TSH-first Both ~sts
$50 $50 $50
$91.28 $97.02 $122.00
0.0186 0.0198 0.0200
$4.908 $4.900 $6,100
$4.908 $4.786 $124.878
T4-first TSH-first B~h ~sts
$100 $100 $100
$141.28 $147.02 $172.00
0.0186 0.0198 0.0200
$7.596 $7.42B $8.600
$7.596 $4,786 $124,878
*This representsthe cost of any additionaltests (besidesthyroid function tests) and servicesdeemed necessary.
These costs are on the order of $ 1 0 0 , 0 0 0 for each additional case of hypothyroidism detected. This estimate is p r o b a b l y conservative given that the analysis was biased in favor of this testing strategy b y assuming perfect sensitivity and specificity. Furthermore, patients with central hypothyroidism w h o are missed in a TSHfirst strategy are likely to have other findings leading to diagnosis. On the other hand, the relative c o s t - e f f e c t i v e n e s s of an initial T4 or TSH test is very d e p e n d e n t on analytic assumptions. As the T4 test charge falls (relative to that o f TSH), the marginal cost for each additional case diagnosed b y the TSH-first testing a p p r o a c h sharply rises. W h e n a c h e a p T4 test (costing o n l y 20% that o f the TSH) is available, this marginal cost for the TSH-first strategy is substantial ( $ 1 8 , 0 0 0 ) if other baseline ass u m p t i o n s hold true. However, the cost p e r case diagnosed b y each of the two testing strategies remains within 10% w h i l e o t h e r analytic assumptions are varied over reasonable ranges.;~ Several potential caveats a p p l y to this study. First, the test characteristics and cost assumptions utilized in the analysis are, of course, subject to dispute. However, most w e r e based on empirical studies or fairly well-acc e p t e d estimates. Second, w e based o u r analysis on index visit charges w i t h o u t consideration of the costs of f o l l o w - u p or treatment. But, if one assumes f o l l o w - u p and additional laboratory costs are similar for the T4first and TSH-first strategies, including such costs in the analysis favors the TSH-first a p p r o a c h (Table 4). Third, it was assumed that in the T4-first strategy, an algorithm for obtaining a TSH level w h e n T4 was b e l o w the diagnostic cut-off w o u l d incur no additional cost besides that of the TSH assay. Fourth, in the interests of simplicity and clarity, the unit of effectiveness e m p l o y e d was the diagnosis of disease. W e c o n s i d e r e d the advantages :~Evenunder an assumption of a very low TSHspecificity of 80% in a very elderly population, the T4-firststrategy is only 14% cheaper (assuming T4 test characteristics do not also change in the elderly).
of a m o r e c o m p l e x analysis to b e offset b y the n e e d for m a n y additional assumptions and estimates (such as the utility of early, delayed, or missed diagnosis and the probability and timing of s u b s e q u e n t diagnosis). By assigning no value to the diagnosis or misdiagnosis of hypothyroidism, w e have left this difficult task to the reader. Is an initial TSH justified if the marginal cost is $18,000 p e r additional case diagnosed? Is it w o r t h w h i l e to order b o t h tests together so as " n e v e r to miss the diagnosis" despite marginal costs of $ 1 0 0 , 0 0 0 p e r additional case found? The answers d e p e n d on the i m p o r t a n c e p l a c e d on patient symptoms, risks o f untreated hypothyroidism, and the likelihood of subseq u e n t diagnosis versus the i m p o r t a n c e b e s t o w e d on patient and health care system costs. At the health m a i n t e n a n c e organization in this study, a p p r o x i m a t e l y 500 patients p e r year are tested for hypothyroidism ( f r o m a total adult e n r o l l m e n t o f 2 5 , 0 0 0 ) . Under o u r base assumptions, in ten years of such testing by the TSH-first a p p r o a c h ( 5 , 0 0 0 patients tested), one case of hypothyroidism w o u l d b e missed. By ordering T4 and TSH tests together, missing this case c o u i d be avoided at a cost of $ 1 2 5 , 0 0 0 in added laboratory expenses (a 50% higher laboratory bill than w o u l d be generated b y the TSH-first a p p r o a c h ) . Given the l o w m o r b i d i t y and mortality of mild h y p o t h y r o i d i s m and likelihood of s u b s e q u e n t diagnosis in o u r setting, w e do not believe that the high marginal costs of the comb i n e d strategy are justified. In contrast, for the T4-first strategy, laboratory costs are 6.5% lower than for the TSH-first a p p r o a c h (a net savings of $28,700 o v e r ten years). However, this savings is at a cost o f six missed diagnoses m o r e than the TSH-first strategy. Furthermore, the marginal cost of roughly $4,800 p e r additional case diagnosed b y a TSH-first a p p r o a c h is not that m u c h greater than the average cost p e r case o f the T4-first strategy ( $ 2 , 2 0 0 using o u r base assumptions). Thus, the TSHofirst testing strategy a p p e a r s to b e the m o s t reasonable o n e in o u r setting.
JOURNALOFGENERALINTERNALMEDICINE.Volume5 (January/February), 1990
W e c o n c l u d e t h a t i n m o s t c i r c u m s t a n c e s , a TSHfirst t e s t i n g s t r a t e g y is p r e f e r a b l e d u e t o i t s g r e a t e r s e n sitivity and relatively similar cost-effectiveness comp a r e d w i t h a T4-first a p p r o a c h . H o w e v e r , i n t h e s e t t i n g o f a l o w c o s t o f T~ t e s t i n g r e l a t i v e t o T S H t e s t i n g , t h e T4-first s t r a t e g y m a y b e p r e f e r r e d . T h e r o u t i n e o r d e r i n g of both tests together for suspicion of hypothyroidism i n a p r i m a r y c a r e s e t t i n g s h o u l d g e n e r a l l y b e discouraged on the basis of the very high marginal cost- effectiveness.
REFERENCES 1. SchectmanJM, Kallenberg GA, Shumacher RJ, Hirsch RP. Yield of hypothyroidism in symptomatic primary care patients. Arch Intern Med. 1989;149:861-4. 2. Goldstein BJ, Mushlin AI. Use of a single thyroxine test to evaluate ambulatory medical patients for suspected hypothyroidism. J Gen Intern Med. 1987;2:20-4. 3. Sawin CT. Hypothyroidism. Med Clin North Am. 1985;695: 989-1005. 4. Caldwell G, Kellett HA, Gow SM, et al. A new strategy for thyroid function testing. Lancet. 1985;1:1117-9. 5. WoOdhead JS, Weeks I. Circulating thyrotropin as an index of thyroid function. Ann Clin Biochem. 1985;22:455-9. 6. Ridgeway EC. Thyrotropin radioimmunoassays: birth, life, and demise. Mayo Clin Proc. 1988;63:1028-34. 7. Toft AD. Use of sensitive immunoradiometric assay for thyrotropin in clinical practice, Mayo Clin Proc. 1988;63:1035-42. 8. NolanJP, Tarsa NJ, DiBenedettoG. Case-findingfor unsuspected thyroid disease: costs and health benefits. Am J Clin Pathol. 1985;83:346-55. 9. Cooper DS. Subclinical hypothyroidism. JAMA. 1987; 258:246-7. 10. Corns CM, Miller A. Evaluation of strategy for testing thyroid function applied to hypothyroidism. J Clin Pathol. 1986;39: 293-6. 11. Kumar MS, et al. The relationship of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) in pri-
15
mary thyroid failure. Am J Clin Pathol. 1977;68:747-51. 12. Wong ET, McCarron MM, Shaw ST. Ordering of laboratory tests in a teaching hospital. JAMA. 1983;249:3076-80. 13. de los Santos ET, Starich GH, Mazzaferri EL. Sensitivity, specificity, and cost-effectiveness of the sensitive thyrotropin assay in the diagnosis of thyroid disease in ambulatory patients. Arch Intern Med. 1989;149:526-32. 14. Nystrom E, et al. Thyroid disease and high concentration of serum thyrotropin in a population sample of women. Acta Med Scand. 1981;210:39-46. 15. Rosenthal MJ, et al. Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy.JAMA. 1987;258:209-47. 16. Tunbridge WMG, et al. Natural history of autoimmune thyroiditis. Br MedJ. 1981;282:258-62. 17. Sawin CT. Hypothyroidism. Med Clin North Am. 1985;69: 989-1004. 18. Capiferri R, Evered D. Investigation and treatment of hypothyroidism. Baillieres Clin Endocrinol Metab. 1979;8:39-48. 19. Evered DC, et al. Grades of hypothyroidism. Br Med J. 1973;1:657-62. 20. Evered DC, Hall R. Hypothyroidism: clinical endocrinology. Br MedJ. 1972;1:290-3. 21. Gorman CA. Thyroid function testing: a new era. Mayo Clin Proc. 1988;63:1026-7. 22. Hershman JM. Hypothalamic and pituitary hypothyroidism. In Bastenie PA, Bonnyns M, VanHaelst L (eds). Recent progress in diagnosis and treatment of hypothyroid conditions. Princeton, New Jersey: Excerpta Medica, 1980. 23. Caldwell G, et al. A new strategy for thyroid function testing. Lancet. 1985;1117-9. 24. Hopton MR, HarropJS. Immunoradiometric assay ofthyrotropin as a "first-line" thyroid-function test in the routine laboratory. Clin Chem. 1986;32:691-3. 25. Toft AD. Use of sensitive immunoradiometric assay for thyrotropin in clinical practice. Mayo Clin Proc. 1988;63:1035-42. 26. Heikoff LE, et al. Low yield of screening for hypothyroidism in healthy elderly. J Am Geriatr Soc. 1984;616-7. 27. Tunbridge WMG, et al. The spectrum of thyroid disease in a community: the Wickham Survey. J Clin Endocrinol. 1977;7: 481-93. 28. Sawin CT, et al. The aging thyroid: increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA. 1979;242:247-5.0.
sitive and specific for p r i m a r y hypothyroidism, is supp o r t e d b y s o m e , 37 w h i l e others favor a s e r u m thyroxine (T4) determination as the less costly initial test o f choice.2, S-ll However, in actual clinical practice, ordering the tests together (and often others as well) appears to b e the most c o m m o n strategy b y far. 2, t2 T w o studies have addressed the c o s t - e f f e c tiveness ratios of thyroid function testing strategies w h e n hypothyroidism is suspected. 2, 13 In one study, two strategies w e r e compared: ordering an initial TSH versus ordering an initial T4 f o l l o w e d b y a TSH only if the T4 w e r e b e l o w a certain cut-off level. The authors f o u n d that laboratory savings of 30% c o u l d b e achieved w i t h o u t a substantial sacrifice of diagnostic effectiveness b y using the T4-first strategy. 2 However, this savings estimate d e p e n d s on their specific assumptions regarding cost and test characteristics, as a sensitivity analysis was not reported. The second study c o m p a r e d the c o s t - e f f e c t i v e n e s s of an initial T 4 w i t h that of an initial TSH and c o n c l u d e d that "TSH may be most costeffective w h e n hypothyroidism is suspected. ''t3 However, evidence to s u p p o r t this statement was not provided. This r e p o r t first analyzes the sensitivity and specificity ofT4 in the diagnosis of hypothyroidism, and then incorporates this information into a c o s t - effectiveness analysis. Three diagnostic strategies for suspicion o f h y p o t h y r o i d i s m are c o m p a r e d : T4-first, TSH-first, and b o t h tests together. A sensitivity analysis on critical ass u m p t i o n s and estimates is also reported.
METHODS SYMPTOMS SUGGESTIVEof hypothyroidism are c o m m o n in p r i m a r y care practice and f r e q u e n t l y trigger thyroid function testing. Previous reports indicate that the yield of disease identification from such testing is l o w (in the range of 1 - 4%). 1. z Given the high f r e q u e n c y o f such s y m p t o m s and the l o w yield, a better understanding of the c o s t - e f f e c t i v e n e s s ratios of different diagnostic a p p r o a c h e s w o u l d be useful. The use of o n l y a thyroid-stimulating h o r m o n e (TSH) test, w h i c h is senReceived from the Department of Health Care Sciences, George Washington University Medical Center, Washington, DC. Presented in part at the 1 lth annual meeting of the Society of General Internal Medicine, April 29, 1988, Arlington, Virginia. Address correspondence and reprint requests to Dr. Schectman: Department of Health Care Sciences, George Washington University Medical Center, Washington, DC 20037.
Receiver Operating Characteristics The sensitivity and specificity of T4 w e r e determ i n e d using data collected f r o m a chart audit of consecutive patients for w h o m b o t h TSH and T4 determinations w e r e o r d e r e d for the suspicion of hypothyroidism b e t w e e n January 1985 and February 1987. To increase the sample size of patients w i t h elevated TSH (and thus the precision of the sensitivity estimates for T4), the record r e v i e w was e x t e n d e d to March 1988 for patients s u s p e c t e d of having hypothyroidism w h o w e r e f o u n d to have elevated TSH. Patients w h o had k n o w n histories of thyroid disease or w e r e taking medications k n o w n to affect thyroid function tests w e r e excluded. All patients w e r e p r i m a r y care patients from the adult practice of the D e p a r t m e n t of Health Care Sciences of George 9
10
SchectTnan. Paw/son. COST-EFFECTIVENESSOF TESTING FOR HYPOTHYROIDISM
Washington University, and nearly all w e r e enrolled in its staff m o d e l health m a i n t e n a n c e organization. For p u r p o s e s of calculating the sensitivity of 3"4 in the diagnosis of hypothyroidism, patients w e r e considered h y p o t h y r o i d if the TSH level was > 5 m U / L a b o v e the u p p e r normal limit. This cut-off was chosen as the " g o l d standard" because, in a p r i o r study, t 73% of patients w i t h only b o r d e r l i n e TSH elevations of 0 - 5 m U / L above normal w e r e found to have normal TSH levels w h e n tests w e r e s u b s e q u e n t l y r e p e a t e d (and the patients w e r e not felt to b e h y p o t h y r o i d b y their physicians). No patient w i t h a TSH above this cut-off had a normal repeat level and all w e r e clinically considered to be hypothyroid. Furthermore, other studies suggest that the majority of patients with a TSH above this or a similar cut-off go on to d e v e l o p overt h y p o t h y r o i d i s m within several years, even w h e n they are a s y m p t o m a t i c initially. 14-t6 The gold standard for the absence of hypothyroidism was a TSH level within normal limits. This is a w e l l - a c c e p t e d standard in regard to p r i m a r y hypothyroidismtT-2t; central hypothyroidism is so rare 22 that it is unlikely to affect this analysis. We identified a total of 31 patients w h o had simultaneous T 4 and TSH determinations w i t h the TSH > 5 m U / L above normal. These 3"4 TSH pairs w e r e used to calculate the sensitivities of various levels of T4 in the diagnosis of hypothyroidism. A total of 785 patients had simultaneous T4 and TSH determinations in w h i c h the TSH level was within normal limits. These T4/TSH pairs w e r e used to calculate the specificities of various T 4 levels in the diagnosis of hypothyroidism. Ninety-five p e r c e n t confidence intervals (CI) for the sensitivity and specificity estimates w e r e calculated using standard m e t h o d s for a binomial distribution.
Cost- Effectiveness Analysis MODEL
The three strategies c o m p a r e d were: ordering a T4 test first, ordering a TSH test first, and ordering these tests together. In o u r model, e a c h test result was initially categorized as normal or abnormal. W h e n o n l y one test was done initially, any a b n o r m a l result triggered the p e r f o r m a n c e of the o t h e r thyroid function test (i.e., if T4 w e r e b e l o w the specified diagnostic cutoff, a TSH test w o u l d automatically be done w i t h o u t requiring an additional patient visit). Each strategy's estimated sensitivity and specificity w e r e used to calculate its true/false-positive and true/false-negative rates. The strategy of initially obtaining b o t h T4 and TSH determinations was assigned 100% sensitivity and 100% specificity in order to bias the analysis in favor o f this m o r e conservative and p o p u l a r a p p r o a c h . Costs w e r e measured in dollars spent on the thyroid function tests alone, although additional costs w e r e considered in the sensitivity analysis. Effective-
ness was m e a s u r e d in terms of the n u m b e r o f hypothyroid cases identified. Decision-Maker 6.0 (© Pratt Associates) was used to p e r f o r m this analysis. The results of the c o s t - e f f e c t i v e n e s s analysis are r e p o r t e d in terms o f b o t h average and marginal c o s t effectiveness ratios. Average c o s t - e f f e c t i v e n e s s refers to the total costs divided b y the total effectiveness (as defined above) of a strategy. It thus represents the casefinding laboratory cost for hypothyroidism. Marginal c o s t - effectiveness c o m p a r e s one strategy w i t h another and represents the difference in costs divided b y the difference in effectivenesses of the two strategies." It thus represents the extra cost incurred to identify an additional case b y the m o r e sensitive b u t m o r e costly strategy. ASSUMPTIONS (TABLE 1)
TSH T e s t C h a r a c t e r i s t i c s . In the c o s t effectiveness analysis, a TSH level is considered abnormal w h e n it is above the u p p e r limit of normal o f the clinical laboratory. Using this criterion, the sensitivity of a TSH test in identifying s y m p t o m a t i c patients w i t h p r i m a r y hypothyroidism a p p r o a c h e s 100%, tT-2t w h i l e the p r o p o r t i o n of patients w i t h primary as o p p o s e d to central hypothyroidism has b e e n estimated to be greater than 99.9%. 22 In the c o s t - e f f e c t i v e n e s s analysis, the base estimate for TSH sensitivity is 99%, w i t h a range of 97% to 99.5% used in the sensitivity analysis. The base estimate for TSH specificity is 98%, similar to that o b t a i n e d in prior studies t, 23-25and consistent with standard laboratory test characteristics derived from " r e f e r e n c e " samples. However, d u e to a larger p r o p o r t i o n of borderline abnormal results, the specificity of this TSH cut-off m a y b e m u c h l o w e r in an exclu"in this analysis the T4-flrststrategy serves as a baseline with the marginal cost-effectiveness of the TSH-firststrategy calculated by comparison with it. The marginal cost-effectiveness of ordering both tests is calculated by comparison with the TSH-firststrategy. TABLE 1
Summary of Assumptions Baseline
Range
Test characteristic
T. Sensitivity Specificity TSH Sensitivity Specificity 3"4-I- TSH Sensitivity Specificity
0.93 0.68
0.80-0.95
0.99 0.98
0.97-0.995 0.93-0.98
1.00 1.00
Cost 1"4 TSH Additional
$26 $46 $0
Prevalenceof disease
2%
(0.2-0.6) X TSHcost
$40-$60 $0-$100
1%-5q,~
JOURNALOF GENERALINTERNALMEDICINE, VolumeS (January/February), 1990
11
Receiver Operator Characteristics
1.00
.....----------0 8 m
7
0.8O -
FIGURE 1. Thyroxine (1"4) test sensitivity versus ( 1 -specificity) in the diagnosis of hypothyroidism for T 4 cut-offs (listed in graph) between 4 and 8 /lg/dl (51.6 and 103.2 nmol/I).
0.60 > ~o tO 09
0.4O - 4
0.20-
0.00 0.00
I
I
0.20
I
I
I
0.40
I
0.60
I
I
0.80
I
1.00
1-Specificity
sively elderly population, w i t h estimates ranging from 80% to 99%. 14, 15, 26-28~. Therefore, TSH specificity was varied from 93% to 98% in the analysis to a c c o m m o d a t e varying p r o p o r t i o n s of elderly patients in a test p r i m a r y care population. 2:4 Test Characteristics. The characteristics of a T 4 test in identifying s y m p t o m a t i c hypothyroidism dep e n d on the diagnostic cut-off used. Goldstein and Mushlin 2 r e p o r t e d a sensitivity of 93% and a specificity of 81% using a cut-off of 7 g g / d l (90.3 nmol/1). The results of o u r receiver operating characteristic analysis revealed a similar sensitivity (93%) for this 374 cut-off, but a substantially l o w e r specificity of 68% + 3% (95% CI). This result is similar to the 69% specificity rep o r t e d to us b y Ciba-Corning (personal c o m m u n i c a tion) for the T4-radioimmunoassay utilized in this study. In this analysis, a T4 level of 7 ]/g/dl (90.3 n m o l / l ) was used as the cut-off for considering a patient to be potentially hypothyroid. The specificity of this T 4 cutoff, as indicated above, is estimated to b e 68%. The base estimate for sensitivity is 93%, b u t it was varied bet w e e n 80% and 95% in o u r sensitivity analysis. This range was used because o u r baseline estimate c a m e f r o m two studies w i t h very small sample sizes. This base estimate of 93% may be high due to the higher TSH threshold used as a gold standard in o u r study as w e l l as T4 results potentially biasing diagnostic categorization -~This tremendous variability may be due to differences in the age, sex, ethnicity, and health of the populations; the definition of and inquiry for symptoms; whether any follow-up was undertaken; and assay performance.
in the other study. 2 Test Costs. Charges for 374 and TSH determinations (not laboratory costs) w e r e obtained f r o m eight clinical laboratories in the m e t r o p o l i t a n Washington, D.C., area. Wide variations w e r e found, w i t h T4 charges ranging from $10 to $51 ( m e a n $26) and TSH charges f r o m $25 to $62 ( m e a n $46). In this analysis, the base estimates for T4 and TSH charges w e r e $26 and $46, r e s p e c t i v e l y (the m e a n charges in o u r area survey). In a sensitivity analysis, TSH charges w e r e varied f r o m $40 to $60 w h i l e T4 charges w e r e varied f r o m 20 to 60% of the charges for TSH (i.e., w h e n TSH charge = $40, T4 was varied f r o m $8 to $24). Additional Costs. Additional costs r e p r e s e n t miscellaneous costs for any additional tests and services (exclusive of thyroid function tests) d e e m e d necessary given the p a t i e n t ' s nonspecific symptoms. These costs w e r e assumed to b e the same regardless of w h i c h thyroid function test was ordered. They w e r e varied bet w e e n $ 0 (thereby isolating the cost of thyroid function tests alone) and $100 (incorporating o t h e r laboratory a n d / o r visit charges generated in the diagnostic process). A baseline estimate of $0 is used, thus including the thyroid function test costs alone in the analysis. Prevalence o f Hypothyroidism. Yields of hypothyroidism identifications in s y m p t o m a t i c adult prim a r y care patients s u s p e c t e d of this condition w e r e 2% in a p r i o r study ~ and 4% in a previous and smaller study. 2 In this analysis, the p r e v a l e n c e o f disease in the tested p o p u l a t i o n was varied b e t w e e n 1% and 5%, w i t h a base estimate of 2%.
12
SchectTnan, Paw/son, COST-EFFECTIVENESS
OF T E S T I N G
FOR HYPOTHYROIDISM
TABLE 2
Cost- Effectiveness Ratios of Three Tests Strategies for Hypothyroidism Under BaselineAssumptions Average Cost Per Patient Tested
Average Cost-Effectiveness Per Patient Tested
Average Cost-Effectiveness
T4-first
$41.28
0.0186
$2,219
$2,219
TSH-first
$47.02
0.0198
$2.375
$4,786
Both tests
$72.00
0.0200
$3,600
$124,878
Strategy
RESULTS Receiver Operating Characteristics Figure 1 displays the true-positive-versus-falsepositive rates of several T4 cut-offs in the diagnosis of
$50001
$4000] E O0)
c¢> $ > ~o -
both tests
$3000 t
Cost- Effectiveness Analysis
\
/ T4-first strategy
8
o
$1000-
$o .80
hypothyroidism, using a TSH > 5 mU/L above normal as the gold standard. The T4 cut-off of 7 gg/dl (90.3 nmol/1) is 93% sensitive (95% CI = 8 5 - 1 0 0 % ) and 68% specific (95% CI = 6 5 - 7 1 % ) in diagnosing the disease. Higher T4 levels are much less specific, while lower ones are substantially less sensitive. Varying the T4 cut-off utilized in the cost-effectiveness analysis (with resultant changes in test sensitivity and specificity as depicted in Figure 1) revealed that the chosen cut-off of 7 gg/dl (90.3 nmol/l) optimized c o s t effectiveness of the T4-first strategy.
TSH-fitst stralegy
$2000-
Marginal Cost-Effectiveness
I
I
I
I
I
.83
.86
.89
.92
.95
T4 Sensitivity
Table 2 compares the average and marginal c o s t effectiveness ratios of the three test strategies under baseline assumptions. The average cost-effectiveness of the TSH-first strategy is only $155 per case more than that of the T4-first approach. Therefore, using the T4first strategy would result in a savings of only 6.5%. The marginal cost- effectiveness of the TSH-first strategy is $4,786, or roughly $2,500 more than the average cost per case of the T4-first approach ($2,219).
FIGURE 2. Averagecost - effectivenessratios of three strategies as a function of thyroxine (T4) test sensitivity. TSH = thyroid-stimulating hormone.
$5000 ~~,~~... $4000==
$5000-
$4000
both tests
-
u) ¢/) ~) c-
O
o
< w
/
$3000-
Q) E
TSH-first strategy
/
T4-fL~st st ra~egy
O (O
TSH-first~/
both tests
T4-.~t
O
c)
$1000
.970
~
>..~-
\
$2000-
$3000-
strategy
$1000I
I
I
I
I
.975
.980
.985
.990
.995
TSH Sensitivity FIGURE 3. Averagecost- effectivenessratios ofthree strategies as a function of thyroid-stimulating hormone (TSH) test sensitivity. T4 = thyroxine.
$0 .01
I
I
I
I
.02
.03
.04
.05
Prevalence FIGURE 4. Averagecost - effectivenessratios of three strategies as a function of prevalenceof hypothyroidism among those tested. TSH = thyroid-stimulating hormone; T4 = thyroxine.
13
JOURNALOFGENERALINTERNALMEDICINE,Volume S (January/February), 1990
TABLE 3 Cost- Effectiveness Ratios of Three Test Strategies with Various Ratios of T4 to TSH Charges
Strategy
Ratio*
Cost
Effectiveness
Average Cost- Effectiveness
Marginal Cost- Effectiveness
T4-first TSH-first Both tests
0.2 0.2 0.2
$24.48 $46.36 $55.20
0.0186 0.0198 0.0200
$1,316 $2,342 $2,760
$1,316 $18,234 $44,188
T4-first TSH-first Both tests
0.4 0.4 0.4
$33.68 $46.73 $64.40
0.0186 0.0198 0.0200
$1,811 $2,360 $3,220
$1,811 $10,870 $88,375
T4-first TSH-first Both tests
0.6 0.6 0.6
$42.88 $47.09 $73.60
0.0186 0.0198 0.0200
$2,305 $2,378 $3,680
$2,305 $3,505 $132,563
*This represents the ratio of T 4 tO TSH chargesand represents a variation in T 4 charge between $9.20 and 27.60 (ratio of 0.2-0.6) with a TSH charge = $46 (other assumptions remain at baseline).
The average cost-effectiveness of using the tests together is $1,225 per case (or 52%) more than that of the TSH-first strategy. Since the increase in case-finding effectiveness by ordering both tests is small (sensitivity increases from 0.99 to 1.0 u n d e r base assumptions), the marginal cost is very high ( $ 1 2 5 , 0 0 0 ) to detect each additional case. The marginal cost-effectiveness of ordering both tests remains high (minimum---$ 4 0 , 0 0 0 ) across the entire range of values tested in the sensitivity analysis. As the sensitivities of the two testing methods and the prevalence o f disease are varied (Figs. 2 - 4 ) , the T4-first strategy varies from 8% less costly per case diagnosed to 8% more costly per case than the TSH-first approach to testing. Reducing the TSH specificity from 98% to 93% increases the per-case savings achieved by the T4-first strategy only to 9% (from the 6.5% at baseline). Varying the test charges results in large changes in the relative c o s t - effectiveness ratios of the two testing approaches. At the base estimate of $46 for TSH charge, as T4 charge declines from 60% ( $ 2 7 . 6 0 ) to 20% that of TSH ($ 9.20), the average c o s t - effectiveness of the T4first strategy changes from 3% to 44% less costly than the TSH-first testing strategy per case of hypothyroidism diagnosed (Table 3). Across the same range of T4 charges ( $ 2 7 . 6 0 to $9.20), the marginal c o s t effectiveness of the TSH-first strategy increases from $3,500 to $18,000 per additional hypothyroid case discovered. As shown in Figure 5, w h e n TSH charge is varied from $40 to $60, the marginal cost-effectiveness ratios of the TSH-first and T4-first strategies are similar at a T~ charge of 60% that of TSH, but the TSH-first marginal cost-effectiveness increases linearly as the ratio ofT4 to TSH test charges decreases. At a test charge ratio of 20% (i.e., T4 charges, $ 8 - $12; TSH, $ 4 0 - $60), the marginal cost-effectiveness of the TSH-first strategy varies from $16,000 to $24,000.
$25,000- -- TSH charge $40 TSH charge $60
$20,000o) c
.~
~
TSH-first strategy
$15,000$10,000-
0
o
$5,000$0 0.2
!
013
o14
I
0.5
o;
Ratio T4/TSH Cost FIGURE 5. Marginal cost-effectiveness of thyroid-stimulating hormone (TSH)-first strategy versus thyroxine (T4)-first strategy as a function of the ratio of T4 charge to TSH charge for fixed TSH chargesof $40 and $60 (other base assumptions unchanged).
Table 4 illustrates the effects of including miscellaneous additional costs among the case-finding costs. As such costs increase equally for all strategies, the differences in cost b e t w e e n the T~-first and TSH-first strategies remain constant at $ 5.74 u n d e r our baseline assumptions. However, the ratio of total T4-first costs to TSH-first costs approaches the ratio of T4-first effectiveness to TSH-first effectiveness w h e n additional costs equal about $50. At the point w h e r e the ratio of total costs equals the ratio o f effectiveness of the two strategies, the methods are o f equal c o s t - effectiveness.
DISCUSSION This analysis reveals that the c o m m o n clinical practice of ordering both a T4 test and a TSH test as o p p o s e d to a single test w h e n hypothyroidism is susp e c t e d results in a high marginal cost for each of the few additional hypothyroid patients thus identified.
14
Schectman. Paw~son, CoST-EFFECTIVENESSOF TESTING FOR HYFOTHYROIDISM TABLE 4
Cost- EffectivenessRatios of Three Test Strategies with VariousAdditionalCosts
Strategy
Other Charges*
Cost
Effectiveness
Average Cost- Effectiveness
Marginal Cost- Effectiveness
T4-first TSH-flrst Both~sts
$0 $0 $0
$41.28 $47.02 $72.00
0.0186 0.0198 0.0200
$2,219 $2.375 $3.600
$2.219 $4,786 $124.878
T4-first TSH-first Both ~sts
$50 $50 $50
$91.28 $97.02 $122.00
0.0186 0.0198 0.0200
$4.908 $4.900 $6,100
$4.908 $4.786 $124.878
T4-first TSH-first B~h ~sts
$100 $100 $100
$141.28 $147.02 $172.00
0.0186 0.0198 0.0200
$7.596 $7.42B $8.600
$7.596 $4,786 $124,878
*This representsthe cost of any additionaltests (besidesthyroid function tests) and servicesdeemed necessary.
These costs are on the order of $ 1 0 0 , 0 0 0 for each additional case of hypothyroidism detected. This estimate is p r o b a b l y conservative given that the analysis was biased in favor of this testing strategy b y assuming perfect sensitivity and specificity. Furthermore, patients with central hypothyroidism w h o are missed in a TSHfirst strategy are likely to have other findings leading to diagnosis. On the other hand, the relative c o s t - e f f e c t i v e n e s s of an initial T4 or TSH test is very d e p e n d e n t on analytic assumptions. As the T4 test charge falls (relative to that o f TSH), the marginal cost for each additional case diagnosed b y the TSH-first testing a p p r o a c h sharply rises. W h e n a c h e a p T4 test (costing o n l y 20% that o f the TSH) is available, this marginal cost for the TSH-first strategy is substantial ( $ 1 8 , 0 0 0 ) if other baseline ass u m p t i o n s hold true. However, the cost p e r case diagnosed b y each of the two testing strategies remains within 10% w h i l e o t h e r analytic assumptions are varied over reasonable ranges.;~ Several potential caveats a p p l y to this study. First, the test characteristics and cost assumptions utilized in the analysis are, of course, subject to dispute. However, most w e r e based on empirical studies or fairly well-acc e p t e d estimates. Second, w e based o u r analysis on index visit charges w i t h o u t consideration of the costs of f o l l o w - u p or treatment. But, if one assumes f o l l o w - u p and additional laboratory costs are similar for the T4first and TSH-first strategies, including such costs in the analysis favors the TSH-first a p p r o a c h (Table 4). Third, it was assumed that in the T4-first strategy, an algorithm for obtaining a TSH level w h e n T4 was b e l o w the diagnostic cut-off w o u l d incur no additional cost besides that of the TSH assay. Fourth, in the interests of simplicity and clarity, the unit of effectiveness e m p l o y e d was the diagnosis of disease. W e c o n s i d e r e d the advantages :~Evenunder an assumption of a very low TSHspecificity of 80% in a very elderly population, the T4-firststrategy is only 14% cheaper (assuming T4 test characteristics do not also change in the elderly).
of a m o r e c o m p l e x analysis to b e offset b y the n e e d for m a n y additional assumptions and estimates (such as the utility of early, delayed, or missed diagnosis and the probability and timing of s u b s e q u e n t diagnosis). By assigning no value to the diagnosis or misdiagnosis of hypothyroidism, w e have left this difficult task to the reader. Is an initial TSH justified if the marginal cost is $18,000 p e r additional case diagnosed? Is it w o r t h w h i l e to order b o t h tests together so as " n e v e r to miss the diagnosis" despite marginal costs of $ 1 0 0 , 0 0 0 p e r additional case found? The answers d e p e n d on the i m p o r t a n c e p l a c e d on patient symptoms, risks o f untreated hypothyroidism, and the likelihood of subseq u e n t diagnosis versus the i m p o r t a n c e b e s t o w e d on patient and health care system costs. At the health m a i n t e n a n c e organization in this study, a p p r o x i m a t e l y 500 patients p e r year are tested for hypothyroidism ( f r o m a total adult e n r o l l m e n t o f 2 5 , 0 0 0 ) . Under o u r base assumptions, in ten years of such testing by the TSH-first a p p r o a c h ( 5 , 0 0 0 patients tested), one case of hypothyroidism w o u l d b e missed. By ordering T4 and TSH tests together, missing this case c o u i d be avoided at a cost of $ 1 2 5 , 0 0 0 in added laboratory expenses (a 50% higher laboratory bill than w o u l d be generated b y the TSH-first a p p r o a c h ) . Given the l o w m o r b i d i t y and mortality of mild h y p o t h y r o i d i s m and likelihood of s u b s e q u e n t diagnosis in o u r setting, w e do not believe that the high marginal costs of the comb i n e d strategy are justified. In contrast, for the T4-first strategy, laboratory costs are 6.5% lower than for the TSH-first a p p r o a c h (a net savings of $28,700 o v e r ten years). However, this savings is at a cost o f six missed diagnoses m o r e than the TSH-first strategy. Furthermore, the marginal cost of roughly $4,800 p e r additional case diagnosed b y a TSH-first a p p r o a c h is not that m u c h greater than the average cost p e r case o f the T4-first strategy ( $ 2 , 2 0 0 using o u r base assumptions). Thus, the TSHofirst testing strategy a p p e a r s to b e the m o s t reasonable o n e in o u r setting.
JOURNALOFGENERALINTERNALMEDICINE.Volume5 (January/February), 1990
W e c o n c l u d e t h a t i n m o s t c i r c u m s t a n c e s , a TSHfirst t e s t i n g s t r a t e g y is p r e f e r a b l e d u e t o i t s g r e a t e r s e n sitivity and relatively similar cost-effectiveness comp a r e d w i t h a T4-first a p p r o a c h . H o w e v e r , i n t h e s e t t i n g o f a l o w c o s t o f T~ t e s t i n g r e l a t i v e t o T S H t e s t i n g , t h e T4-first s t r a t e g y m a y b e p r e f e r r e d . T h e r o u t i n e o r d e r i n g of both tests together for suspicion of hypothyroidism i n a p r i m a r y c a r e s e t t i n g s h o u l d g e n e r a l l y b e discouraged on the basis of the very high marginal cost- effectiveness.
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