a zebra is not always a zebra and a zero is not always a zero

2
LETTERS TO THE EDITOR onstrate normal defecation dynamics on follow-up (2). Therefore, the high clinical relapse rate and the low recovery rate are not explained by a high rate of physiologic relapse (2, 4). It appears, that chronic constipation with encopresis results from an intricate weave of a number of primary, secondary, physical, and psychological factors. As pointed out in our publication, there may be benefits from biofeedback treatment that cannot be measured by evaluating recovery rates (1). Biofeed- back-treated patients may achieve all of their treat- ment gains quicker than conventionally treated pa- tients, and the benefit may be reduction of symptoms such as less laborious defecation or fewer and lower laxative dosages, rather than complete recovery. I hope that my publication (1) and the comments by Dr. Wald will bring about further randomized studies in order to clarify the contribution of biofeedback training to the treatment of chronic constipation, encopresis, and abnormal defecation dynamics in children. VERA LOENING-BAUCKE, M D University of Iowa Iowa City, Iowa REFERENCES 1. Loening-Baucke V: Biofeedback training in children with func- tional constipation: A critical review. Dig Dis Sci 41:65-71, 1996 2. Loening-Baucke V: Modulation of abnormal defecation dynam- ics by biofeedback treatment in chronically constipated children with encopresis. J Pediatr 116:214-222, 1990 3. Loening-Baucke V: Persistence of chronic constipation in chil- dren after biofeedback treatment. Dig Dis Sci 36:153-160, 1991 4. Loening-Baucke V: Biofeedback treatment for chronic consti- pation and encopresis in childhood: Longterm outcome. Pedi- atrics 96:105-110, 1995 5. Wald A, Chandra R, Gabel S, Chiponis D: Evaluation of biofeedback in childhood encopresis. J Pediatr Gastroenterol Nutr 6:554-558, 1987 6. Cox DJ, Sutphen J, Borowitz S, Dickens MN, Singles J, White- head WE: Simple electromyographic biofeedback treatment for chronic pediatric constipation/encopresis: Preliminary report. Biofeedback Self Regul 19:41-50, 1994 7. Nolan T, Catto-Smith A, Coffey C, Wells J: EMG biofeedback training in anismus-related encopresis does not produce sus- tained continence. Arch Pediatr Adolesc Med 149:48A, 1995 A ZEBRA IS NOT ALWAYS A ZEBRA AND A ZERO IS NOT ALWAYS A ZERO To The Editor: Valdimarsson et al, in their paper on suspected celiac disease and IgA anti-endomysium antibodies (IgA EmA), maintain that they have a 100% positive predictive value for celiac disease in adults (1). After correctly defining sensitivity, specificity, and positive and negative predictive value in the Materials and Methods section they proceed by suggesting that "small bowel biopsy is not necessary to diagnose celiac disease in symptomatic adults with IgA EmA" and "IgA EmA are useful when selecting adult pa- tients for further investigation of suspected celiac disease." Their conclusions are based on a group of 144 symptomatic patients who underwent small bowel biopsy, where 19 had biopsy-verified celiac disease. Bayes theorem (2) emphasizes that the probability of disease--conditional upon a positive outcome of the test--depends on both how characteristic the symptoms are of the disease and how frequent the condition is among the people in question. Valdimarsson et al state that the positive predictive value (diagnostic sensitivity) is 100% since none of the 125 persons without celiac disease had a titer of IgA EmA at or above 1:10. The sensitivity (nosologic sensitivity) was 78%. A specificity (nosologic specific- ity) of 100% for IgAEmA is in accordance with other studies (3-5). They further say that in a population with a lower prevalence of celiac disease, the negative predictive value will be higher. Depending on various selection mechanisms, the prevalence of celiac dis- ease will most probably vary considerably among dif- ferent populations. According to the estimates by Valdimarsson et al, the prevalence of symptomatic celiac disease among adults in their catchment area is 0.2%. In their highly selected patient group, the prev- alence of celiac disease was 13%. As a screening method in a population with a prevalence of, let us say, 5%, the negative predictive value will be 98%, and with a prevalence of 10% it will be 95%. However, the authors do not discuss the problem of a lower positive predictive value during the same conditions. They do not give us the uncertainty of their observation of a zero in the nondiseased/test- positive group or confidence limits for the zero be- hind the 100% specificity, which are of some interest, since even a small change in specificity will have consequences for the predictive values and especially so if the actual prevalence lies more to the stated population prevalence of 0.2%. The 95% confidence interval for a point estimate of an observation of a zero in a group of 125 goes from 0 to roughly 3 (6). By changing the zero for a 3 (ie, the "worst case") in the calculations of the authors, the positive predictive value will be 85% and the negative predictive value 95%. Most probably this confidence interval is an underestimate, since we have not taken Digestive Diseases and Sciences, Vol. 41, No. 8 (August 1996) 1655

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LETTERS TO THE EDITOR

onstrate normal defecation dynamics on follow-up (2). Therefore, the high clinical relapse rate and the low recovery rate are not explained by a high rate of physiologic relapse (2, 4). It appears, that chronic constipation with encopresis results from an intricate weave of a number of primary, secondary, physical, and psychological factors.

As pointed out in our publication, there may be benefits from biofeedback treatment that cannot be measured by evaluating recovery rates (1). Biofeed- back-treated patients may achieve all of their treat- ment gains quicker than conventionally treated pa- tients, and the benefit may be reduction of symptoms such as less laborious defecation or fewer and lower laxative dosages, rather than complete recovery. I hope that my publication (1) and the comments by Dr. Wald will bring about further randomized studies in order to clarify the contribution of biofeedback training to the treatment of chronic constipation, encopresis, and abnormal defecation dynamics in children.

VERA LOENING-BAUCKE, M D

University of Iowa Iowa City, Iowa

REFERENCES

1. Loening-Baucke V: Biofeedback training in children with func- tional constipation: A critical review. Dig Dis Sci 41:65-71, 1996

2. Loening-Baucke V: Modulation of abnormal defecation dynam- ics by biofeedback treatment in chronically constipated children with encopresis. J Pediatr 116:214-222, 1990

3. Loening-Baucke V: Persistence of chronic constipation in chil- dren after biofeedback treatment. Dig Dis Sci 36:153-160, 1991

4. Loening-Baucke V: Biofeedback treatment for chronic consti- pation and encopresis in childhood: Longterm outcome. Pedi- atrics 96:105-110, 1995

5. Wald A, Chandra R, Gabel S, Chiponis D: Evaluation of biofeedback in childhood encopresis. J Pediatr Gastroenterol Nutr 6:554-558, 1987

6. Cox D J, Sutphen J, Borowitz S, Dickens MN, Singles J, White- head WE: Simple electromyographic biofeedback treatment for chronic pediatric constipation/encopresis: Preliminary report. Biofeedback Self Regul 19:41-50, 1994

7. Nolan T, Catto-Smith A, Coffey C, Wells J: EMG biofeedback training in anismus-related encopresis does not produce sus- tained continence. Arch Pediatr Adolesc Med 149:48A, 1995

A ZEBRA IS NOT ALWAYS A ZEBRA AND A ZERO IS NOT ALWAYS A ZERO

To The Editor: Valdimarsson et al, in their paper on suspected

celiac disease and IgA anti-endomysium antibodies (IgA EmA), maintain that they have a 100% positive predictive value for celiac disease in adults (1). After

correctly defining sensitivity, specificity, and positive and negative predictive value in the Materials and Methods section they proceed by suggesting that "small bowel biopsy is not necessary to diagnose celiac disease in symptomatic adults with IgA EmA" and "IgA EmA are useful when selecting adult pa- tients for further investigation of suspected celiac disease." Their conclusions are based on a group of 144 symptomatic patients who underwent small bowel biopsy, where 19 had biopsy-verified celiac disease.

Bayes theorem (2) emphasizes that the probability of disease--conditional upon a positive outcome of the test--depends on both how characteristic the symptoms are of the disease and how frequent the condition is among the people in question.

Valdimarsson et al state that the positive predictive value (diagnostic sensitivity) is 100% since none of the 125 persons without celiac disease had a titer of IgA EmA at or above 1:10. The sensitivity (nosologic sensitivity) was 78%. A specificity (nosologic specific- ity) of 100% for IgAEmA is in accordance with other studies (3-5). They further say that in a population with a lower prevalence of celiac disease, the negative predictive value will be higher. Depending on various selection mechanisms, the prevalence of celiac dis- ease will most probably vary considerably among dif- ferent populations. According to the estimates by Valdimarsson et al, the prevalence of symptomatic celiac disease among adults in their catchment area is 0.2%. In their highly selected patient group, the prev- alence of celiac disease was 13%. As a screening method in a population with a prevalence of, let us say, 5%, the negative predictive value will be 98%, and with a prevalence of 10% it will be 95%.

However, the authors do not discuss the problem of a lower positive predictive value during the same conditions. They do not give us the uncertainty of their observation of a zero in the nondiseased/test- positive group or confidence limits for the zero be- hind the 100% specificity, which are of some interest, since even a small change in specificity will have consequences for the predictive values and especially so if the actual prevalence lies more to the stated population prevalence of 0.2%.

The 95% confidence interval for a point estimate of an observation of a zero in a group of 125 goes from 0 to roughly 3 (6). By changing the zero for a 3 (ie, the "worst case") in the calculations of the authors, the positive predictive value will be 85% and the negative predictive value 95%. Most probably this confidence interval is an underestimate, since we have not taken

Digestive Diseases and Sciences, Vol. 41, No. 8 (August 1996) 1655

LETTERS TO THE EDITOR

the uncertainties of the numbers in all the cells of the fourfold table into consideration.

What is the probability of disease provided the test is positive and of nondisease if it is negative? Many investigators believe that these probabilities may be obtained merely from a horizontal interpretation of a fourfold table. The problem is that the numbers are contrived by the investigator. The nosological proba- bilities will remain constant, but the predictive values will not. The greater the proportion of controls to cases, the more influential are the false positive out- comes.

In a population of 1000 individuals with a hypo- thetical 2% disease prevalence (sensitivity 78% and specificity 97%, as above) the positive predictive value will be 34%, ie, 66 of 100 positive IgA EmA patients will get lifelong unnecessary dietary restric- tions when a small bowel biopsy would not have shown any pathological signs. Also at the core of the matter lies the clinical impression that celiac disease in adults in comparison to children often gives very vague and imprecise symptoms.

From the patient perspective it is of interest how many really diseased are missed and how many are biopsied unnecessarily. The suggested procedure by Valdimarsson et al does not seem to help too much in either way. Of the 144 patients who came to their clinic, they propose to refrain from biopsy in 19, who really have celiac disease. The other 125 will need a biopsy for a differential diagnosis due to their IgAEmA test having a sensitivity of only 78%.

In the end it seems as if by side-stepping the international criteria for a celiac disease diagnosis (7), Valdimarsson et al through their suggested diagnostic procedure risk estrangement from the scientific dis- course on celiac disease.

INGELA KRANTZ, MD PHD PER NORDIN, MScI

HANS WEDEL, PROFESSOR

Nordic School of Public Health GOteborg, Sweden

SVANTE BLOMSTRAND, MD Department of Pediatrics,

Bor~s Hospital, Bor~s, Sweden

HENRY ASCHER, MD, PHD

Department of Pediatrics GOteborg University

GOtebot~,, Sweden

REFERENCES

1. Valdimarsson T, Franz6n L, Grodzinsky E, Skogh T, StrOm M: ls small bowel biopsy necessary in adults with suspected celiac disease and IgA anti-endomysium antibodies? 100% positive predictive value for celiac disease in adults. Dig Dis Sci 41(1):83-87, 1996

2. Feinstein AR: Clinical Epidemiology. The Architecture of Clin- ical Research. Philadelphia, WB Saunders, 1985

3. McMillan SA, Haughton D J, Biggart JD, Edgar JD, Porter KG, McNeill TA: Predictive value for coeliac disease of antibodies to gliadin, endomysium, and jejunum in patients attending for jejunal biopsy. BMJ 303:1163-1165, 1991

4. Grodzinsky E, Hed J, Skogh T: IgA-anti-endomysial antibodies have a high positive predictive value for celiac disease in asymp- tomatic patients. Allergy 49:593-597, 1994

5. Ascher H, Hahn-Zoric M, Hanson L~, Kilander AF, Nilsson L~,, Tlaskov,'i H: Value of serological markers for clinical diag- nosis and population studies of coeliac disease. Scand J Gastro- enterol 31:61-67, 1996

6. Documenta Geigy. Scientific Tables. Diem K, Lentner C (eds). Basle, Ciba-Geigy Limited, 1975

7. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling Visakorpi JK: Revised criteria for diagnosis of coeliac disease. Arch Dis Child 65:909-911, 1990

Response by Dr. Valdimarsson: Krantz et al are correct to note the uncertainty of

our observation of a zero in the false positive group (non-diseased/test-positive group). In the hypotheti- cal case of a 95% confidence interval of 0-3 and the "worst case" with three false positive cases out of 125, the positive predictive value would decrease.

To lower the 95% confidence limits below 1 or 0.5, when the specificity is 100% the number of subjects in the test group would have to be 400 or 800, respec- tively (1). However, many others have also reported a specificity of 100% for IgA anti-endomysium antibod- ies (IgA EmA) (2-7). Furthermore, cases with a nor- mal biopsy and a positive test for IgA EmA at pre- sentation have turned out to develop mucosal atrophy later on (8).

With lower disease prevalence, the positive predic- tive value would be lower. In our population of symp- tomatic patients with a clinical suspicion of celiac disease and with the high disease prevalence of 13%, the influence of a possible false positive case is smaller.

We do not suggest that a positive IgA EmA test should replace the small bowel biopsy when screening unselected populations with a low disease prevalence or in subjects with vague or no symptoms. We do, however, suggest that a positive IgA EmA test could replace the invasive small bowel biopsy in adults with a clinical suspicion of celiac disease. On the other hand, in a case with high clinical suspicion of celiac

1656 Digestive Diseases and Sciences, Vol. 41, No. 8 (August 1996)