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LABORATORY DATA AND DIAGNOSIS
267 the organisation of such endoalveolar necrotic debris, by cells from the alveolar walls, with final formation of fibrosclerotic endoalveolar plugs, were observed (fig. 3). The lung vessels were constantly affected by lesions of perivascular and endovascular type, with parietal foci of fibrinoid necrosis, and many showed fibrohaemorrhagic thrombosis of the lumen. These pulmonary findings are similar to those observed in patients with the so-called collagen diseases, or with radiation pneumonitis.11-14 However, none of these diseases was present in our case, while the type of vascular lesions and the composition of the septal infiltrates exclude the possibility of urxmic, viral, or parasitic origin of the pulmonary alterations. Consequently it is likely that our findings were caused by the homotransplant as a result of the antigenic similarity between kidney and lung and, particularly, between the basal membranes of these organs.15 16 V. TISON Institute of Pathology, G. BARUZZI. Bologna University.
LABORATORY DATA AND DIAGNOSIS SIR,-It is usual to regard laboratory measurements on patients as normal if they lie inside, and suspicious if they lie outside, the 95% confidence limits determined for a healthy population. While this procedure serves well, in practice, to aid detection of disease, the use of such confidence limits presents a logical difficulty. The limits do establish, by their definition, the small probability (P=0-05) that an individual, known to be healthy, would have a measurement lying outside those limits. For diagnosis, however, a different probability is required-namely, the probability that a patient, known to have an outlying measurement is, none the less, healthy. If laboratory data are to be helpful in diagnosis, this second probability must be small and a necesary condition is derived below. Consider some measurement made on members of a population known to be healthy. For portion A of the population (see accompanying figure) the values of the measurements would lie within the 95% confidence limits, and for portion B they would lie outside; A will equal 19B. Consider now a population known to have a particular illness which can be recognised by the magnitude of the above measurement. For that measurement to have diagnostic value the majority of persons with the illness must give a value lying outside the 95% confidence limits determined for healthy individuals; let this portion be D. The remainder (C) of ill persons will have a measurement lying within the 95% confidence limits (determined for a healthy
population). For a mixed population of ill and healthy individuals B + D would have a measurement lying outside the 95% confidence limits. Thus the probability that an individual, with an outlying measurement, would be healthy is given by B/(B+D) and this can be written as:
In the mixed population the ratio of ill persons to those who are would be given by (D+C)/(A+B). Since B is smaller than A, and C smaller than D, this ratio is approximately equal to D/A. Thus P, the probability that a person with an outlying measurement is healthy, is related to the ratio of ill to healthy persons. This is demonstrated below. Measurements of protein-bound iodine, reported by Crooks et al.,’ can be expressed, in terms of the above diagram, as A=36, B=2, C=1, D=52. Thus B/(B+D) is 1/27. In the population studied the ratio of those with thyrotoxicosis to those without was found to be 1-4. When this value for D/A is used to calculate P the value obtained is 1/25, in close agreement with the first value. For a
Proportions of 95% confidence limits.
population with
a smaller ratio (0-75) of persons with thyrotoxicosis, be 1/12, in close agreement with the value 1/ 11-5 for B/(B+D). As the ratio of ill to healthy persons, in the population submitted for a laboratory test, is increased by prior selection on clinical grounds, the diagnostic value of that test increases (i.e., P decreases). Thus, far from being partisan, the values of clinical diagnoses and laboratory measurements depend upon one another in an important and fundamental way.
P was
found
to
When, in a population submitted to a laboratory test, the number of persons with an illness equals the number of healthy persons, p is approximately 1/20. For most medical purposes this value is sufficiently low. Selection on clinical grounds can
readily produce a suspected population of which at least 50% a particular disease, and results of subsequent laboratory tests on such a population can be assessed satisfactorily in terms of the 95% confidence limits for a healthy population. These limits would not be satisfactory for screening populations. There the ratio D/A would be small, and P correspondingly large. In such a case it would be necessary to choose different confidence limits and achieve a compromise between the sensitivity of a test (C/[C--Dj) and its specificity (A/[A+B]). have
Department of Statistics, University of Aberdeen, Old Aberdeen.
GORDON HEMS.
ACTION OF PHENOBARBITONE IN PREECLAMPSIA have SIR,—I suggested that a high blood-progesterone level due to inadequate inactivation of the hormone in the liver may be an important factor in the aetiology of pre-eclamptic toxaemia of pregnancy. Recently, attention has been drawn to the action of phenobarbitone in stimulating the hepatic inactivation or conjugation of several compounds, notably bilirubin.2 Phenobarbitone is one of the very few methods of treatment of preeclampsia which is found useful and is employed by most obstetricians. Its efficacy is always attributed to its sedative properties. However, I wonder whether part of its action may be the facilitation of hepatic inactivation of progesterone. Hexham General Hospital, Hexham, D. F. HORROBIN. Northumberland.
healthy
12. Hume, D. M. The Kidney; p. 409. Baltimore, 1966. 13. Mancini, A. M., Tison, V., Baruzzi, G., Ferracini, R. Archo ital. Anat. Istol. patolo. 1967, 41, 3. 14. Mancini, A. M., Tison, V. Unpublished. 15. Read, J. J. Path. Bact. 1958, 76, 403. 16. Seegal, B. L., Hasson, M. W., Gaynor, E. C., Rothenberg, M. S. J. exp. Med. 1955, 102, 789. 17. Crooks, J., Murray, I. P. C., Wayne, E. J. Q. Jl Med. 1959, 28, 211.
ANÆSTHETIC DEATHS AND THE SICKLE-CELL TRAIT SIR,-Every now and then a previously reasonably well Ghanaian dies in a British hospital during or soon after a nottoo-major surgical operation. The morbid anatomist may report " cerebral thrombosis " as cause of death. One wonders how many of these deaths are due to sludging of sickled cells during short periods of hypoxia and hypotension. There is a widespread mistaken notion that persons with the sickle-cell trait (AS genotype) are resistant to stress. Nothing is further from the truth, for, given the appropriate (or rather inappropriate) change in the internal environment, persons with 1. 2.
Horrobin, D. F. Lancet, 1968, i, 170. Trolle, D. ibid. p. 251; ibid. 1968, ii, 705. Thompson, R. P. H. Eddleston, A. L. W. F., Williams, R. ibid. Jan. 4, 1969, p. 21.
LABORATORY DATA AND DIAGNOSIS SIR,-It is usual to regard laboratory measurements on patients as normal if they lie inside, and suspicious if they lie outside, the 95% confidence limits determined for a healthy population. While this procedure serves well, in practice, to aid detection of disease, the use of such confidence limits presents a logical difficulty. The limits do establish, by their definition, the small probability (P=0-05) that an individual, known to be healthy, would have a measurement lying outside those limits. For diagnosis, however, a different probability is required-namely, the probability that a patient, known to have an outlying measurement is, none the less, healthy. If laboratory data are to be helpful in diagnosis, this second probability must be small and a necesary condition is derived below. Consider some measurement made on members of a population known to be healthy. For portion A of the population (see accompanying figure) the values of the measurements would lie within the 95% confidence limits, and for portion B they would lie outside; A will equal 19B. Consider now a population known to have a particular illness which can be recognised by the magnitude of the above measurement. For that measurement to have diagnostic value the majority of persons with the illness must give a value lying outside the 95% confidence limits determined for healthy individuals; let this portion be D. The remainder (C) of ill persons will have a measurement lying within the 95% confidence limits (determined for a healthy
population). For a mixed population of ill and healthy individuals B + D would have a measurement lying outside the 95% confidence limits. Thus the probability that an individual, with an outlying measurement, would be healthy is given by B/(B+D) and this can be written as:
In the mixed population the ratio of ill persons to those who are would be given by (D+C)/(A+B). Since B is smaller than A, and C smaller than D, this ratio is approximately equal to D/A. Thus P, the probability that a person with an outlying measurement is healthy, is related to the ratio of ill to healthy persons. This is demonstrated below. Measurements of protein-bound iodine, reported by Crooks et al.,’ can be expressed, in terms of the above diagram, as A=36, B=2, C=1, D=52. Thus B/(B+D) is 1/27. In the population studied the ratio of those with thyrotoxicosis to those without was found to be 1-4. When this value for D/A is used to calculate P the value obtained is 1/25, in close agreement with the first value. For a
Proportions of 95% confidence limits.
population with
a smaller ratio (0-75) of persons with thyrotoxicosis, be 1/12, in close agreement with the value 1/ 11-5 for B/(B+D). As the ratio of ill to healthy persons, in the population submitted for a laboratory test, is increased by prior selection on clinical grounds, the diagnostic value of that test increases (i.e., P decreases). Thus, far from being partisan, the values of clinical diagnoses and laboratory measurements depend upon one another in an important and fundamental way.
P was
found
to
When, in a population submitted to a laboratory test, the number of persons with an illness equals the number of healthy persons, p is approximately 1/20. For most medical purposes this value is sufficiently low. Selection on clinical grounds can
readily produce a suspected population of which at least 50% a particular disease, and results of subsequent laboratory tests on such a population can be assessed satisfactorily in terms of the 95% confidence limits for a healthy population. These limits would not be satisfactory for screening populations. There the ratio D/A would be small, and P correspondingly large. In such a case it would be necessary to choose different confidence limits and achieve a compromise between the sensitivity of a test (C/[C--Dj) and its specificity (A/[A+B]). have
Department of Statistics, University of Aberdeen, Old Aberdeen.
GORDON HEMS.
ACTION OF PHENOBARBITONE IN PREECLAMPSIA have SIR,—I suggested that a high blood-progesterone level due to inadequate inactivation of the hormone in the liver may be an important factor in the aetiology of pre-eclamptic toxaemia of pregnancy. Recently, attention has been drawn to the action of phenobarbitone in stimulating the hepatic inactivation or conjugation of several compounds, notably bilirubin.2 Phenobarbitone is one of the very few methods of treatment of preeclampsia which is found useful and is employed by most obstetricians. Its efficacy is always attributed to its sedative properties. However, I wonder whether part of its action may be the facilitation of hepatic inactivation of progesterone. Hexham General Hospital, Hexham, D. F. HORROBIN. Northumberland.
healthy
12. Hume, D. M. The Kidney; p. 409. Baltimore, 1966. 13. Mancini, A. M., Tison, V., Baruzzi, G., Ferracini, R. Archo ital. Anat. Istol. patolo. 1967, 41, 3. 14. Mancini, A. M., Tison, V. Unpublished. 15. Read, J. J. Path. Bact. 1958, 76, 403. 16. Seegal, B. L., Hasson, M. W., Gaynor, E. C., Rothenberg, M. S. J. exp. Med. 1955, 102, 789. 17. Crooks, J., Murray, I. P. C., Wayne, E. J. Q. Jl Med. 1959, 28, 211.
ANÆSTHETIC DEATHS AND THE SICKLE-CELL TRAIT SIR,-Every now and then a previously reasonably well Ghanaian dies in a British hospital during or soon after a nottoo-major surgical operation. The morbid anatomist may report " cerebral thrombosis " as cause of death. One wonders how many of these deaths are due to sludging of sickled cells during short periods of hypoxia and hypotension. There is a widespread mistaken notion that persons with the sickle-cell trait (AS genotype) are resistant to stress. Nothing is further from the truth, for, given the appropriate (or rather inappropriate) change in the internal environment, persons with 1. 2.
Horrobin, D. F. Lancet, 1968, i, 170. Trolle, D. ibid. p. 251; ibid. 1968, ii, 705. Thompson, R. P. H. Eddleston, A. L. W. F., Williams, R. ibid. Jan. 4, 1969, p. 21.