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LABORATORY DATA AND DIAGNOSIS
531 A HOMOZYGOUS CHROMOSOMAL VARIANT SIR,-In the course of cytological investigations in cases of mental subnormality, a patient, aged 14 years, with Klinefelter’s syndrome and 47/XXY chromosome complement was consistently found to have a satellited no. 17. His unrelated parents, whose karyotypes were otherwise normal, showed precisely similar satellites on one no. 17. The patient has two normal sisters; the karyotype of the elder showed satellites on both members of the no. 17 pair, and that of the younger showed them on neither (see accompanying figure).
Pedigree of satellited
no.
17 chromosomes.
All cultures were of leucocytes from blood, and satellite association with a no. 17 chromosome was not observed. This family may represent the first demonstration of a human chromosomal structural variant in homozygous form. The incidence of carriers of a large satellite on no. 17 (or no. 18), in the general population, was estimated at 1/250 by Court Brown et al.,! so that the homozygote has an expected frequency of about 1/250,000. There is no evidence that the presence of a satellited chromosome of this type causes any abnormality. The present family indicates that even in homozygous form it is harmless, and that its association with Klinefelter’s syndrome is fortuitous.
J.
M. B. and L. S. P.
are
in
receipt of
grants from the Medical
Research Council-
J. M. BERG JANET A. FAUNCH Kennedy-Galton Centre for Mental Retardation Research and Diagnosis, Harperbury Hospital Harper Lane, nr. St. Albans, Hertfordshire.
MADELEINE J. PENDREY L. S. PENROSE M. A. C. RIDLER A. SHAPIRO.
VIRAL TRANSFORMATION OF CELLS SIR,-The paper by Dr. Miller and Dr. Todaro (Jan. 11, p. 81) and the accompanying annotation (p. 87) remind us of some largely unpublished observations on the sensitivity of fibroblasts to virus infection, as estimated by cytopathic changes, which we made about 8 years ago at the department of bacteriology, University of Lund. Skin fibroblasts were cultivated in vitro from five legal abortions (karyotype 46 in all cases), one adult patient with Turner’s syndrome (karyotype 45), and two adults2 with Klinefelter’s syndrome (one karyotype 47, and one 47,48 mosaic with 48 chromosomes in every seventh mitotic figure). The cells were grown out on slides as previously described.3 The passage numbers of the cell cultures were 1-9 for the foetuses and 12-24 for the adult cells in the present experiments. For each experiment several slides from three individuals were inoculated with either adenovirus type 7 or poliomyelitis virus type 3. After different times, the slides were harvested, fixed, and stained, and examined under the light microscope. The
1. Court
numbers of cells, per 1000, with specific cytopathic changes were recorded. In four experiments with adenovirus, the slides from the patients with Klinefelter’s syndrome showed a 5-10-times higher rate of virus-attacked cells than the slides from the foetuses. In two experiments with poliomyelitis virus, the same ratio was up to 100. In two experiments with fibroblasts, inoculated with adenovirus, the rate of virus-attacked cells was 10-fold lower in the Turner’s syndrome patient than in the foetuses. In all experiments the fibroblasts with higher chromosome number were thus more sensitive to virus attack than those with lower number. However, no conclusions can be drawn from such a small series. Factors other than the karyotype may also have been of importance, such as the age of the individuals, and the in-vitro-passage number of the cells, which was throughout lower for the foetuses. The results may still be of importance in view of Dr. Miller and Dr. Todaro’s results, and discussions on the possibly increased risk of malignancy in patients with Klinefelter’s syndrome.4 UNNE STENRAM Department of Pathology, INGRID STENRAM. University of Uppsala, Sweden. Department of Clinical Bacteriology, SVEN BERGMAN. University of Umeå, Sweden.
Brown, W. M., Buckton, K. E., Jacobs, P. A., Tough, I. M., Kuenssberg, E. V., Knox, J. D. E. Chromosome Studies on Adults. Eugenics Laboratory Memoirs 42. London, 1966. 2. Nowakowski, H., Lenz, W., Bergman, S., Reitalu, J. Acta endocrinol., Copenh. 1960, 34, 483. 3. Bergman, S., Stenram, I., Stenram, U. Acta path. microbiol. scand. 1963, 58, 141.
LABORATORY DATA AND DIAGNOSIS
SIR,-When assessing the significance of laboratory results, it is certainly necessary to take into account the frequency of the disease suspected in the population under study. As Professor Dudley remarks (Feb. 15, p. 373), Dr. Hems’ (Feb. 1, p. 267) contribution to the problem is esentially Bayesian. Vecchio5 has provided a similar analysis. It may be helpful to express the approach in more explicitly Bayesian terms, incorporating a modification in the form of reporting laboratory results already suggested.s Suppose information is available about the mean and standard deviations of a given variable, S, in two groupsa group with the disease, Di, and the group consisting of the remainder of the population, D2. Then the Bayes formula enables us to express the probability of the disease Dl being present when a given value of S is observed, P(D1/S).7 Thus,
Similarly, the probability of the observation S group without the disease, P(D2/S), would be:
arising
in the
where P(Di)=incidence of disease Du P(D2)==incidence of non-disease D2, P(SjD1)=probability of observation S in disease D, and P(SjD2)=probability of observation S in absence of disease D. P(SjD1) and P(SjD2) may easily be obtained as values of probability density from tables of the normal curve. This task would be made simpler if all laboratory results were expressed in terms of units of standard deviation from the mean, both of the population with the disease suspected and of the population without it. With automatic analysers and automatic cell counters generating data at increasing rates it ought not to take long for the statistics required for most common diseases to accumulate. Moreover, if a record were kept with each measurement of the corresponding clinical diagnoses, the various P(D);)s could also be calculated quite quickly. As it is, we have to rely on tables of " normal values " obtained from a different laboratory, by a different method, at a different time, and from a different population. This seems to me to extend the intuitive capacity of the clinician to an unreasonable and unnecessary extent. G. H. HALL. Exeter, Devon. Fraumeni, J. F., Jr., Miller, R. W. J. natn. Cancer Inst. 1967, 38, 593. Vecchio, T. J. New Engl. J. Med., 1966, 274, 1171. Hall, G. H. Lancet, 1967, i, 1329. Campbell, D. G., Owen, J. A. ibid. 1967, ii, 256. 7. Hall, G. H. ibid. 1967, ii, 555.
4. 5. 6.
Pedigree of satellited
no.
17 chromosomes.
All cultures were of leucocytes from blood, and satellite association with a no. 17 chromosome was not observed. This family may represent the first demonstration of a human chromosomal structural variant in homozygous form. The incidence of carriers of a large satellite on no. 17 (or no. 18), in the general population, was estimated at 1/250 by Court Brown et al.,! so that the homozygote has an expected frequency of about 1/250,000. There is no evidence that the presence of a satellited chromosome of this type causes any abnormality. The present family indicates that even in homozygous form it is harmless, and that its association with Klinefelter’s syndrome is fortuitous.
J.
M. B. and L. S. P.
are
in
receipt of
grants from the Medical
Research Council-
J. M. BERG JANET A. FAUNCH Kennedy-Galton Centre for Mental Retardation Research and Diagnosis, Harperbury Hospital Harper Lane, nr. St. Albans, Hertfordshire.
MADELEINE J. PENDREY L. S. PENROSE M. A. C. RIDLER A. SHAPIRO.
VIRAL TRANSFORMATION OF CELLS SIR,-The paper by Dr. Miller and Dr. Todaro (Jan. 11, p. 81) and the accompanying annotation (p. 87) remind us of some largely unpublished observations on the sensitivity of fibroblasts to virus infection, as estimated by cytopathic changes, which we made about 8 years ago at the department of bacteriology, University of Lund. Skin fibroblasts were cultivated in vitro from five legal abortions (karyotype 46 in all cases), one adult patient with Turner’s syndrome (karyotype 45), and two adults2 with Klinefelter’s syndrome (one karyotype 47, and one 47,48 mosaic with 48 chromosomes in every seventh mitotic figure). The cells were grown out on slides as previously described.3 The passage numbers of the cell cultures were 1-9 for the foetuses and 12-24 for the adult cells in the present experiments. For each experiment several slides from three individuals were inoculated with either adenovirus type 7 or poliomyelitis virus type 3. After different times, the slides were harvested, fixed, and stained, and examined under the light microscope. The
1. Court
numbers of cells, per 1000, with specific cytopathic changes were recorded. In four experiments with adenovirus, the slides from the patients with Klinefelter’s syndrome showed a 5-10-times higher rate of virus-attacked cells than the slides from the foetuses. In two experiments with poliomyelitis virus, the same ratio was up to 100. In two experiments with fibroblasts, inoculated with adenovirus, the rate of virus-attacked cells was 10-fold lower in the Turner’s syndrome patient than in the foetuses. In all experiments the fibroblasts with higher chromosome number were thus more sensitive to virus attack than those with lower number. However, no conclusions can be drawn from such a small series. Factors other than the karyotype may also have been of importance, such as the age of the individuals, and the in-vitro-passage number of the cells, which was throughout lower for the foetuses. The results may still be of importance in view of Dr. Miller and Dr. Todaro’s results, and discussions on the possibly increased risk of malignancy in patients with Klinefelter’s syndrome.4 UNNE STENRAM Department of Pathology, INGRID STENRAM. University of Uppsala, Sweden. Department of Clinical Bacteriology, SVEN BERGMAN. University of Umeå, Sweden.
Brown, W. M., Buckton, K. E., Jacobs, P. A., Tough, I. M., Kuenssberg, E. V., Knox, J. D. E. Chromosome Studies on Adults. Eugenics Laboratory Memoirs 42. London, 1966. 2. Nowakowski, H., Lenz, W., Bergman, S., Reitalu, J. Acta endocrinol., Copenh. 1960, 34, 483. 3. Bergman, S., Stenram, I., Stenram, U. Acta path. microbiol. scand. 1963, 58, 141.
LABORATORY DATA AND DIAGNOSIS
SIR,-When assessing the significance of laboratory results, it is certainly necessary to take into account the frequency of the disease suspected in the population under study. As Professor Dudley remarks (Feb. 15, p. 373), Dr. Hems’ (Feb. 1, p. 267) contribution to the problem is esentially Bayesian. Vecchio5 has provided a similar analysis. It may be helpful to express the approach in more explicitly Bayesian terms, incorporating a modification in the form of reporting laboratory results already suggested.s Suppose information is available about the mean and standard deviations of a given variable, S, in two groupsa group with the disease, Di, and the group consisting of the remainder of the population, D2. Then the Bayes formula enables us to express the probability of the disease Dl being present when a given value of S is observed, P(D1/S).7 Thus,
Similarly, the probability of the observation S group without the disease, P(D2/S), would be:
arising
in the
where P(Di)=incidence of disease Du P(D2)==incidence of non-disease D2, P(SjD1)=probability of observation S in disease D, and P(SjD2)=probability of observation S in absence of disease D. P(SjD1) and P(SjD2) may easily be obtained as values of probability density from tables of the normal curve. This task would be made simpler if all laboratory results were expressed in terms of units of standard deviation from the mean, both of the population with the disease suspected and of the population without it. With automatic analysers and automatic cell counters generating data at increasing rates it ought not to take long for the statistics required for most common diseases to accumulate. Moreover, if a record were kept with each measurement of the corresponding clinical diagnoses, the various P(D);)s could also be calculated quite quickly. As it is, we have to rely on tables of " normal values " obtained from a different laboratory, by a different method, at a different time, and from a different population. This seems to me to extend the intuitive capacity of the clinician to an unreasonable and unnecessary extent. G. H. HALL. Exeter, Devon. Fraumeni, J. F., Jr., Miller, R. W. J. natn. Cancer Inst. 1967, 38, 593. Vecchio, T. J. New Engl. J. Med., 1966, 274, 1171. Hall, G. H. Lancet, 1967, i, 1329. Campbell, D. G., Owen, J. A. ibid. 1967, ii, 256. 7. Hall, G. H. ibid. 1967, ii, 555.
4. 5. 6.