A C T A O P H T H A L M O L O G I C A VOL. 5 4 1 9 7 6
From the Dalby Health Service Research Centre, (Head: Ake Nordkn) and The Department of Experimental Ophthalmology (Head: C . E. T . Krakau), Universitetet, Lund
RESEMBLANCE BETWEEN TONOMETER READINGS ON RELATIVES AND SPOUSES BY
BO BENGTSSON
The resemblance between tonometer readings on relatives and spouses was studied in a material derived from a population survey and consisting of 1042 unique individuals forming 365 nuclear families and 1333 pairs divided into groups with different sex-composition and type of connection. Persons in whom glaucoma was suspected were excluded. The general level of resemblance in the present study was similar to that in previous studies. Differences between groups with different sex-composition conformed to a pattern expected from environmental effects. The resemblance between husbands and their wives was highly significant and of the same order of magnitude as that in relatives sharing a common genetic background. W e concluded that a common environment contributes materially to the resemblance between tonometer readings on relatives. The possibility of a cumulative environmental effect was suggested by an increase in resemblance with age.
Key words: population study - intraocular pressure - applanation tonometry - inheritance - environment.
Armaly (1965, 1966, 1967) and Armaly et al. (1968) reported that the ocular pressure level is genetically determined in the normal eye. Levene et al. (1970) considered themselves able to confirm a significant heritability for ocular tenReceived September 18, 1975.
27
Bo Bengtsson sion. A comparison between the results of Levene et al. and those of A r m a l y
et al. was alleged, however, to indicate a disparity - possibly reflecting a t r u e difference in heritability between different populations w i t h different environments. T h e present study of the resemblance between tonometer readings o n first degree relatives therefore seemed appropriate a s p a r t of an attempt to assess different source of variation in a n a t i v e population.
The phenotypic (=total”) variance Vp of a metric (“quantitative”) character P is usually regarded as consisting of separate causal components (“effects”) Vp.,, Vp,, Vp.M etc. attributable to sources of variation (“factors”) K, L, M etc. with variances V,c, V,, V,, etc. of their own. The effects of mutually uncorrelated factors are additive: vp = v p . g + Vp.1. + vp.M . . . . Interactions can usually be removed by suitable transformations of scale and will not be discussed further.
A simple regression analysis suffices to determine the linear effect Vp.hI of a measurable factor M which is uncorrelated to other sources of variation. v p . =~ bzp,IV,, = r2pMVp (b = regression coefficient; r = correlation coefficient).
A multiple regression analysis is needed to assess the combined effect Vp measurable but mutually correlated sources of variation.
of several
VP p x p = R2V,~ (R = multiple correlation coefficient). Many sources of variation are themselves inaccessible to measurement. Their effects can, nevertheless, be revealed by simple measurements of phenotypic values - provided that it is possible to divide the population into groups consisting of individuals independently inferred to be equally influenced by the factor under consideration. The members of such groups covariate, i. e. the variance between such groups is larger and within groups smaller - than expected from pure chance. In theory the covariance of phenotypic values would be equal to the effect of the concealed factor. In practice, however, the grouping of the population can seldom be made totally independent of all pertinent factors but one. In accordance with the method chosen to divide the population into groups, causal components therefore have to be estimated in a more indirect way, which requires knowing how they contribute to the covariance. The covariance of relatives, for instance, is composed of effects caused by dominance and common environment as well as of additive genetic effects. covpsiblingpsibling = Vp covpoffspringpparent= VP
+ LVp add env +
tv~
+ 1/4 V , ( I , , , ~ ~ ccIl
In a population divided into pairs, rather than larger groups, a simple regression analysis is, again, the method of choice. It should be appreciated, however, that this time the regression (or correlation -) coefficient itself - not its square - should be used to determine the effect of the common sources of variation. covpdeppindep = bVpindep = r VVpindep Vpdep
28
I.O.P. on Relatives and
Sfiouses
The covariance is in fact often expressed as a proportion of the phenotypic variance, that is as the regression (or correlation -) coefficient. Within our own species this type of analysis is performed intuitively - resulting in an instantaneous recognition of the phenomenon known as resemblance between similarly affected persons, e. g. relatives.
Material The material was derived from a general ophthalmic population survey, which was carried out at the Dalby Health Centre in southern Sweden from March 1969 to April 1970. Invitations with a brief questionnaire were mailed in rotation, following a directory, to all persons aged 8 years or more, who had been resident in the village surrounding the Health Centre since December 1968. Out of 1917 persons invited, 1702 (88.80/0) took part in the study. Information about persons who failed to turn up or in whom the examination was incomplete has been given in earlier reports (Bengtsson 1972a,b, 1973). Twenty cases subject to antiglaucomatous treatment, lesions in the anterior chamber angle, active uveitis or glaucomatous field defects were excluded from the present study. Th e official identification numbers of the eldest sibling and the eldest child of each person were requested in the questionnaire and orally verified at the examination. (In Sweden every inhabitant has his own “person number” consisting of ten figurcs - birth date, birth number and control number - and more or less universally used for the purpose of identification in all types of official registers.) Using those data 365 nuclear family groups consisting of 1042 unique
Table I . Number of families with different compositions
Type of family
Mother, father and offspring Mother and offspring Father and offspring Siblings
117 40 19 -
29
Number of children 2 3 4
5
70 21 8 49
1 0 0 0
23 3 2 7
3 2 0 0
Bo Bengtsson individuals w e r e (subsequently) assembled and pairs of first degree relatives and spouses constructed as detailed later. The composition of families is shown in Table I. Serological verification of the different types of first degree relations was not attempted. The method used here to establish different kinds of kinship is of course not infallible but was deliberately chosen because it was practical. In half sibships one of the two full sibships was only referred to the joint parent and the second full sibships only to the other parent. In such cases the fact that the parents had children in common was obscured. It is also possible that a few halfsibs have been registered as full sibs, even if the children in the older full sibship often retained their original surname when following their mother into a second marriage. The degree of interrelationship, on the other hand, has been underestimated in monozygotic twins and persons with multiple relationships. A previous very comprehensive study (EssenMoller 1967) of familial interrelatedness and consanguinity in a population partly identical with the present one, admits of the conclusion that errors caused by the concise registration of relatives are few and therefore of little or no consequence. In comparison with collection of data pertaining to ancestors the present procedure has several advantages that are worth mentioning. It is easier for parents to state the identification numbers of their children than vice versa. Involvement of persons not alive and/or not investigated was minimized. Discussions of illegitimacy were avoided. It was possible to abbreviate the procedure for people lacking children and/or siblings. It should be appreciated that one person may be a member of two nuclear family groups andlor may appear both as child and sibling in one of those (Table 11). Three, six or ten pairs of siblings can be formed in families with three, four or five children.
Age and sex distributions are given in Table 111. Table tion of applanation pressures in the present material.
IV shows the distribu-
Table II. Types of first degree relationships formed by 1042 unique individuals Type of relation
Number of individuals
Parent Child Sibling Parent and child Parent and sibling Child and sibling Parent, child and sibling
440 158 66 18 53 295 12
30
I.O.P.on Relatives and Spouses Table 111. Age and sex distributions
36 124 34 13 11 4 1 0 0 0
25 99 45 16 14 10 11 6 I 0
17 93 27 11 16 8 9 15 3 0
44 129 64 84 89 54 44 10 3 0
38 125 46 105 90 53 32 23 8
0
9 98 85 46 25 11 5 1
43 127 58 20 6 5 1 0 0 0
243
280
260
223
227
199
521
521
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
0 0 0 68 84 48 36 5
Total Meanage
2
47.8
0 0
45.7
18.4
18.3
24.7
27.9
33.3
1
34.9
Methods Visual acuity, ophthalmometry, slit lamp examination, Goldmann tonometry, Schiotz tonometry, sphygmomanometric measurements of the systemic blood pressure, ophthalmoscopy in mydriasis, subjective refraction in cycloplegia and fundus photography were attempted in every case. Conventional equipment was used according to a fixed program. The applanation tonometry was performed by the author using a Goldmann tonometer mounted on a Haag Streit 900 slit lamp. The tonometer was tested at PTB in Berlin and found to be completely devoid of demonstrable errors in the pertinent pressure range. (For method, see Jessen 1969.) The right eye was always measured first, the instrument was read to the nearest millimeter and the first reliable reading was recorded. The arithmetic mean of the Goldmann readings on the two eyes was used to represent the intraocular pressure of the individual. All data were immediately codified and recorded on special forms. Transfer 31
Bo Bengtsson
the computer centre i n Lund. The analysis was carried out with a s t a n d a r d computer program -
to punch cards and further processing were performed at
SPSS.
ResuIts Several different final methods of analysis have been reported in earlier studies. Initially we used both “crude” pressure readings and “corrected” pressures (Bengtsson 1972a). In both cases we calculated covariances and coefficients of regression as well as correlation coefficients.
Table IV. Distribution of Goldmann readings
Goldmann readings
Number of individuals Right eye
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Total
Left eye
1 0 1 7 18 36 70 134 153 150 157 131 97 41 24 16 1 1 2 0 0 1 1
1 0 0 7 15 38 61 133 157 146 154 131 101 49 29 17 1 1 0 1 0 0 0
1042
1042
32
I.O.P. on Relatives and Sflouses “Correction” of applanation pressures did not affect the results significantly or systematically and was therefore omitted. In quantitative genetics the degree of resemblance between relatives is eventually used to predict the outcome of selective breeding. In this situation parameters relating the covariance to the variance of potential parents of future offspring - i. e. heritability and/or coefficient of regression - are the natural choice. For a more descriptive purpose, like the present one, the coefficient of correlation was considered to be equally adequate and more generally known as well as being more easily understood. In order to make different correlation coefficients directly comparable, constructed variables such as the pressure of “midparents” and -mean children“ were avoided. All pairs therefore consisted of two individuals. The part of the independent member of a pair was always assigned to the older relative and to the male spouse. Estimates of probabilities that observed correlation coefficients have arisen by chance were obtained from the standard computer program (SPSS). In Fig. 1 the standard deviations were calculated according to the convention that SD of r = (l-rz)/Vn if the value of n is large and the value of r is small.
Pair members independent
Number of pairs dependent
SDOf
SDOf
indep. var.
dep. var.
Correlation coefficient
mother mother father father
daughter son daughter son
21 1 23 1 165 219
2.37 2.39 2.57 2.61
2.35 2.24 2.30 2.19
0.15 ( P = 0.27 ( P 0.05 (P = 0.18 (P =
sister brother sibling
sister brother sibling of the other sex
64 85 144
2.47 2.38 2.35
2.32 2.28 2.28
0.41 ( P 0.001) 0.24 (P = 0.012) 0.10 (P = 0.121)
sibling
sibling of the same sex
149
2.50
2.30
0.33 ( P
mother father
offspring off spring
442 384
2.38 2.59
2.31 2.27
0.20 ( P 0.001) 0.12 (P = 0.010)
parent sibling husband
offspring sibling wife
826 293 214
2.50 2.42 2.53
2.29 2.29 2.45
0.16 ( P 0.22 (P 0.22 ( P
0.013)
< 0.001) 0.263) 0.003)
From the Dalby Health Service Research Centre, (Head: Ake Nordkn) and The Department of Experimental Ophthalmology (Head: C . E. T . Krakau), Universitetet, Lund
RESEMBLANCE BETWEEN TONOMETER READINGS ON RELATIVES AND SPOUSES BY
BO BENGTSSON
The resemblance between tonometer readings on relatives and spouses was studied in a material derived from a population survey and consisting of 1042 unique individuals forming 365 nuclear families and 1333 pairs divided into groups with different sex-composition and type of connection. Persons in whom glaucoma was suspected were excluded. The general level of resemblance in the present study was similar to that in previous studies. Differences between groups with different sex-composition conformed to a pattern expected from environmental effects. The resemblance between husbands and their wives was highly significant and of the same order of magnitude as that in relatives sharing a common genetic background. W e concluded that a common environment contributes materially to the resemblance between tonometer readings on relatives. The possibility of a cumulative environmental effect was suggested by an increase in resemblance with age.
Key words: population study - intraocular pressure - applanation tonometry - inheritance - environment.
Armaly (1965, 1966, 1967) and Armaly et al. (1968) reported that the ocular pressure level is genetically determined in the normal eye. Levene et al. (1970) considered themselves able to confirm a significant heritability for ocular tenReceived September 18, 1975.
27
Bo Bengtsson sion. A comparison between the results of Levene et al. and those of A r m a l y
et al. was alleged, however, to indicate a disparity - possibly reflecting a t r u e difference in heritability between different populations w i t h different environments. T h e present study of the resemblance between tonometer readings o n first degree relatives therefore seemed appropriate a s p a r t of an attempt to assess different source of variation in a n a t i v e population.
The phenotypic (=total”) variance Vp of a metric (“quantitative”) character P is usually regarded as consisting of separate causal components (“effects”) Vp.,, Vp,, Vp.M etc. attributable to sources of variation (“factors”) K, L, M etc. with variances V,c, V,, V,, etc. of their own. The effects of mutually uncorrelated factors are additive: vp = v p . g + Vp.1. + vp.M . . . . Interactions can usually be removed by suitable transformations of scale and will not be discussed further.
A simple regression analysis suffices to determine the linear effect Vp.hI of a measurable factor M which is uncorrelated to other sources of variation. v p . =~ bzp,IV,, = r2pMVp (b = regression coefficient; r = correlation coefficient).
A multiple regression analysis is needed to assess the combined effect Vp measurable but mutually correlated sources of variation.
of several
VP p x p = R2V,~ (R = multiple correlation coefficient). Many sources of variation are themselves inaccessible to measurement. Their effects can, nevertheless, be revealed by simple measurements of phenotypic values - provided that it is possible to divide the population into groups consisting of individuals independently inferred to be equally influenced by the factor under consideration. The members of such groups covariate, i. e. the variance between such groups is larger and within groups smaller - than expected from pure chance. In theory the covariance of phenotypic values would be equal to the effect of the concealed factor. In practice, however, the grouping of the population can seldom be made totally independent of all pertinent factors but one. In accordance with the method chosen to divide the population into groups, causal components therefore have to be estimated in a more indirect way, which requires knowing how they contribute to the covariance. The covariance of relatives, for instance, is composed of effects caused by dominance and common environment as well as of additive genetic effects. covpsiblingpsibling = Vp covpoffspringpparent= VP
+ LVp add env +
tv~
+ 1/4 V , ( I , , , ~ ~ ccIl
In a population divided into pairs, rather than larger groups, a simple regression analysis is, again, the method of choice. It should be appreciated, however, that this time the regression (or correlation -) coefficient itself - not its square - should be used to determine the effect of the common sources of variation. covpdeppindep = bVpindep = r VVpindep Vpdep
28
I.O.P. on Relatives and
Sfiouses
The covariance is in fact often expressed as a proportion of the phenotypic variance, that is as the regression (or correlation -) coefficient. Within our own species this type of analysis is performed intuitively - resulting in an instantaneous recognition of the phenomenon known as resemblance between similarly affected persons, e. g. relatives.
Material The material was derived from a general ophthalmic population survey, which was carried out at the Dalby Health Centre in southern Sweden from March 1969 to April 1970. Invitations with a brief questionnaire were mailed in rotation, following a directory, to all persons aged 8 years or more, who had been resident in the village surrounding the Health Centre since December 1968. Out of 1917 persons invited, 1702 (88.80/0) took part in the study. Information about persons who failed to turn up or in whom the examination was incomplete has been given in earlier reports (Bengtsson 1972a,b, 1973). Twenty cases subject to antiglaucomatous treatment, lesions in the anterior chamber angle, active uveitis or glaucomatous field defects were excluded from the present study. Th e official identification numbers of the eldest sibling and the eldest child of each person were requested in the questionnaire and orally verified at the examination. (In Sweden every inhabitant has his own “person number” consisting of ten figurcs - birth date, birth number and control number - and more or less universally used for the purpose of identification in all types of official registers.) Using those data 365 nuclear family groups consisting of 1042 unique
Table I . Number of families with different compositions
Type of family
Mother, father and offspring Mother and offspring Father and offspring Siblings
117 40 19 -
29
Number of children 2 3 4
5
70 21 8 49
1 0 0 0
23 3 2 7
3 2 0 0
Bo Bengtsson individuals w e r e (subsequently) assembled and pairs of first degree relatives and spouses constructed as detailed later. The composition of families is shown in Table I. Serological verification of the different types of first degree relations was not attempted. The method used here to establish different kinds of kinship is of course not infallible but was deliberately chosen because it was practical. In half sibships one of the two full sibships was only referred to the joint parent and the second full sibships only to the other parent. In such cases the fact that the parents had children in common was obscured. It is also possible that a few halfsibs have been registered as full sibs, even if the children in the older full sibship often retained their original surname when following their mother into a second marriage. The degree of interrelationship, on the other hand, has been underestimated in monozygotic twins and persons with multiple relationships. A previous very comprehensive study (EssenMoller 1967) of familial interrelatedness and consanguinity in a population partly identical with the present one, admits of the conclusion that errors caused by the concise registration of relatives are few and therefore of little or no consequence. In comparison with collection of data pertaining to ancestors the present procedure has several advantages that are worth mentioning. It is easier for parents to state the identification numbers of their children than vice versa. Involvement of persons not alive and/or not investigated was minimized. Discussions of illegitimacy were avoided. It was possible to abbreviate the procedure for people lacking children and/or siblings. It should be appreciated that one person may be a member of two nuclear family groups andlor may appear both as child and sibling in one of those (Table 11). Three, six or ten pairs of siblings can be formed in families with three, four or five children.
Age and sex distributions are given in Table 111. Table tion of applanation pressures in the present material.
IV shows the distribu-
Table II. Types of first degree relationships formed by 1042 unique individuals Type of relation
Number of individuals
Parent Child Sibling Parent and child Parent and sibling Child and sibling Parent, child and sibling
440 158 66 18 53 295 12
30
I.O.P.on Relatives and Spouses Table 111. Age and sex distributions
36 124 34 13 11 4 1 0 0 0
25 99 45 16 14 10 11 6 I 0
17 93 27 11 16 8 9 15 3 0
44 129 64 84 89 54 44 10 3 0
38 125 46 105 90 53 32 23 8
0
9 98 85 46 25 11 5 1
43 127 58 20 6 5 1 0 0 0
243
280
260
223
227
199
521
521
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
0 0 0 68 84 48 36 5
Total Meanage
2
47.8
0 0
45.7
18.4
18.3
24.7
27.9
33.3
1
34.9
Methods Visual acuity, ophthalmometry, slit lamp examination, Goldmann tonometry, Schiotz tonometry, sphygmomanometric measurements of the systemic blood pressure, ophthalmoscopy in mydriasis, subjective refraction in cycloplegia and fundus photography were attempted in every case. Conventional equipment was used according to a fixed program. The applanation tonometry was performed by the author using a Goldmann tonometer mounted on a Haag Streit 900 slit lamp. The tonometer was tested at PTB in Berlin and found to be completely devoid of demonstrable errors in the pertinent pressure range. (For method, see Jessen 1969.) The right eye was always measured first, the instrument was read to the nearest millimeter and the first reliable reading was recorded. The arithmetic mean of the Goldmann readings on the two eyes was used to represent the intraocular pressure of the individual. All data were immediately codified and recorded on special forms. Transfer 31
Bo Bengtsson
the computer centre i n Lund. The analysis was carried out with a s t a n d a r d computer program -
to punch cards and further processing were performed at
SPSS.
ResuIts Several different final methods of analysis have been reported in earlier studies. Initially we used both “crude” pressure readings and “corrected” pressures (Bengtsson 1972a). In both cases we calculated covariances and coefficients of regression as well as correlation coefficients.
Table IV. Distribution of Goldmann readings
Goldmann readings
Number of individuals Right eye
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Total
Left eye
1 0 1 7 18 36 70 134 153 150 157 131 97 41 24 16 1 1 2 0 0 1 1
1 0 0 7 15 38 61 133 157 146 154 131 101 49 29 17 1 1 0 1 0 0 0
1042
1042
32
I.O.P. on Relatives and Sflouses “Correction” of applanation pressures did not affect the results significantly or systematically and was therefore omitted. In quantitative genetics the degree of resemblance between relatives is eventually used to predict the outcome of selective breeding. In this situation parameters relating the covariance to the variance of potential parents of future offspring - i. e. heritability and/or coefficient of regression - are the natural choice. For a more descriptive purpose, like the present one, the coefficient of correlation was considered to be equally adequate and more generally known as well as being more easily understood. In order to make different correlation coefficients directly comparable, constructed variables such as the pressure of “midparents” and -mean children“ were avoided. All pairs therefore consisted of two individuals. The part of the independent member of a pair was always assigned to the older relative and to the male spouse. Estimates of probabilities that observed correlation coefficients have arisen by chance were obtained from the standard computer program (SPSS). In Fig. 1 the standard deviations were calculated according to the convention that SD of r = (l-rz)/Vn if the value of n is large and the value of r is small.
Pair members independent
Number of pairs dependent
SDOf
SDOf
indep. var.
dep. var.
Correlation coefficient
mother mother father father
daughter son daughter son
21 1 23 1 165 219
2.37 2.39 2.57 2.61
2.35 2.24 2.30 2.19
0.15 ( P = 0.27 ( P 0.05 (P = 0.18 (P =
sister brother sibling
sister brother sibling of the other sex
64 85 144
2.47 2.38 2.35
2.32 2.28 2.28
0.41 ( P 0.001) 0.24 (P = 0.012) 0.10 (P = 0.121)
sibling
sibling of the same sex
149
2.50
2.30
0.33 ( P
mother father
offspring off spring
442 384
2.38 2.59
2.31 2.27
0.20 ( P 0.001) 0.12 (P = 0.010)
parent sibling husband
offspring sibling wife
826 293 214
2.50 2.42 2.53
2.29 2.29 2.45
0.16 ( P 0.22 (P 0.22 ( P
0.013)
< 0.001) 0.263) 0.003)
