Deborah A. Meyers, Ph.D., Linda I?. Freidhoff, David G. Marsh, Ph.D. Baltimore, Md.
MS., and
A total of 278 individuals in 42 randomly ascertained nuclear families were studied to determine correlations among family members for skin test response and total serum IgE levels. The major aim was to determine whether these meusures of allergic response in farnit”y members could be used to predict whether the last child in the family would be skin test positive. There were signifzant correlations in total log&E] levels between parents and their children and an even higher correlation between siblings. For the measurement of skin test response (allergy index), the only signt$cant correlation was between siblings. Discriminant analysis was performed with the fourth child in the family as the index cuse. This was done to determine how muny of the index cases could be correctly predicted to be skin test positive or negative based on family information. With just the skin test results on the parents, only three of the 13 positive index cases were correctly predicted. However, when the mean value for the skin test results in the siblings (mean allergy index) was used, eight qf the 13 skin test positive index cases were correctly predicted. These results suggest that, although there is a high degree of concordance for allergic disease within families, information from other siblings may be the most useful predictor of allergic status in another child. (J ALLERGY CLIN IMMJNOL 77:60&/5, 1986.)
Although the importance of a positive family history of atopic allergy is recognized by the practicing allergist, well-designed family studies are neededto elucidate the genetic and environmental factors involved in the expression of allergic disease. It is especially inportant that these studies not be performed with families selectedon the basis of having multiple affected members. Although such families represent the type often observedby an allergist, obviously this would bias the results toward finding a genetic basis for allergic disease. We have studied a total of 278 individuals from 42 nuclear families (both parentsand all available children). The families were randomly ascertained(selected through our ongoing Westinghouse Corp. studies) and were not selected for the presenceof allergic diseasein the family. It has also been recognizedthat allergic individuals tend to have higher total serum IgE levels than nonFrom the Division of Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Good Samaritan Hospital, Baltimore, Md. Received for publication May 22, 1985. Accepted for publication Sept. 12, 1985. Reprint requests: Deborah A. Meyers, Ph.D., Division of Clinical Immunology, Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, MD 21239. Publication No. 615 from the O’Neill Research Laboratories, Good Samaritan Hospital, Baltimore, Md. 608
allergic subjects, but previous studies do not agree as to the mode of inheritance of total serum 1gE levels either. In 1974, Marsh et al. ’ found evidence for recessive inheritance of high total IgE levels. Gerrard et al.’ also found evidence for recessive inheritance of high levels with a significant polygenic component. However, Blumenthal et al.’ found overall evidence for dominant inheritance of high levels with possible different modes of inheritance in the different pedigrees. In addition, in our study of Amish families.’ the codominant mode of inheritance elicited the best fit to the data, whereas in our study of Mormon pedigrees,5the polygenic model (additive effect from alleles at multiple independentloci) best fit the dater. Also, these previous studies did not determine whether total serum IgE levels and skin test results in one family member can be used to predict either 01 both in another family member. The purpose of tbc present study was to determine the accuracy with which one could predict whether a given individual will be skin test positive basedon results from family members.The relationships of an AI of skin test positivity and basal total serum IgE levels among indi-
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viduals from randomly selected nuclear families were studied. METHODS Study subjects A total of 278 individuals in 42 nuclear families consisting of both parentsand all available children were studied. The families were selectedfor the study through a parent who worked at the WestinghouseElectric Corp. and who had previously completedour original questionnairesent to a total of 2097 employees.6All probands had stated that they had four or more children by one spouseand that all family members would probably be available for study. Families were not selectedfor study becauseof the presence of allergic diseasein the family membersbut for large family size. Each family was visited during February to mid-May when blood sampleswere drawn for determination of total IgE levels, typing of HLA and other blood groups,and when skin testing by the puncture methodwas performed.In most casesa secondblood sample was drawn at a random time during the year to completethe HLA and other blood group typings and for a seconddeterminationof serumIgE levels. There was a total of 11 family membersfrom which it was not possible to obtain a blood sampleduring the time of the year when IgE levels are believed to be at their lowest (basal)levels (February to mid-May for the Baltimore area). Four of thesewere the two parentsand the only two available children in one family who were all sampled in mid-November. The remaining seven subjectswere children from six different families. Four of thesewere skin test negative to seasonalallergens, and the remaining three (who were sampledin June and August) were skin test positive to rye grassand/or ragweed. Total IgE determinations Total serum IgE levels were measuredby a modification of the direct RIST radioimmunoassay,’in duplicate, in at least two separateassays. An assay was repeated if the coefficient of variation was > ? 10% either within or between assays.IgE values were computedin nanogramsper milliliter (1 IU = 2.42 rig/ml) by use of a standardserum of known content that had been standardizedagainst the World Health Organization reference. Allergens Family members were skin tested with the following crudeantigens:short ragweed,rye grass,mixed trees,mixed weeds,cat and dogdanders,Alternariu, mixed molds, house dust, and mite plus histamine, and diluent controls in the concentrations presented in Table I. All pollen allergens were preparedin our laboratory from dialyzed aqueousextracts of petroleum ether-defatted pollens.* The pollens (Greer Laboratories, Lenoir, N. C.) were freshly collected, dried, and stored in sealed containers at -20” C until needed.The well-standardized short ragweedand rye grass extracts were the sameas those describedpreviously.’ The cat, dog, and Alternariu extracts were the sameprocessed
Skin test sensitivity
IgE levels in family
members
609
commercial extracts as those described previously.8 Standardized mite extract, as well as the Cladosporium and Penicillium extracts, were kindly supplied by ALK Laboratories, Copenhagen,Denmark.Fusarium sporeand house dust extracts were preparedin our laboratory. Skin testing The puncture method used* is a modification of the method developedby Santilli et a1.9Basically, it consisted of applying drops of the allergen solution to the forearm and then pricking through the drops with a bifurcated smallpox vaccination needle (Wyeth Laboratories, Philadelphia, Pa.) Any positive reactionswere recordedby tracing around the wheal 15 minutes after puncturing the skin and transferring the tracing to graph paper with transparentsurgical tape (Transpore; 3M Corp., St. Paul, Minn.). Any later reactions were also noted and traced. Any reactions that were difficult to interpret or where there was poor reproducibility betweenthe duplicate testswere repeatedduring the secondvisit to the family. This simple procedurehas been demonstrated,by titration experiments, to correlate well with the intradermal skin testprocedure,sincethe regression lines of mean wheal diameter versus log[allergen] were found to be parallel.* From the puncture skin test results, an individual’s sensitivity toward a given allergen was expressedas the concentrationof allergen that would give rise to a wheal of 6 mm diameterbasedon the regressionlines.* In order to quantitate the IgE-mediated skin sensitivity of each subjectfor all the antigens tested, the AI was computed. The method for calculating the AI has developed from the results of skin testson 192 skin test positive Westinghouse employeesand is describedin detail elsewhere.8 Basically, this method allows us to standardizethe results for all the allergensby adjusting the meanvaluesof response for eachallergen. Then responseto individual allergenscan be summedfor that subjectto elicit one value that can then be comparedto the values calculated for the other family members.Becausethere were so few positive responders to the mixed fungal extract, it was not included in the computation of the AI. The allergenic extracts for mixed trees and mixed weeds (Table I) were not used in the original study, but were usedin this family study, and were included in the AI calculation. Since only three (weak responders) of the 44 subjectsskin test positive to house dust were not skin test positive to mite, only the mite results were used for the AI computations. All the other allergens presented in Table I were used to computethe AI. Statistical
analyses
The data were storedand analyzed on IBM 3033 of The Johns Hopkins University. Log transformation of the total IgE data was performed to reduce skewness. The distributions of both log[IgE] in the total sampleand AI in skin test positive subjectswere not significantly different from normal distributions. The statistical packageBMPD” was used for the stepwise regressionand discriminant function analyses,and the family correlations were calculatedby the method of Donner and Koval.”
610 Meyers et al.
A
3
2B II) 10 2
~
TOTAL SERUM IgE, b-q/ml 1 FIG. 1. A, The log[lgE] levels in male subjects (n = 150). B, The log[lgE] levels in female subjects In = 128). Neither was significantly different from a normal distribution.
RESULTS Data from 42 nuclear families (both parentsand all available children) with a total of 278 individuals were analyzed. The mean number of children per family was 4.62 + 1.19. The results of the studies on HLA typing, blood group markers, and red cell enzymes will be reported elsewhere. However, it should be noted that data on one child were deleted from all of the analysesbecauseof nonpatemity detectedby the HLA typing. For 230 of the family members, two IgE values were available (one basal and one from a serum sample drawn at random during the year). The two log[IgE] levels were highly correlated (r = 0.97; p < 0.001). Thirty-five percent of the family members had a positive AI (n = 97). In 13 of the 42 families, all memberswere skin test negative. These findings suggestthat this sampleof families is as random as it is practical to obtain. The correlation between the basal total log[IgEl level and AI was 0.48 (p < 0.001) for the total sample. Unless noted otherwise, all results are listed for the basal total log[IgE] values. The distributions of
TABLE I. Allergenic testing
extracts
---__I_
used fn~- skr’l ___.
--
^ _
~~~~~~~~a~~~:~
Extract Pollens Short ragweed (Ambrosia artemisiifolia)t Perennial rye grass (Lolium perenne)l Mixed trees (10 different species)+ Mixed weeds3 Animal danders Cat Dog Fungi Alter-n&n spp. (mycelium plus spore extract) Mixed11 Other House dust Mite (Dermatophqoides pteronyssinus) Controls Histaminei’ Diluentt
jmg;ml)”
ii .$
!
i ..I
1.o 3.2 3.0 1J.S
0.5 0.05 molit of sodium phosphate phenol buffer, pH 7.4, containing 0.03% human scrum albumin as a stabilizer?
*Expressed in terms of nondialyzable solids, except that histamine is expressedin terms of histamine base. tTested in duplicate. tOak (0.3 mg/ml) plus equal parts of hickory, birch, beech, ash, sycamore, maple, willow, cottonwood, mulberry, walnut, elm, and hackberry (1.8 mg/ml). @qua1parts of marshelder, lamb’s quarters, English plantain, and sheepsorrel. /[Composedof Cladosporium and Penicillium mycehum plus spore extracts (2.0 mglml each);Fusurium sporeextract (0.3 mgiml).
log[IgE] levels in male (n = 150) and in female (n = 128) subjects were not significantly different from normal distributions (Fig. 1). Male subjectshad a significantly higher mean l@IgE] than female subjects (by Student’s t test, p < 0.05, Table H). There was not a sign&ant difference between the sexesfor log{IgE] levels in the smaller number of skin test positive subjects(Table II). The distribution of AI values in the 97 skin test positive individuals was also not significantly different from a normal distribution-. For the total sample, there was a significant difference in
VOLUME NUMBER
TABLE
77 4
Skin test sensitivity
II. Mean values of the various
parameters
Age
for the family
IgE levels in family
members
members Geometric mean IgE (nglml)
Al
1.94 * 0.74 2.44 + 0.67
87.1 275.4
0.17 ? 0.37 0.49 zt 0.48
28.3 + 15.0 29.2 k 14.8
2.02 * 0.74* 2.53 -c 0.61
104.7 338.8
0.21 k 0.41* 0.51 +- 0.49
28.6 ” 14.5 28.4 k 13.2
1.84 k 0.72* 2.29 t 0.77
69.2 195.0
0.12 2 0.32* 0.47 k 0.47
Basal
Sample
(mean + SD)
LogllgEl
Total (n = 278) Skin test positive (n = 97) Male (n = 150) Skin test positive (n = 63) Female (n = 128) Skin test positive (n = 34)
28.4 r 14.8 28.9 k 14.2
611
*A significant difference in log[IgE] levels and in Al was observed between male and female subjects @ < 0.05).
TABLE III. Correlations
between
family
members
for the 42 families
IogllgEl
Al
Relationship
r
P
r
P
Parent-parent Father-child Mother-child Sibling-sibling
0.33 0.33 0.29 0.43
=0.05 CO.05 CO.05 CO.001
0.22 0.17 0.16 0.43
NS ‘NS NS CO.001
NS = not significant.
mean AI values in male versus female subjects (by Student’s t test, p = 0.04, Table II) that was expected, since there was a higher proportion of skin test positive male than female subjects (42% versus 27%). The mean age for male (28.3 + 14.8 years) and female (28.6 ? 15.Oyears) subjectswas very similar (Table II). No significant relationships were found between total log[IgE] levels and age except in skin test positive female subjects(r = - 0.44, p c 0.01, n = 34). Dividing the total sample by sex for age groups less than 20 years or more than or equal to 20 years did not reveal any significant correlations with age. Also, for the skin test positive family members, there was not a significant relationship between the AI and age. However, it should be pointed out that the sample sizes of most of the subgroupsare small. In view of the large variation observed in IgE levels, the age-relatedeffects would have to be quite large to be significant in these subgroups. The following decisions for the purposes of the genetic analyseswere made in regard to age and sex adjustmentof log[IgE] levels and AI values basedon our results and other results in the literature.‘* Log[IgE] and AI values for female subjectswere adjusted to male subjectvalues by useof a factor of 1.1.
For adult male and female subjects(2 20 years), both log[IgE] and positive AI values were adjustedto those at age 20 years (with a slope of -0.01 per year). No age adjustmentswere made for children of either sex (age range of 7 to 20 years) to adjust their values to those at age 20 years. Significant differences in total IgE levels between smokers and nonsmokers have been reported.‘* Smoking was not consideredto be a factor in any of the analyses, since there were very few smokersin the presentstudy. There were no significant differences in mean log[IgE] levels for both male and female subjectsbetween smokersand nonsmokers(whether or not the data were age adjusted). For example, in male subjects the mean log[IgE] level for smokerswas 2.03 + 0.60 (n = 36) versus 1.92 + 0.82 (n = 94) for nonsmokers(not age adjusted). Also, no differenceswere observedfor female subjectsin which there were even fewer smokers. Table III illustrates the correlations found between family membersfor log[IgE] levels and for AI values. There was an unexpected correlation of 0.33 with borderline significance for log[IgE] levels betweenthe parents. There were significant positive correlations in log[IgE] levels between fathers and their children and between mothers and their children and an even higher correlation between siblings. The only signif-
Meyers et al.
612
IV. Family correlations for the 39 index cases
TABLE
Relationship to index case
LogOgEl
Al
r
r
LoglWl
Father Mother Mean value for other siblings Sameindividual
0.31 0.35*
Father Mother Mean value for other siblings
0.43t
0.52t
0.08 0.14 0.25
(1.0)
0.53t
AI 0.12 0.31
0.26 -0.08 0.44*
*p < 0.05. fp < 0.01.
icant correlation for the AI was between siblings (r = 0.43, p < 0.001, Table III). Next, we wanted to determine whether it was possible to use either the age- and sex-adjusted log[IgE] levels or AI values in parents and other siblings to predict either the log[IgE] level or the AI in a younger sibling. The 39 families with four or more children that had been sampled were used for these analyses with the fourth child being the index case (the individual whose values we tried to predict). Data on the parents and the older three siblings were used for the various analyses. Before the use of the multivariate techniques of stepwise linear regression and discriminant analysis, we looked at the correlations between the traits in the index case versus the other family members. As presented in Table IV for the log[IgE] of the index case, there were significant correlations with the log[IgE] of the mother and the mean value for the other siblings. There was also a significant correlation with the father’s AI and, as expected, with the index case’s own AI. The only other significant correlation for the AI in the index case was with the mean AI for the other siblings (Table IV). Discriminant analysis was then performed to determine how many of the index cases could be correctly classified as skin test positive or negative with the index case’s log[IgE], the AI of the other family members, or the log[IgE] values in other family members. As observed in Table V, using the index case’s own log[IgE] gave an overall correct classification rate of 82.1%, whereas using the mean values for the siblings gave a slightly lower rate (74.4%). In the latter case, eight of the 13 skin test positive index cases were classified as positive, and 21 of the 26
skin test negative index cases were cl~~srilicd it;, c,‘-s ative. The use of the siblings’ mean lo)~ilpl-L] ‘,:c~;!L(I a slightly lower overall rate that was tilt, \:j~::ri 8.%. : i:i’ ,’ 8, rate found if the father’s and mother’\ .A! :I~uI:. ssh. used. However, when the parents’ 4’ 1.t!:lc, 1’ b-1,’ used, only thret: of the 13 skin ICS; /KIL~:~:‘I ~!II!I A cases (23. 1%) were classified correctly ,-in C$‘TU:IJ’*“:. overall correct classification rate was liiiinti whet-1:j:r. parents’ log[IgE] values were used (53 X’+ :, Next, we looked at the predictive vaiuc of GIL ‘:I on just the first sibling (analogous 1~ :hc sittiitli<>ri where there is only one other child). The results \rr~~ somewhat more similar to those obtained whru the parents’ AIs were used. For the skin test positrvc m&:x cases, 30.8% were correctly classified versus 76.YC::> of the skin test negative index cases. This elicited an overall rate of 61.5% correct classifications. We analyzed also the predictive value of the number of skin test positive siblings instead of usins their AI values. The percent correctly classified fell to an overall rate of 64.1% when just the number si’ skin test positive siblings were used. For the skin test positive index cases, 38.5% were correctly classified versus 76.9% of the skin test negative index cases Then stepwise linear regressions were perfomled to determine how much of the variation observed in the trait value in the index case could be explained by the values in the other family members. This was not done to try to classify index cases as negative
DISCUSSION There are two major points on the design of this study that need to be discussed. First, it was decided to study skin test positivity and total log[IgE] levels because these are relatively objective measurements that can be made and are correlated with the presence of clinical disease. Of course, not all skin test positive subjects or subjects with high total IgE levels are clinically allergic. However, understanding the genetic and environmental factors involved in the expression of these two traits would serve as a foundation for studies of clinical disease. Second, it is very important that such studies be conducted on families ascertained either randomly or through the presence of a proband.
VOLUME NUMBER
TABLE
77 4
Skin test sensitivity IgE levels in family members
V. Use of other traits to determine
if the index case is skin test negative Percent
Trait
Positive
Index case’s log[IgE] (n = 39)
correctly
Siblings Mean AI* Mean log[IgE]*
LogUgEl
classified Overall
80.8
82.1
(21126)
61.5
80.8 (21126) 73.1
(8/13) 69.2 (9/13)
Father and mother AI
or positive
Negative
84.6
(11/13)
613
74.4 71.8
(19126)
23.1
96.2 (25/26) 53.8
(3/13) 53.8 (7/13)
71.8 53.8
(14/26)
*Meanvaluefor othersiblingsin that family wasused.
Ascertaining a family for study becauseof a positive family history for allergy can severely bias one’s results. Becauseof the relative high frequency of allergic diseasein the generalpopulation, it waspossible to samplefamilies randomly with the criteria that they had four or more children and both parentsavailable for testing. Therefore, it was not necessaryto correct for any biasesin ascertainmentof the families, since totally nonallergic families as well as families with one or more allergic memberswere studied. In addition, total IgE levels were measuredwhen they were believed to be at their basal level in the Baltimore area(mid-February to mid-May). Since another blood samplewas neededto completethe HLA typings, total IgE levels were again measuredwhenever the HLA typing sample was drawn. Although there was a high correlation (r = 0.97, p < 0.01) between the two samples, there were significant increasesin levels in some allergic individuals. Therefore, the basal levels were used for all of the analyses with the exception of the few individuals whom we were unable to sample at the basal time of the year (see Methods). It should be noted that basal levels may not have been obtained on all subjectssensitive to household allergens, such as animal danders and house dust mites. However, it is not clear whether it would have been possible to obtain basal levels even if we had sampledsuchindividuals many times during the year. As observed in Table II, there was a sigpificant
TABLE
VI. Predictive
members’ Index case’s
Log[kEl AI
log[lgEl
value of family or Al
Variable
Individual’s AI Mean log[IgE] for the siblings Individual’s log[Wl Mean AI for the siblings
Amount of variation explained (%I
28 44* 28 37*
*This denotesthetotalamountof variationin theoutcomevariable that wasexplainedby this variableandthe previousone.
levels for the overall group. This may have been due to the age distribution in the sample. Since all the parents were old enough to have had four children more than the age of 6 years, there were relatively few individuals in their 20s (only the older children). However, since the decreasein total IgE levels from young adulthood to old age has been well documented,‘* an age adjustment was made to the adult data (see Methods). No significant age-associated changes in log[IgE] were found either in male or fe-
betweenthe sexesthat was expected, since numerous studies have documented that male subjects tend to
male subjects less than 20 years of age. Although it is generally acceptedthat total IgE levls increase in childhood, especially in children less than the age of 7 years, the progressionof the overall changesis not clear from reviewing the literature. ‘2-15 Although Gerrard found evidencethat IgE levels peak at puberty,13 evidencefor such a peak was not found in the Arizona epidemiologic studyI or in thesedata. Since all of the
be more allergic than female subjects. I2 There was no
children studied were .more than 7 years of age in
significant relationship betweenageand total log[IgE]
which the changes appear to be slight, we did not
difference in both the mean total log[IgE] and the AI
614
Meyers et al.
consider it to be appropriate to age adjust our data on children. It is important to note that, although these families represent a random sample from the general white population, they do not represent families in which one would actually be interested in predicting whether the next child would be allergic. This is because the mean age of the index case (fourth child) was 16.7 it 5.5 years. Therefore, age effects are probably less important in these families. Our information on the predictive status of family information is not as dependent on the child in question being old enough to develop allergies as it would have been if we had used data from families with younger children. The strongest family correlations were observed between siblings for both total log[IgE] levels and the AI (Table III). In fact, the only significant correlation found for the AI was between siblings, whereas all the family correlations approached significance for total log[lgE]. There is no obvious reason for the borderline significant correlation observed between the parents for total log[IgE] levels, which probably occurred by chance. Since only three of the parents were more than 60 years of age and seven were between 55 and 60 years, it appears unlikely that this correlation was due to parents who demonstrated little variation in IgE levels because of their advanced ages. It is important to remember that the family correlations observed in Table IV are for one particular sibling (the index case) versus the other family members. The correlations for total log[IgE] between the index case and the father, mother, or other siblings were similar to correlations observed in Table III. Interestingly, a correlation of 0.43 was observed between the father’s AI and the total log[IgE] of the index case. The only significant correlation for the AI was between the index sibling and the other siblings that is also similar to the results in Table III. The results of the discriminant analysis (Table V) make the same point, i .e , that information on multiple siblings is more important in predicting the allergic status of the index case than information on the parents. When the parents’ AIs were used, only three of the 13 skin test positive index cases were correctly classified as skin test positive. This result was also observed in the stepwise regression analyses that were performed to determine how much of the variation observed in the index case’s value for either his total log[IgE] level or AI could be explained in terms of his immediate relatives’ values (Table VI). A significant amount of the variation for total log[IgE] levels observed in the index case was explained by his own total AI value and the total log[IgE] levels in the remaining siblings. Similar results were obtained for the
AI of the index case. Interestingly, for neither the total log[IgE] level or the AI were the other value< in rite siblings chosen as a significant predictor Fi *I’cx;u n;>i:‘~ in explaining the index case’s IgE level. thz ;41
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and there were no children lessthan the ageof 7 years in this study. However, this raises the question as to whether the advancedage of the parentswas the reason for data from the other siblings being more significant than the data from the parents. This question can never be completely answeredwithout doing longitudinal studies of families that, of course, are very difficult to perform. The only other feasible approach would be to study families with younger parentsand, therefore, younger children. However, large fluctuations in total IgE levels occur in very young children causedby age and environmental influences such as viral infections. Also, younger children may not have had sufficient exposure to be skin test positive to the relevant allergens. It is also more difficult to receive institutional approval as well as parental approval for skin testing and drawing blood from normal children less than 7 years of age. We believed that it was important to the accuracy of the study that the index casesandtheir older siblings had a high probability of already being skin test positive if they were going to develop allergic disease. Age and sexcorrectionsbasedon our dataanda review of the literature were performed on the data before the family analyseswere undertaken. In conclusion, from this study of large families, it appearsthat information from the other siblings is more important in predicting the status of the index casethan information from the parents. REFERENCES 1. Marsh DG, Bias WB, lshizaka K: Genetic control of basal serum immunoglobulin E level and its effect on specific reaginic sensitivity. Proc Nat1 Acad Sci USA 71:3588, 1974 2. Gerrard JW, Rao DC, Morton NE: A genetic study of immunoglobulin E. Am J Hum Genet 30:46, 1978 3. Blumenthal MN, Namboodiri KK, Mendell N, Gleich G, Elston RC, Yunis E: Genetic transmission of serum IgE levels. Am J Med Genet l&219, 1981
Skin test sensitivity
IgE levels in family
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4. Meyers DA, Bias WB, Marsh DG: A genetic study of total IgE levels in the Amish. Hum Hered 32:15, 1982 5. Hasstedt SJ, Meyers DA, Marsh DG: Inheritance of Immunoglobulin E: genetic model fitting. Am J Hum Genet 14:61, 1983 6. Freidhoff LR, Meyers DA, Bias WB, Chase GA, Hussain R, Marsh DG: A genetic epidemiologic study of human immune response to allergens in an industrial population. I. Epidemiology of reported allergy and skin test positivity. Am J Med Genet 9:323, 1981 7. Schellenberg RR, Adkinson NF: Measurement of absolute amounts of antigen-specific human IgE by radioallergosorbent test (RAST) elution technique. J Immunol 115:1577, 1975 8. Freidhoff LR, Marsh DG, Meyers DA, Hussain R: The structuring of an allergy index based on IgE-mediated skin sensitivity to common environmental allergens. J ALLERGY CLIN IMMUNOL 72~274, 1983 9. Santilli J Jr, Potsus RL, Goodfriend L, Marsh DG: Skin sensitivity to purified pollen allergens in highly ragweed-sensitive individuals. J ALLERGY CLIN IMMUNOL 65:406, 1980 10. BMDP statistical software. Department of biomathematics. University Park, Pa, 1982, Pennsylvania State University 11. Donner A, Koval JJ: Variance-component estimation from human sibship data. Biometrics 39:599, 1980 12. Freidhoff LR: Epidemiology of allergy. In Marsh DG, Blumenthal MN, editors: Genetic and environmental factors in clinical allergy. Minneapolis, University of Minnesota Press (in press) 13. Gerrard JW, Home S, Vickers P, MacKenzie JWA, Goluboff N, Garson JZ, Maningas CS: Serum IgE levels in parents and children. J Pediatr 85:66O, 1974 14. Kjellman N-I M, Johansson SGO, Roth A: Serum IgE levels in healthy children quantified by a sandwich technique (PRIST). Clin Allergy 6:51, 1976 15. Barbee RA, Halonen M, Lebowitz MD, Burrows B: The distribution of IgE in a community population sample: correlation with age, sex, and allergen skin test reactivity. J ALLERGY CLIN IMMIINOL 68:106, 1981 16. Lebowitz MD, Barbee R, Burrows B: Family concordance of IgE, atopy, and disease. J ALLERGY CLM IMMUNOL 73:259, 1984 17. Bazaral M, Orgel HA, Hamburger RN: IgE levels in normal infants and mothers and an inheritance hypothesis. J Immunol 107:794, 1971 18. Orgel HA: Genetic and developmental aspects of IgE. Pediatr Clin North Am 22:17, 1975