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Height Growth Velocity, Islet Autoimmunity and Type 1 Diabetes
Development: the Diabetes Autoimmunity Study in the Young
MM Lamb1, X Yin1, GO Zerbe1, GJ Klingensmith2, D Dabelea1, TE Fingerlin1, M Rewers1,2,
and JM Norris1
1Colorado School of Public Health, University of Colorado Denver, Aurora, CO
2Barbara Davis Center for Childhood Diabetes, Aurora, CO
Abstract
Aims/hypothesis—Larger childhood body size and rapid growth have been associated with
increased type 1 diabetes risk. We analyzed height, weight, body mass index (BMI), and velocities
of growth in height, weight, and BMI, for association with development of islet autoimmunity (IA)
and type 1 diabetes.
Methods—Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed
children at increased type 1 diabetes risk, based on HLA DR,DQ genotype or family history, for
development of IA and type 1 diabetes. IA was defined as presence of autoantibodies to insulin, GAD
or IA2 twice in succession, or autoantibody positive on one visit and diabetic at the next consecutive
visit within one year. Type 1 diabetes was diagnosed by a physician. Height and weight were collected
starting at age 2 years. Of 1,714 DAISY children < age 11.5 years, 143 children developed IA, and
21 progressed to type 1 diabetes. We conducted Cox proportional hazards analysis to explore growth
velocities and size measures for association with IA and type 1 diabetes development.
Results—Higher height growth velocity was associated with IA development (HR: 1.63, CI:
1.31-2.05) and type 1 diabetes development (HR: 3.34, CI: 1.73-6.42) for a 1 standard deviation
difference in velocity.
Conclusions/interpretation—Our study suggests that greater height growth velocity may be
involved in the progression from genetic susceptibility to autoimmunity and then to type 1 diabetes
in pre-pubertal children.
Keywords
childhood height; height growth velocity; islet autoimmunity; type 1 diabetes
Introduction
Type 1 diabetes is an autoimmune disease in which the insulin-producing beta cells of the
pancreas are destroyed. A long preclinical phase of islet autoimmunity (IA) often precedes the
clinical diagnosis of type 1 diabetes. Children progress from islet autoimmunity to type 1
diabetes at different rates (1;2), and it is still unknown whether or not all children that develop
IA will eventually develop type 1 diabetes. Identifying the predictors of IA and type 1 diabetes
Corresponding Author: Dr. Jill M. Norris Colorado School of Public Health, University of Colorado Denver 13001 East 17th Place,
Box B-119 Aurora, CO 80045 Jill.Norris@ucdenver.edu Phone: (303) 724-4428 Facsimile: (303) 724-4488.
Duality of interest statement: The authors declare that there is no duality of interest associated with this manuscript.
NIH Public Access
Author Manuscript
Diabetologia. Author manuscript; available in PMC 2010 October 1.
Published in final edited form as:
Diabetologia. 2009 October ; 52(10): 2064. doi:10.1007/s00125-009-1428-2.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
might shed light on the biologic mechanisms that influence the early stages of this autoimmune
disease process.
Two recent hypotheses postulate that the current childhood obesity epidemic is driving the
increasing incidence and earlier age of type 1 diabetes onset seen around the world (3-6). The
Overload Hypothesis (7) suggests that the high insulin demand on the beta cell that results
from the overfeeding and resultant accelerated growth of today’s youth make the beta cells
vulnerable to autoimmune attack and apoptosis. The Accelerator Hypothesis postulates that
insulin resistance caused by excess weight gain may accelerate beta cell apoptosis in
individuals at genetic risk (8).
Ecologic studies have suggested a correlation between increasing BMI, weight and height and
incidence of type 1 diabetes in the population (9;10). Several studies have shown an association
between higher body mass index (BMI) standard deviation (SD) scores and earlier age at
diagnosis of type 1 diabetes(11-14), although others have not (15-17). In case-control studies,
children with type 1 diabetes showed increased weight, height or BMI SD scores compared to
non-diabetic children either in infancy or early childhood (18-26). Analysis of a birth cohort
suggested that increased BMI in childhood increased risk of self-reported type 1 diabetes
(27). A recent study examined this in a cohort of children at increased risk of type 1 diabetes
and found that higher weight and BMI SD scores were associated with development of islet
autoimmunity (28). Childhood obesity and rapid growth may trigger autoimmunity by creating
higher insulin demands on the pancreas, which may make the beta cell more active and more
visible to the immune system. Higher insulin demands might also exacerbate autoimmunity
by stressing beta cells already under autoimmune attack. We used a prospective cohort of
healthy children age 2 to 11 years who are at increased genetic risk for type 1 diabetes, to
explore the association of childhood size and growth rate with two outcomes: earlier IA
development, and more rapid progression to type 1 diabetes in children with evidence of IA.
Methods
DAISY is a prospective study of three groups of young children at increased risk for developing
type 1 diabetes. One group consists of unaffected first-degree relatives of patients with type 1
diabetes, identified and recruited between birth and age eight years through the Barbara Davis
Center for Childhood Diabetes in Denver, Colorado, other diabetes care clinics, and the
Colorado IDDM Registry. The second group consists of babies born at St. Josephs Hospital in
Denver, Colorado, and screened by umbilical cord blood samples for diabetes-susceptibility
alleles in the HLA region. The third group is composed of siblings of the second (newborn
screened) group, who are also screened and enrolled into DAISY and followed for the
development of autoimmunity and type 1 diabetes. The details of the newborn screening (29)
have been published elsewhere. DAISY has enrolled 2,600 children from 1993 to 2004. The
Colorado Multiple Institutional Review Board approved all study protocols, and informed
consent was obtained from the parents/legal guardians of all children.
HLA genotype status of the child was determined from a cord blood sample, if obtained at
birth, or from a blood draw at the first clinic visit. Blood was sent to Roche Molecular Systems,
Inc, Alameda, CA for PCR-based HLA class II typing. The high-risk HLA DR,DQ genotype
was defined as (DRB1*03/ DRB1*04, DQB1*0302). Prospective follow-up of DAISY
children included testing for autoantibodies to insulin, protein tyrosine phosphatase islet
antigen 2 (IA2), and glutamic acid decarboxylase (GAD) at clinic visits at 9,15, and 24 months
(if child enrolled at birth) or at enrollment visit (if child enrolled later in childhood), and
annually thereafter up to age 15 years. GAD autoantibodies and IA2 autoantibodies were
measured with a combined radiobinding assay (30;31). Insulin autoantibody was measured by
a micro–insulin autoantibody assay as described previously (31;32).
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The outcome of IA was defined as presence of autoantibodies to insulin, GAD or IA2 at two
consecutive clinic visits, or autoantibody positive on one visit and diabetic on the next
consecutive visit within one year. The age at the first of two consecutive IA positive visits, or
the age at the IA positive visit that was followed by type 1 diabetes diagnosis within one year,
was used as the age at IA development (ie, in the time to event analyses). Children who tested
positive for ≥ 1 autoantibody were examined every 3-6 months, and hemoglobin A1c and
random glucose were also measured. A child was referred to a physician for type 1 diabetes
diagnosis if they had a random glucose >200 mg/dl and/or a hemoglobin A1c > 6.2%. The
criteria used for diagnosis included typical symptoms of polyuria and/or polydipsia and a
random glucose >200 mg/dl or an oral glucose tolerance test with a fasting plasma glucose of
> 125 mg/dl or a 2 hour glucose >200 mg/dl. Details of intensive monitoring and diagnosis
protocol were described previously (33). The age at physician diagnosis was used as the age
at type 1 diabetes development (ie, in the time to event analyses).
Gender, race/ethnicity, maternal education, and household income were collected in an
interview at the time of enrollment. Weight was measured at every clinic visit on a scale with
precision ± 0.1 kg. Height was first measured when the child was able to stand cooperatively,
around 2 years old, and at every clinic visit thereafter, using a stadiometer with a precision of
± 1 mm. Body Mass Index (BMI) was calculated as weight (kilograms) / height (meters)2 for
all clinic visits where the child was at least 2 years old.
These analyses are limited to children who developed IA or type 1 diabetes after the age of 2
years, the age at which we first obtained height measurements. Because puberty is a time of
increased insulin resistance resulting from very rapid growth rate and dramatic hormonal
changes (34), we analyzed records collected prior to age 11.0 for girls, and prior to age 11.5
for boys. These age cutoffs represent the median ages at which a sample of DAISY children
(n=604) reported being at Tanner stage 2 on a self-Tanner staging questionnaires (35).
Cohort for the Analysis of the Development of IA
In order to explore associations between childhood size, growth rate, and time to IA
development, we analyzed DAISY children for whom at least 2 height and weight measures
were available (9,914 records on 1,714 children) prior to or at IA development. Seventy-five
of the 1,714 children developed IA during follow-up.
Cohort for the Analysis of the Development of Type 1 Diabetes in Autoimmune Children
To explore associations between childhood body size, growth rates, and type 1 diabetes
development, we analyzed 143 autoimmune children for whom at least 2 height and weight
measurements were collected at least three months prior to type 1 diabetes diagnosis. Twenty-
one children developed type 1 diabetes. These 143 IA positive children included 73 of the
children who developed IA during the study, 32 who developed autoantibodies before age 2,
and 39 who had autoantibodies at their first clinic visit.
Children often lose weight rapidly just prior to type 1 diabetes diagnosis. We did not want to
include data that may have been influenced by the disease prodrome, rather than reflecting on
a potential predictor of the disease. Therefore, we did not use the height and weight
measurements collected within 3 months of type 1 diabetes diagnosis, and instead extrapolated
these values based on our models, as described in the statistical analysis section below.
Statistical Analyses
In order to get an accurate picture of each child’s overall growth experience, we first produced
graphs of growth values for individual children, as well as population means, of height, weight,
and BMI, at each age (in years). Next, we fit mixed models of the best-fitting polynomials for
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the fixed effects and for the random effects of height, weight, and BMI on age for each gender.
This method is described in Fitzmaurice et al(36) and an example of the use of this method can
be found in Sontag et al. (37). The best-fitting mixed models produced estimates of the mean
growth curves as well as best linear unbiased predictors (BLUPs) for individual subjects’
growth curves with respect to height, weight, and BMI. BMI throughout childhood in this
cohort was best represented by second degree polynomials in the fixed effects and random
effects. Height and weight gain patterns in this cohort were linear in both the fixed and random
effects.
BLUPs of individual subjects’ growth curves were evaluated at each clinic visit, including
records where height, weight, or BMI were missing. Plots indicated that the BLUP curves
closely fit the raw data. Using BLUPs allowed us to disregard the height and weight measures
within 3 months of type 1 diabetes diagnosis, and instead extrapolate these values for clinic
visits close to diagnosis, when the disease process itself may be affecting body size. BLUPS
also allowed us to interpolate body size values that were missing, as either height or weight
was not measured in about 7% of the clinic visits. The first derivatives of the polynomial
equations used to calculate the above growth curves gave BLUPs of the instantaneous growth
velocities for height, weight, and BMI at each clinic visit. The instantaneous growth velocity
of BMI varied over time, while the instantaneous growth velocities of height and weight were
constant for each child. Cox proportional hazards models allowed us to examine the BLUPs
of height, weight, BMI, and instantaneous velocity of BMI as time varying covariates for
association with IA, and for association with type 1 diabetes in children with IA. Hazard Ratios
were calculated for a 1 standard deviation (SD) difference in velocity. BLUPs of instantaneous
height growth velocity and instantaneous weight growth velocity were analyzed as fixed
covariates, because height and weight growth velocity remained constant over age. All models
were adjusted for ethnicity (non-Hispanic White or other), HLA DR,DQ genotype (high-risk
or not) and family history of type 1 diabetes. Analyses with type 1 diabetes as the outcome
were also adjusted for the age at which the first autoantibody was detected. All statistical
modeling and analyses were conducted using SAS version 9.1 (SAS institute, Cary, NC).
The term “instantaneous growth velocity” refers to growth velocity, ie, change in size per unit
time, as the unit of time approaches zero. For ease of presentation, we refer to these variables
simply as growth velocity rather than instantaneous growth velocity throughout the remainder
of the manuscript.
Results
Height, Weight, BMI and Growth Velocity in the DAISY Cohort
As shown in cross sections of the DAISY cohort (Table 1), estimates of height and weight are
higher in the older age groups. BMI is stable or slightly decreases between ages 3 and 5 years,
and then is increased at age 8 years, suggestive of adiposity rebound(38). Growth velocity of
BMI is negative in the 3 and 5-year olds, suggesting a slowdown of growth in BMI. In 8 year
olds, the BMI growth velocity is positive, reflecting increasing growth in the older ages. The
growth velocities of height and weight were similar in 3, 5 and 8 year olds.
Analysis of the Development of IA in Children at Increased Risk of Type 1 Diabetes
Seventy-five of the 1,714 DAISY children in this analysis developed IA, at a mean age of 6.6
years (Table 2). The minimum number of size measurements per child in this analysis was 2,
the median was 5, and maximum was 16. Mean heights, weights and BMIs by age of children
who did and did not become IA positive are presented in Supplemental Online Figure 1.
Adjusting for ethnicity, HLA DR,DQ genotype and family history of type 1 diabetes, greater
height growth velocity was strongly associated with IA development (Table 2). Height and
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weight were also inversely associated with IA development, although the associations were
weaker, particularly for weight. Height was inversely correlated with height growth velocity
in these children (Pearson r: −0.09, p = 0.0007). When both height and height growth velocity
were included in the model together, the estimates were HR: 0.01, CI: 0.002-0.02 for height,
and HR: 5.26, CI: 3.77-7.33) for height growth velocity.
Analysis of the Development of Type 1 Diabetes in Autoimmune Children
This analysis included 143 children who had developed IA, of whom 21 developed type 1
diabetes. All children had at least 2 height and weight measurements at or after the development
of IA. Those who developed type 1 diabetes had at least 2 height and weight measurements
collected at least three months prior to type 1 diabetes diagnosis. The minimum number of size
measurements per child in this analysis was 2, the median was 7, and maximum was 31. Mean
heights, weights and BMIs by age of IA positive children who did and did not develop type 1
diabetes are presented in Supplemental Online Figure 2. The 21 children who developed
diabetes had a mean IA development age of 2.32 years (compared with 5.29 years in those who
had not developed diabetes during follow-up), and developed type 1 diabetes at a mean age of
6.86 years (Table 3).
In models adjusted for age at first autoantibody positive visit, ethnicity, HLA DR,DQ genotype,
and family history of type 1 diabetes, greater height growth velocity was strongly associated
with progression to type 1 diabetes (HR: 3.34, CI: 1.73–6.42) for a 1 SD difference in velocity,
in children with autoimmunity. Height, weight, BMI, weight growth velocity, and BMI growth
velocity were not associated with more rapid progression to type 1 diabetes in autoimmune
children (Table 3).
Discussion
In this analysis of children at increased genetic risk for type 1 diabetes, greater height growth
velocity was associated with earlier IA development in healthy children, and was even more
strongly associated with more rapid progression to type 1 diabetes in autoimmune children.
Shorter height was weakly associated with IA development, but was not associated with
progression to type 1 diabetes in IA positive children. Weight, BMI, and growth velocities of
weight and BMI were not associated with either IA development or progression to type 1
diabetes.
Many of the previous studies had used SD scores for height, weight, and BMI, calculated from
general population data for the analysis of association with type 1 diabetes, using a case-control
design. However, since the DAISY cohort is selected to be at increased genetic risk for type 1
diabetes, and therefore is not expected to be representative of the general population, and
because we have an excellent comparison group embedded within our cohort (i.e., the higher
risk children who did not develop the outcome), it was not necessary to calculate SD scores to
examine the association between body size and the development of islet autoimmunity and
type 1 diabetes. Prospective follow-up of our cohort produced longitudinal data on size, which
gave us the opportunity to examine velocity of growth. We note that our results regarding height
velocity are consistent with what has been reported, even though other studies had used other
statistical approaches and had used SD scores for their measure of height. Our analyses extend
the previous findings by suggesting that the velocity of linear growth, rather than attained height
or change in height (growth), may be the operative factor.
The mean difference in height growth velocity between DAISY children who did and did not
develop IA is 0.18 cm per year (Table 2). It is not clear whether an increase in growth velocity
of this small of a magnitude is biologically relevant. However, the difference in height growth
velocity between those autoimmune children who did and did not develop diabetes is much
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larger. IA-positive children that subsequently developed type 1 diabetes had a mean height
growth velocity that was 0.54 cm per year greater than IA-positive DAISY children that did
not develop type 1 diabetes. The consistency of the associations between greater height growth
velocity and more rapid development of both IA and type 1 diabetes is intriguing. Our findings
may offer preliminary support for the Overload Hypothesis (7), which suggests that high
growth rate may exacerbate the autoimmune process via beta cell overload. A causal link
between rapid linear growth rate and greater risk of IA and subsequent type 1 diabetes
development could be postulated. However, we acknowledge that greater height growth
velocity may simply be a side effect of the underlying biologic mechanisms that drive the
autoimmune disease process.
One potential explanation for our findings is that increased linear growth velocity, perhaps
associated with higher levels of IGF-1, may result in greater insulin secretion and insulin
resistance, which have also been shown to be associated with greater IGF-1 levels (34;39;
40). Insulin resistance may increase demands on the beta cell, and has been shown to precede
type 1 diabetes development (41), especially when coupled with reduced insulin secretion
(42). However, there is currently little evidence supporting a role of insulin resistance in
predicting islet autoimmunity. Finally, we cannot rule out a primary increase in insulin levels
as the explanation for the more rapid linear growth. Chronic hyperinsulinemia, perhaps due to
a genetic tendency for hyperinsulinemia, would result both in greater growth rate (43) and
greater demands for insulin from the beta cell. The class III allele of the INS gene, which is
considered to be protective against type 1 diabetes (44), is also associated with lower BMI and
lower fat mass in children with rapid infant growth (45), possibly through lower insulin
secretion. Thus, exploration of the role of the insulin (INS) gene and its effect on insulin
secretion may further our understanding of the association between rapid linear growth velocity
and progression through the autoimmune disease process. In considering potential genetic
influences on the observed associations between increased linear growth velocity and the
autoimmune disease process, it is useful to note that statistical adjustment for HLA and family
history did not materially affect these associations.
While a variety of biologic mechanisms may be responsible for greater demand on the beta
cell to produce insulin, the mechanism by which increased beta cell stress may lead to IA and
type 1 diabetes may be more straight-forward. Greater beta cell activity in response to high
glucose concentrations has been linked with increased beta cell expression of the GAD antigen
(46). Also, more active beta cells have been shown to be more susceptible to cytokine damage
(47;48). Thus, increasing beta cell activity, due to any cause, may trigger or exacerbate an
autoimmune disease process. We are limited in this exploration by our lack of measurements
on IGF-1, growth hormone, insulin, insulin resistance and beta cell function in DAISY children.
Our finding that shorter height was a weak risk factor for IA development was unexpected in
light of the previously described associations between greater height and type 1 diabetes
development(19;20;22;24;25). One possible explanation of this unexpected finding is that
shorter children may have experienced fetal or early life growth restriction, and may be more
likely to grow more rapidly than their peers. Therefore, shorter height may simply proxy greater
height growth velocity in the analysis of healthy children for the development of IA. We note
that shorter height was not associated with earlier type 1 diabetes development in autoimmune
children, which suggests that the biologic mechanisms represented by shorter height may only
be important at the earliest stages of the disease.
Childhood obesity and rapid weight gain, as measured by childhood BMI, weight growth
velocity, and BMI growth velocity, were not associated with earlier IA development in healthy
children, or more rapid progression to type 1 diabetes in autoimmune children. These findings
run contrary to previous reports (18;20-23;25-28) which suggested that increased height,
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weight, and/or BMI may be associated with type 1 diabetes or islet autoimmunity development.
It is possible that the effects of obesity (weight or BMI) on the autoimmune disease process
might be more evident in children without genetic risk for type 1 diabetes, and therefore may
not be detectable in DAISY’s higher risk population. Also, the majority of these studies found
associations with size or growth in very young ages, which was not the population of the current
study. Our results suggest that the association with height velocity and type 1 diabetes is present
at later ages in childhood. We are not able to make any inferences regarding the role of height
growth velocity in the risk of islet autoimmunity and type 1 diabetes in children under the age
of 2 years.
In conclusion, greater height growth velocity is either directly involved, or correlated with
unmeasured factors involved, in the natural evolution from genetic susceptibility to
autoimmunity and type 1 diabetes development in pre-pubertal children. Our results support
further exploration of the biologic mechanisms underlying the association between rapid linear
childhood growth rate, IA development, and progression to type 1 diabetes.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Research supported by National Institutes of Health grants R01-DK49654, DK32493, Diabetes Endocrine Research
Center, Clinical Investigation & Bioinformatics Core P30 DK 57516, and the General Clinical Research Centers
Program, National Center for Research Resources M01RR00069.
Abbreviations
BLUP best linear unbiased predictors
DAISY Diabetes Autoimmunity Study in the Young
IA islet autoimmunity
IA2 protein tyrosine phosphatase islet antigen 2
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Table 1
Childhood Size and Growth Velocities in 3, 5 and 8 year old children in the Diabetes Autoimmunity Study in
the Young (DAISY)
Age 3 (Mean (SD)) Age 5 (Mean (SD)) Age 8 (Mean (SD))
N = 1,319 N = 1,140 N = 796
Height (cm)a97.06 (4.25) 110.94 (4.78) 130.86 (5.95)
Weight (kg)a14.78 (1.68) 20.34 (2.95) 29.44 (5.90)
BMI (kg/m2)a16.04 (1.08) 15.85 (1.42) 16.83 (2.38)
Height growth velocity
(change in cm per year) 6.84 (0.54) 6.75 (0.56) 6.63 (0.57)
Weight growth velocity
(change in cm per year) 2.78 (0.84) 2.81 (0.91) 2.96 (1.01)
BMI growth velocity
(change in kg / m2 · year) −0.26 (0.29) 0.08 (0.32) 0.58 (0.47)
aBest linear unbiased predictor (BLUP) estimates of height, weight, or BMI.
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Table 2
Analysis of Body Size and Growth in the Development of IA in Children at Increased Risk of Type 1 Diabetes
Developed Islet
Autoimmunity
(N = 75)
Did not Develop
Islet Autoimmunity
(N = 1,639)
Hazard Ratio
(95% Confidence
Interval)
Variable % Yes (N) % Yes (N)
High-risk HLA DR,DQ genotype 34.7 (26) 19.5 (319) 2.13 (1.32 – 3.42)
Family history of type 1 diabetes 57.3 (43) 48.0 (786) 1.44 (0.91 – 2.28)
Female 53.3 (40) 47.4 (777) 1.29 (0.82 – 2.04)a
Non-Hispanic White Ethnicity 80.0 (60) 75.6 (1,239) 1.12 (0.63 – 2.00)a
Maternal education > 12 years
(N = 1,656) 83.8 (62) 78.6 (1,244) 1.36 (0.73 – 2.52)a
Annual Income ≥ $30,000
(N = 1,617) 76.4 (55) 76.9 (1,188) 1.01 (0.58 – 1.74)a
Mean (SD) Mean (SD)
Age at first autoantibody positive
visit or most recent visit (yrs) 6.63 (2.39) 7.91 (2.71) N/A
Height (cm)bN/AcN/Ac0.34 (0.16–0.72) d
Weight (kg)bN/AcN/A c0.61 (0.39–0.98) d
BMI (kg/m2)bN/AcN/Ac0.99 (0.80–1.21) d
Height growth velocity
(change in cm / year) 6.96 (0.45) 6.78 (0.55) 1.63 (1.31–2.05)d
Weight growth velocity
(change in kg / year) 2.80 (0.70) 2.80 (0.87) 0.88 (0.69–1.11)d
BMI growth velocity
(change in kg / m2 · year) N/AcN/Ac0.88 (0.64–1.21) d
aHazard ratios adjusted for HLA DR,DQ genotype and family history of type 1 diabetes
bBest linear unbiased predictor (BLUP) estimates of height, weight, or BMI.
cNot applicable due to the time-varying nature of the data. See Table 1 for details regarding these variables.
dHazard ratios for a 1 standard deviation (SD) difference, adjusted for ethnicity, HLA DR,DQ genotype, and family history of type 1 diabetes. The
standard deviations for height, weight, BMI, height growth velocity, weight growth velocity and BMI growth velocity were 17.84, 8.67, 1.99, 0.57,
0.93, and 0.57, respectively.
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Table 3
Analysis of Body Size and Growth in the Development of Type 1 Diabetes in Autoimmune Children at Increased
Risk of Type 1 Diabetes
Progressed to
Type 1 Diabetes
(N = 21)
Did Not Progress to
Type 1 Diabetes
(N = 122)
Hazard Ratio
(95% Confidence
Interval)
Variable % Yes (N) % Yes (N)
High-risk HLA DR,DQ genotype 52.4 (11) 27.1 (33) 2.14 (0.91 – 5.06)
Family history of type 1 diabetes 71.4 (15) 52.5 (64) 2.02 (0.78 – 5.23)
Female 47.6 (10) 48.4 (59) 1.51 (0.62 – 3.64)a
Non-Hispanic White Ethnicity 85.7 (18) 82.0 (100) 0.54 (0.15 – 1.90) a
Maternal education >12 years (N = 138) 71.4 (15) 81.2 (95) 0.81 (0.30 – 2.18) a
Annual Income ≥ $30,000 (N = 133) 75.0 (15) 77.9 (88) 0.60 (0.19 – 1.93) a
Mean (SD) Mean (SD)
IA development age (yrs) 2.32 (1.78) 5.29 (2.97) 0.84 (0.64 – 1.09) a
Age at type 1 diabetes development or
most recent visit (yrs) 6.86 (2.12) 8.80 (2.58) N/A
Height (cm) bN/AcN/A c0.98 (0.22–4.36) d
Weight (kg) bN/A cN/A c0.88 (0.33–2.32) d
BMI (kg/m2) bN/A cN/A c1.12 (0.70–1.81) d
Height growth velocity
(change in cm / year) 7.16 (0.49) 6.62 (0.64) 3.34 (1.73–6.42) d
Weight growth velocity
(change in kg / year) 2.74 (1.34) 3.17 (1.22) 1.01 (0.58–1.77) d
BMI growth velocity
(change in kg / m2 · year) N/A cN/A c1.28 (0.79–2.08) d
aHazard ratios adjusted for age at first autoantibody positive visit, HLA DR,DQ genotype and family history of type 1 diabetes
bBest linear unbiased predictor (BLUP) estimates of height, weight, or BMI.
cNot applicable due to the time-varying nature of the data. See Table 1 for details regarding these variables.
dHazard ratios for a 1 standard deviation (SD) difference, adjusted for age at first autoantibody positive visit, ethnicity, HLA DR,DQ genotype and
family history of type 1 diabetes. The standard deviations for height, weight, BMI, height growth velocity, weight growth velocity and BMI growth
velocity were 18.19, 9.26, 2.05, 0.68, 1.14, and 0.58, respectively.
Diabetologia. Author manuscript; available in PMC 2010 October 1.
