The Effect of Ethnicity in the Rate of Beta-Cell Functional Loss in the First 3 Years After Type 1 Diabetes Diagnosis

Abstract

Objective

We set forth to compare ethnicities for metabolic and immunological characteristics at the clinical diagnosis of type 1 diabetes (T1D) and assess the effect of ethnicity on beta-cell functional loss within 3 years after clinical diagnosis.

Research Methods and Design

We studied participants in TrialNet New Onset Intervention Trials (n = 624, median age = 14.4 years, 58% male, 8.7% Hispanic) and followed them prospectively for 3 years. Mixed meal tolerance tests (MMTT) were performed within 6 months following clinical diagnosis and repeated semiannually. Unless otherwise indicated, analyses were adjusted for age, sex, BMI Z-score, and diabetes duration.

Results

At T1D clinical diagnosis, Hispanics, compared with non-Hispanic whites (NHW), had a higher frequency of diabetic ketoacidosis (DKA) (44.7% vs 25.3%, OR = 2.36, P = 0.01), lower fasting glucose (97 vs 109 mg/dL, P = 0.02) and higher fasting C-peptide (1.23 vs 0.94 ng/mL, P = 0.02) on the first MMTT, and higher frequency of ZnT8 autoantibody positivity (n = 201, 94.1% vs 64%, OR = 7.98, P = 0.05). After exclusion of participants in experimental arms of positive clinical trials, C-peptide area under the curve (AUC) trajectories during the first 3 years after clinical diagnosis were not significantly different between Hispanics and NHW after adjusting for age, sex, BMI-z score, and DKA (n = 413, P = 0.14).

Conclusion

Despite differences in the metabolic and immunological characteristics at clinical diagnosis of T1D between Hispanics and NHW, C-peptide trajectories did not differ significantly in the first 3 years following clinical diagnosis after adjustment for body mass index and other confounders. These findings may inform the design of observational studies and intervention trials in T1D.

In the natural history of type 1 diabetes (T1D), there is a progressive loss of beta-cell function beginning at least 2 years prior to diagnosis and continuing postdiagnosis (1). We have previously shown that Hispanic ethnicity influences progression to T1D, and overweight/obesity disproportionately affects Hispanic children <12 years of age in T1D development risk compared with non-Hispanic whites (2). At clinical diagnosis of T1D, Hispanic children had higher C-peptide levels compared with non-Hispanic whites after adjustment for confounding factors (3). However, the influence of race/ethnicity on the trajectory of beta-cell function after clinical onset has not been well-studied.

Preserved beta-cell function correlates with better glucose control (4) and is a well-known protective factor against acute and chronic complications of T1D (5, 6). Various factors, including genetics, age at diagnosis, duration of diabetes, being childhood vs adult-onset, diabetic ketoacidosis (DKA) at diagnosis, and nutrition, have been shown to be associated with preservation of C-peptide after diagnosis of T1D in natural history studies (7-13). Despite the remarkable benefits of glycemic control shown in the Diabetes Control and Complications Trial (DCCT) (14), only 1 in 5 individuals with T1D achieves the goals set by the American Diabetes Association (15). Racial minorities have higher frequencies of acute and chronic complications (16, 17). Among many factors involved in the low rate of glycemic control at recommended goals, health disparities based on biological and/or sociodemographic factors have emerged as critical contributors (17-20). Understanding the effect of these factors in the natural history of T1D may shed light on interventional targets for optimal diabetes care.

A few therapies have demonstrated safety and efficacy in delaying the loss of C-peptide in individuals recently diagnosed with clinical T1D (21-23). In addition to benefits related to maintaining beta-cell function, successful trials provide a rationale for subsequent testing for prevention in at-risk individuals before clinical diagnosis (24). It would be important to evaluate the importance of ethnicity-specific factors that affect beta-cell function to strengthen the design of future trials into the efficacy of potential islet-preserving therapies in T1D.

The Type 1 Diabetes TrialNet cohort provides a unique opportunity to study the effects of ethnicity on the natural history of T1D. The Type 1 Diabetes TrialNet is an international multicenter consortium of clinical centers that aims to prevent, delay, or alter the course of T1D. In an effort to preserve beta-cell functional reserve, the Type 1 Diabetes TrialNet conducted 6 interventional trials on individuals with recently diagnosed T1D (21, 22, 25-28). In this study, we aimed to compare key metabolic and immunologic characteristics between patients of different ethnic groups participating in these trials at the time of clinical diagnosis of T1D, and to assess the effect of ethnicity on their postdiagnosis loss of beta-cell function.

Materials and Methods

Subjects

Our analysis included data from 624 subjects. We included all the participants in the experimental and placebo groups for a pretreatment assessment of baseline characteristics. However, for the analysis of C-peptide trajectories in the first 3 years postdiagnosis, we included data from only 413 subjects after exclusion of participants in experimental groups of positive trials (21, 22, 28). In the 3 negative randomized controlled trials (25-27), the experimental arms received canakinumab (a human monoclonal anti-interleukin-1 antibody) or anakinra (a human interleukin-1 receptor antagonist) in TN14 (25), glutamic acid decarboxylase (GAD) vaccine (3 doses vs 2 doses) in TN08 (26), and mycophenolate mofetil alone or with daclizumab in TN02 (27). Placebo and experimental groups were well-balanced for clinical and demographic characteristics with following exceptions: (1) there were more females in the group who received 2 injections of GAD vaccine as compared with those who received 3 injections of GAD vaccine and the placebo group in TN08 (26), and (2) interleukin-6 and interleukin-1 receptor antagonist concentrations were significantly different in the anakinra group compared with placebo in TN14 (25), which were attributed to extreme values in 3 subjects (1 in placebo and 2 in anakinra group). The number of participants contributed by each trial for the entire cohort as well as the analysis of C-peptide trajectories is shown in Table 1. All participants or parents provided written informed consent, and assent as appropriate. The study protocols were approved by Independent Ethics Committee or Institutional Review Boards. Inclusion criteria for all studies included diagnosis of T1D within 100 days of randomization, positivity for at least one T1D-associated islet autoantibody (glutamic acid decarboxylase-65 [GAD-65] autoantibodies, islet cell antigen-512 [ICA-512] autoantibodies, islet cell autoantibodies [ICA], microinsulin autoantibodies [mIAA], or zinc transporter 8 [ZnT8] autoantibodies), and presence of beta-cell function confirmed by stimulated C-peptide ≥0.2 nmol/L (0.6 ng/mL) on a mixed meal tolerance test (MMTT). While GAD65, ICA-512, mIAA, and ICA were tested in all participants across trials, ZnT8 autoantibody was tested only in individuals who were negative for GAD65, ICA-512, and mIAA in 1 trial (18), and all participants in 2 other trials (14, 15), per TrialNet study protocol.

Entry age criteria showed variation between studies but collectively included ages 3 to 45 years. We excluded 6 subjects because of missing race data (n = 4) and incomplete MMTT data (n = 2). First MMTTs were performed within 6 months (median 2 months; range, 4 days to 6 months) following diagnosis. Participants were monitored under the original study protocols during the first 2 years of participation and then followed under the TrialNet Long Term Investigative Follow-up protocol with regular MMTT assessments every 6 months as long as C-peptide was detectable to a maximum of 6 years (median 29.7 months; range, 1.0-75.2 months).

Race and ethnicity categorization

We determined race and ethnicity categorizations based on self-report and standard National Institutes of Health (NIH) classifications for race and ethnicity (29). We assigned participants to 1 of 3 racial/ethnic groups: Hispanics, non-Hispanic whites (NHW), and non-Hispanic other races (NHO). We included non-Hispanic multiracial participants in the NHO category.

DKA data

DKA data at T1D onset were obtained during screening visit assessment by clinical sites. This information was either provided via self-report by patients/families or obtained from medical records by clinical sites.

Anthropometric measures and laboratory analysis

Body mass index (BMI).

BMI was calculated using data from the screening visit (92%) or the treatment allocation visit. BMI Z-scores were calculated for all participants.

Human leukocyte antigen typing.

Human leukocyte antigen (HLA) genotyping was performed at TrialNet HLA Laboratory at the Barbara Davis Center using the AutoGen QuickGene-610 instrument. Participants were classified by the presence or absence of the highest risk genotype: DR3-DQ2 (DRB1*0301 – DQA1*0501 – DQB1*0201) and DR4-DQ8 (DQA1*0301 – DQB1*0302 with DRB1*0401, *0402 or *0405).

Autoantibody assays.

All islet autoantibodies except ICA were measured by radioimmunoassay in the TrialNet Core Laboratory at the Barbara Davis Center for Childhood Diabetes. However, presence of ICA was tested by indirect immunofluorescence in the Diagnostic Referral Laboratories at the University of Florida. Multiple autoantibody positivity is defined as presence of 2 or more islet autoantibody positivities at baseline.

Mixed meal tolerance test.

A 2-hour MMTT was performed prior to 10:00 am after an overnight fast if fasting glucose levels were 70 to 200 mg/dL as previously described (30). The participants were asked to consume Boost-HP (Nestle Health Care Nutrition, Inc) at a dose of 6 mg/kg to a maximum of 360 mL at the beginning of the test. Measurements of C-peptide and glycated hemoglobin A1c (HbA1c) were performed at Northwest Lipid Laboratories (University of Washington, Seattle, WA). A 2-site immunoenzymatic assay was used to measure C-peptide levels (Tosoh II 600 autoanalyzer).

Assessment of beta-cell function.

Various beta-cell functional assessments were completed using data obtained during MMTTs. The area under the curve (AUC) C-peptide was determined by using the trapezoidal method. C-peptide AUC data have previously been used in TrialNet intervention trials as a significant outcome measure with regard to beta-cell function (21, 25-27). Maximum C-peptide was defined as the highest C-peptide level during each MMTT. Early C-peptide response (30-0 min C-peptide) was defined as the difference between 30-minute C-peptide and baseline C-peptide levels. 60-30 min C-peptide was calculated as the difference between 60-minute C-peptide and 30-minute C-peptide levels. Two separate late-C peptide responses were evaluated: (1) 90-60 min C-peptide level, the difference between 90-minute C-peptide and 60-minute C-peptide levels; and (2) 120/30 min C-peptide, the ratio of 120-minute C-peptide level divided by the 30-minute C-peptide level. C-peptide index was defined as the ratio of the difference between 30 minute and baseline C-peptide levels, and the difference between 30-minute and baseline glucose levels. The pattern of C-peptide responsiveness using oral glucose tolerance test (OGTT) data has been previously shown to shed light on the heterogeneity of T1D development in at-risk individuals participating in the Diabetes Prevention Trial-Type 1 (DPT-1) (31). Assessing these intermediate measures from MMTT data in the current study is entirely exploratory. Index-60 was calculated for each participant using log fasting-C peptide, 60-minute glucose, and 60-minute C-peptide levels from MMTTs. Index-60 was originally developed in DPT-1 and TrialNet Natural History Study participants as an endpoint that could potentially provide an earlier diagnosis of T1D than standard criteria using the abovementioned data obtained from OGTTs (32). In addition, Index-60 has been shown to be more associated with typical characteristics of T1D than glucose measures both prior to (33) and at diagnosis (manuscript in preparation). Thus, it has utility for assessing heterogeneity within the T1D spectrum.

Statistical methods

Descriptive analyses were used to summarize characteristics at baseline across all participants. Characteristics were compared between the race/ethnicity composite groups using Kruskal-Wallis tests for continuous variables, and chi-square tests for categorical/dichotomized factors, where Fisher exact tests were used as appropriate with small numbers in subset groups. Regression analysis was used to determine the associations between race/ethnicity and various covariates. Linear mixed-effects regression models were used to model the C-peptide AUC trajectory over time. The overall ethnicity difference was assessed by testing the ethnicity coefficient in the fitted model. Fitted model estimates (marginal effects) and corresponding delta-method computed standard errors were used to perform comparisons at specific time points. The primary outcome measure was the difference in C-peptide trajectories and beta-cell functional loss between the race/ethnicity composite groups assessed by C-peptide responses on regular MMTTs in the first 3 years postdiagnosis. Secondary outcome measures were the frequency of DKA, fasting glucose level, fasting C-peptide level, and the frequency of multiple autoantibody positivity at baseline assessment. Statistical significance was determined at P ≤ 0.05. All analyses were performed using the Stata version 15.1 statistical program (Stata Corporation, College Station, TX). Unless otherwise indicated, all analyses were adjusted for age, sex, age- and sex-adjusted baseline BMI Z-score, and days from diagnosis to MMTT.

Results

We studied 624 TrialNet participants enrolled in the 6 intervention trials. The study population was 87% (n = 543) NHW, 8.7% (n = 54) Hispanic, and 4.3% (n = 27) NHO. Because of the small sample size and mixed nature of the NHO group, we focused on comparing the NHW and Hispanic groups. The median (interquartile range [IQR]) ages were 13.1 (6.2) and 14.5 (8.2) years for the Hispanic and NHW groups, respectively (P = 0.01). The percentage of female participants (42.6% in Hispanics and 41.6% in NHW) and multiple autoantibody positive participants at diagnosis (94.4% in Hispanics and 90.1% in NHW) were similar between the groups. The demographic and baseline characteristics are summarized in Table 2.

Islet autoantibody positivity at diagnosis

There was no group difference in percentages of positivity for each autoantibody at T1D diagnosis, except for the ZnT8 autoantibody. The frequency of ZnT8 autoantibody positivity was higher in Hispanics compared with NHW after adjustment for age, sex, BMI-z score, and presence of DR3-DQ2/DR4-DQ8 (n = 201; 94.1% vs 64%; OR 7.98; P = 0.05). However, there was no significant difference in ZnT8 autoantibody titers between the groups in participants with available ZnT8 titers (P = 0.20).

DKA at diagnosis

Compared with NHW, Hispanics had a significantly higher rate of DKA at diagnosis after adjustment for age, sex, BMI-z score, and presence of DR3-DQ2/DR4-DQ8 (44.7% vs 25.3%; OR 2.36; 95% CI, 1.18-4.68; P = 0.01).

Metabolites at the time of first MMTT

Compared with NHW, Hispanics had lower fasting glucose (97 mg/dL vs 109 mg/dL; P = 0.02), and higher fasting C-peptide levels (1.23 ng/mL vs 0.94 ng/mL; P = 0.02) after adjustment for age, sex, BMI z-score, presence of DR3-DQ2/DR4-DQ8, and days from diagnosis to MMTT. There were no differences in C-peptide AUC, maximum C-peptide, Index-60, HbA1c, 30-0 min C-peptide level, and 60-30 min C-peptide level between the groups.

C-peptide trajectories in the first 3 years postdiagnosis

After excluding the participants in experimental arms of positive trials, we assessed the C-peptide trajectories in 413 subjects (90.6% [n = 374] NHW and 9.4% [n = 39] Hispanic) after adjusting for age, sex, BMI z-score, and DKA using data obtained through MMTTs. In this subset, there were no differences in gender, duration of diabetes, and BMI-z score, while Hispanics were younger than NHW (13 years vs 14.3 years, P = 0.026), similar to the entire cohort (Table 2). In addition, there was no difference in HbA1c or insulin dose at baseline and during first 3 years postdiagnosis between the Hispanic and NHW groups. On average, Hispanics had higher C-peptide AUC shortly after onset of T1D compared with NHW (average difference at 3 months postdiagnosis = 0.37 ng/mL; P = 0.04; and at 6 months = 0.34 ng/mL; P = 0.05) and tended to have higher levels until 12 months postdiagnosis (difference at 9 months = 0.31 ng/mL; P = 0.065; and 12 months = 0.28 ng/mL; P = 0.091). However, this difference diminished as the disease progressed, so that the 2 trajectories converged by 3 years (Fig. 1, overall trajectory difference, P = 0.14). In addition, there was no significant difference in the slopes between the groups (P = 0.1). In the first 3 years postdiagnosis, overall, we did not find any differences in 30-0 min C-peptide levels (P = 0.14), 90-60 min C-peptide levels (P = 0.64), 120/30 min C-peptide levels (P = 0.18), C-peptide index (P = 0.38), and Index-60 (P = 0.21). Nevertheless, Hispanics had higher early C-peptide response (30-0 min C-peptide levels) during the first year following T1D diagnosis, and lower Index-60 levels in the first 6 months postdiagnosis, compared with NHW (all P ≤ 0.05).

Discussion

The most important new finding of this study is that the rate of beta-cell functional loss in the first 3 years after clinical diagnosis of T1D did not differ by ethnicity despite differences in other parameters observed at clinical diagnosis (frequency of DKA, ZnT8 autoantibody positivity, fasting glucose, and C-peptide levels on first MMTT), and during the first year postdiagnosis (early C-peptide responses, mean C-peptide AUC, and Index-60). Although Hispanics and NHWs had similar mean C-peptide AUC levels at diagnosis, higher mean C-peptide AUC levels were observed in Hispanics compared with NHW in the first 6 months following diagnosis. In addition, there was a trend for higher mean C-peptide AUC levels in Hispanics at 9 and 12 months postdiagnosis, but this difference did not reach statistical significance. These findings suggest that ethnicity-specific factors may not play a significant role in beta-cell loss in the early postdiagnosis period, especially after the first year of diagnosis. Because T1D is more prevalent in NHW than minorities, and historically, there is a low rate of study participation among minorities, the current knowledge is limited regarding T1D natural history in minority populations. These data suggest that it may be possible to generalize findings in T1D intervention trials with an endpoint of beta-cell preservation in the early postdiagnosis phase between NHW and Hispanics.

C-peptide trajectories during the first 2 (34) and 4 years (35) after T1D diagnosis have been previously reported using data obtained from TrialNet intervention trials. A smaller previous study (n = 191, 7.3% Hispanics) suggested that there was no association between ethnicity and various C-peptide indices, including AUC C-peptide and peak C-peptide at baseline and over time during 2 years of follow-up (34). The effect of ethnicity was not reported in the study conducted by Hao et al (35). Our analysis confirms the previous findings of no significant association between ethnicity and C-peptide trajectory with a significantly larger sample size (n = 624, 8.7% Hispanics) and longer duration of follow-up. In addition, it adds new information regarding a tendency towards higher values of C-peptide indices in Hispanics than in NHW that is present during the first year after diagnosis but not maintained. Also, it expands our understanding of the natural history beyond the first 2 years after diagnosis.

We found that, compared with NHW, Hispanics had higher fasting C-peptide levels but not C-peptide AUC in the assessment immediately after T1D diagnosis (median 60 days from diagnosis to MMTT) after adjustment for confounding factors. This finding is in agreement with our previous report showing higher random C-peptide levels in Hispanics than NHW in 712 children with new-onset T1D (3), despite differences in the measurement (random vs fasting) and timing (at diagnosis vs immediate postdiagnosis). Higher C-peptide levels in Hispanics at clinical diagnosis of T1D may be suggestive of higher insulin resistance even after adjustment for BMI. In fact, it is known that BMI underestimates adiposity in Hispanics compared with NHW (36) We previously proposed that multiple mechanisms including insulin resistance play a role in T1D development in Hispanics (3). Lack of a difference in C-peptide AUC despite higher fasting C-peptide levels at baseline in Hispanics may suggest a lower glucose-stimulated insulin production capacity in Hispanics than that of NHW at the clinical diagnosis of T1D. However, Hispanics had slightly higher C-peptide AUC in the early postdiagnosis period, higher early C-peptide response, and lower Index-60 in the first year postdiagnosis compared with NHW, but they did not maintain this advantage over 3 years. Further investigations are warranted to better understand the factors associated with this clinical course. In contrast to these findings in the early postdiagnosis phase, in a cross-sectional analysis with a mean diabetes duration of approximately 10 years, C-peptide level was not associated with ethnicity in 1662 participants with T1D in the SEARCH study (37).

There have been conflicting reports in the literature regarding the differences in immunological factors between T1D patients of different ethnic groups. Although an earlier study reported that NHW with newly diagnosed T1D were more likely to have multiple autoantibodies than Hispanics (38), we did not find any differences in that regard between NHW and Hispanics. Increased availability of ZnT8 autoantibody measurement, and higher rate of positivity in Hispanics in the present study might explain the similar rates of multiple autoantibody positivity in our study. However, in our previous study of 711 children evaluated at Texas Children’s Hospital, in which ZnT8 autoantibody was not assessed, the frequencies of multiple autoantibodies were similar at the onset of T1D (3). Although some studies reported differences in the frequency of individual islet autoantibody positivity between ethnic groups (39-41), there are other reports that did not show any differences (42, 43). Our study confirms the latter studies, with the exception of a higher frequency of the ZnT8 autoantibody in Hispanics compared with NHW, but it differs from a previous report of similar frequencies of the ZnT8 autoantibody among NHW and Hispanics in the Type 1 Diabetes Genetics Consortium Autoantibody Workshop Study (41). If confirmed, this difference in autoantibody positivity between the ethnic groups in our study may imply a heterogeneity of pathophysiological mechanisms at the onset of T1D.

DKA at diagnosis of T1D have been previously shown to be associated with several risk factors, including younger age, ethnic minority, lower BMI, delayed diagnosis, and lower socioeconomic status (SES) (44-47). Having a DKA episode at diagnosis of T1D was related to poor residual beta-cell function in children with T1D in previous studies (11, 48). Our study highlights a striking ethnic difference in the rate of DKA at the diagnosis of T1D. Among newly diagnosed participants, Hispanics had significantly higher rate of DKA after adjustment for confounding factors (44.7% vs 25.3%; OR 2.36; P = 0.01). We speculate that this difference could be in part contributed by lower SES in the Hispanics, as SES data were not available for adjustment. This observation is in agreement with our previous finding of a higher rate of DKA in Hispanics compared with NHW in 711 children with newly diagnosed with T1D (51.5% vs 38.2%; P = 0.006) (3). In contrast, the rates of DKA at diagnosis, and the proportions of any DKA event at or after diagnosis in the first 3 years following diagnosis were similar after adjustment for age and sex between Hispanics and NHW in 927 Pediatric Diabetes Consortium (PDC) participants with T1D (17). Conflicting results between data from TrialNet in the present study and PDC need further investigation. The difference in the rate of DKA expands beyond the time of diagnosis in some studies. Although a similar rate of hospitalization for DKA was reported in Hispanics and NHW with T1D in a cross-sectional study (20), recent T1D Exchange data showed a higher rate of DKA in Hispanics compared with NHW (12.2% vs 7.4%, P = 0.04) in 10 704 youth with T1D for more than 1 year, even after adjustment for annual household income (49). However, upon stratification based on annual household income, the difference persisted only in children with an annual household income ≥$100 000. Because of its significant mortality and morbidity risks, further research is warranted to shed light on health disparities in the rate of DKA.

The limitations of our study include the small number of participants from other racial/ethnic minorities (restricting our focus to differences between NHW and Hispanics only), limited number of measurements for ZnT8 and islet cell autoantibody per TrialNet study protocol, and lack of SES status data. It should be emphasized that Index-60 was derived from OGTTs rather than MMTTs. However, as a combined C-peptide and glucose measure, we found it helpful for comparing metabolic decline between the groups. The Index-60 findings were consistent with findings from the other measures. Our results may not be generalizable to those with lower beta-cell functional reserve at clinical diagnosis of T1D, as one of our inclusion criteria was having a stimulated C-peptide ≥0.2 nmol/L (0.6 ng/mL). In addition, we advise caution against generalization of our results across the T1D population because the study participants represent eligible individuals who opted into fairly intensive intervention studies. Strengths include the large sample size with a significant number of Hispanic participants, and close follow-up with a comprehensive assessment of beta-cell function over time under strict study protocols. To the best of our knowledge, this is the largest study assessing the role of ethnicity in beta-cell function loss over 3 years following clinical diagnosis of T1D. However, future studies with larger number of Hispanic participants as well as those including individuals of other races/ethnicities are needed.

In conclusion, despite ethnic differences in the frequency of DKA, and metabolic and immunological characteristics at clinical diagnosis of T1D, C-peptide trajectories are similar in the first 3 years following diagnosis among Hispanics and NHW. These findings may inform the design of observational studies and intervention trials in the early period following clinical diagnosis of T1D. One should note that there may be subtle differences in the loss of beta-cell function between ethnicities in the first year after diagnosis, which warrants further investigation due to increasing scientific focus on interventions to preserve beta-cell function during this critical time period.

Abbreviations

Abbreviations
 
• AUC

  area under the curve

 
• BMI

  body mass index

 
• DKA

  diabetic ketoacidosis

 
• GAD

  glutamic acid decarboxylase

 
• HbA1c

  glycated hemoglobin A1c

 
• ICA

  islet cell autoantibodies

 
• ICA-512

  islet cell antigen-512

 
• mIAA

  microinsulin autoantibodies

 
• MMTT

  mixed meal tolerance test

 
• OGTT

  oral glucose tolerance test

 
• T1D

  type 1 diabetes

 
• ZnT8

  zinc transporter 8

Acknowledgments

We thank the study participants for their participation in the respective intervention trials.

The datasets generated during and/or analyzed during the current study are available in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository.

Financial Support: We acknowledge the support of the Type 1 Diabetes TrialNet Study Group, which identified study participants and provided samples and follow-up data for this study. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK097835, UC4 DK106993, and JDRF. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the JDRF.

Author Contributions: All authors are members of the Type 1 Diabetes TrialNet Study Group and, as such, contributed to the data used in this article. M.T. and M.J.R. designed the study. All authors contributed to result interpretation. M.T. wrote the initial draft and edited the manuscript. M.C., J.M.S., I.L., D.A.B., A.B. and M.J.R. reviewed and edited the manuscript. M.C. performed statistical analyses. M.T. and M.J.R. are the guarantors of this work, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version of the manuscript.

Prior Presentation: Part of this study was presented at the 79^th Scientific Sessions of the American Diabetes Association, San Francisco, CA, June 7-11, 2019.

Type 1 Diabetes TrialNet Study Group

Steering Committee: C. J. Greenbaum, Chair (Benaroya Research Institute), M. Anderson (University of California, San Francisco), P. Antinozzi (Wake Forest University), M. Atkinson (University of Florida), M. Battaglia (San Raffaele Diabetes Research Institute), D. Becker (University of Pittsburgh), P. Bingley (University of Bristol), E. Bosi (San Raffaele University), J. Buckner (Benaroya Research Institute), P. Colman (Walter & Eliza Hall Institute of Medical Research), L. DiMeglio (Indiana University), S. Gitelman, (University of California, San Francisco), R. Goland (Columbia University), P. Gottlieb (University of Colorado Barbara Davis Center for Childhood Diabetes), K. Herold (Yale University), R. Insel (Juvenile Diabetes Research Foundation), T. Kay (St Vincent’s Institute of Medical Research), M. Knip (University of Helsinki), J. Krischer (University of South Florida), A. Lernmark (Skane University), J.B. Marks (University of Miami), A. Moran (University of Minnesota), J. Palmer (University of Washington), M. Peakman (King’s College), L. Philipson (University of Chicago), A. Pugliese (University of Miami), P. Raskin (University of Texas Southwestern), M. Redondo (Baylor College of Medicine), H. Rodriguez (University of South Florida), B. Roep (Leiden University Medical Center), W. Russell (Vanderbilt University), L. Spain (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]), D.A. Schatz (University of Florida), J. Sosenko (University of Miami), D. Wherrett (University of Toronto), D. Wilson (Stanford University), W. Winter (University of Florida), A. Ziegler (Forschergruppe Diabetes); Previous Members: C. Benoist (Joslin Diabetes Center), J. Blum (Indiana University), K. Bourcier, P. Chase (University of Colorado Barbara Davis Center for Childhood Diabetes), M. Clare-Salzler (University of Florida), R. Clynes (Columbia University), G. Eisenbarth (University of Colorado Barbara Davis Center for Childhood Diabetes), C. G. Fathman (Stanford University), G. Grave (National Institute of Child Health and Human Development), B. Hering (University of Minnesota), F. Kaufman (Children’s Hospital Los Angeles), E. Leschek (NIDDK), J. Mahon (University of Western Ontario), K. Nanto-Salonen (University of Turku), G. Nepom (Benaroya Research Institute), T. Orban (Joslin Diabetes Center), R. Parkman (Children’s Hospital Los Angeles), M. Pescovitz (Indiana University), J. Peyman (National Institute of Allergy and Infectious Disease), M. Roncarolo (San Raffaele University), P. Savage (NIDDK), O. Simell (University of Turku), R. Sherwin (Yale University), M. Siegelman (University of Texas Southwestern), J.S. Skyler (University of Miami), A. Steck (University of Colorado Barbara Davis Center for Childhood Diabetes), J. Thomas (Vanderbilt University), M. Trucco (University of Pittsburgh), J. Wagner (University of Minnesota).

Executive Committee: Carla J. Greenbaum, Katarzyna Bourcier, Richard Insel, Jeffrey P. Krischer, Ellen Leschek, Lisa Rafkin, Lisa Spain. Past Members: Catherine Cowie, Mary Foulkes, Heidi Krause- Steinrauf, John M. Lachin, Saul Malozowski, John Peyman, John Ridge, Peter Savage, Jay S. Skyler, Stephanie J. Zafonte.

Chairman’s Office: Carla J. Greenbaum, Norma S. Kenyon, Lisa Rafkin, Irene Santiago, Jay M. Sosenko. Past Member: Jay S. Skyler,

TrialNet Coordinating Center (University of South Florida): Jeffrey P. Krischer, Brian Bundy, Michael Abbondondolo, Timothy Adams, Darlene Amado, Ilma Asif, Matthew Boonstra, Brian Bundy, Cristina Burroughs, David Cuthbertson, Mary Deemer, Christopher Eberhard, Steve Fiske, Julie Ford, Jennifer Garmeson, Heather Guillette, Susan Geyer, Brian Hays, Courtney Henderson, Martha Henry, Kathleen Heyman, Belinda Hsiao, Christina Karges, Nichole Keaton, Amanda Kinderman, Pat Law, Ashely Leinbach, Cristin Linton, Shu Liu, Jennifer Lloyd, Jamie Malloy, Kristin Maddox, Julie Martin, Jessica Miller, Eric Milliot, Margaret Moore, Sarah Muller, Thuy Nguyen, Ryan O’Donnell, Vanessa Oduah, Jennifer Pilger, Amy Roberts, Kelly Sadler, Tina Stavros, Roy Tamura, Keith Wood, Ping Xu, Kenneth Young. Past Staff Members: Persida Alies, Franz Badias, Aaron Baker, Monica Bassi, Craig Beam, David Boulware, London Bounmananh, Susan Bream, Doug Freeman, Jessica Gough, Jinin Ginem, Moriah Granger, Mary Holloway Michelle Kieffer, Page Lane, Lavanya Nallamshetty, Yazandra Parrimon, Kate Paulus, Joy Ramiro, AQesha Luvon Ritzie, Archana Sharma, Audrey Shor, Xiaohong Song, Amanda Terry, Jeanne Weinberger, Margaret Wootten.

Previous Coordinating Center (George Washington University): John M. Lachin, Mary Foulkes, Pamela Harding, Heidi Krause-Steinrauf, Susan McDonough, Paula F. McGee, Kimberly Owens Hess, Donna Phoebus, Scott Quinlan, Erica Raiden.

TrialNet Clinical Network HUB (Benaroya Research Institute): Carla J. Greenbaum, Emily Batts, Chris Buddy, Kristin Kirpatrick, Mary Ramey, Ann Shultz, Chris Webb, Past Member: Melita Romesco.

NIDDK Staff: Judith Fradkin, Ellen Leschek, Lisa Spain. Past Member: Peter Savage.

Data Safety and Monitoring Board: Emily Blumberg (University of Pennsylvania), Chair, Gerald Beck (Cleveland Clinic), David Brillon (Cornell University), Rose Gubitosi-Klug (Case Western Reserve), Lori Laffel (Joslin Diabetes Center), Robert Veatch (Georgetown University), Dennis Wallace (Research Triangle Institute). Past Members: Jonathan Braun (University of California Los Angeles), Ake Lernmark (Lund University), Bernard Lo (University of California San Francisco), Herman Mitchell (Rho Inc.), Ali Naji (University of Pennsylvania), Jorn Nerup (University of Copenhagen), Trevor Orchard (University of Pittsburgh), Michael Steffes (University of Minnesota), Anastasios Tsiatis (North Carolina State University), Bernard Zinman (University of Toronto).

Infectious Disease Safety Committee: Brett Loechelt (Children’s National Medical Center) (Medical Monitor), Lindsey Baden (Harvard University), Michael Green (University of Pittsburgh), Adriana Weinberg (University of Colorado).

Laboratory Directors: Santica Marcovina (University of Washington), Jerry P. Palmer, Adriana Weinberg, Liping Yu (University of Colorado Barbara Davis Center for Childhood Diabetes), Sunanda Babu (University of Colorado Barbara Davis Center for Childhood Diabetes) William Winter (University of Florida). Past Member: George S. Eisenbarth (late).

Protocol Chair Committee: Polly Bingley, Raphael Clynes, Linda DiMeglio, George Eisenbarth, Carla Greenbaum, Brian Hays, Jeffrey Krischer, Ellen Leschek, Jennifer Marks, Della Matheson, Lisa Rafkin, Henry Rodriguez, Jay Skyler, Jay Sosenko, Lisa Spain, Darrell Wilson.

Clinical Center Staff Involved in this Protocol:

Baylor College of Medicine: Maria J Redondo, David Gomez, Xiati Zheng, Sandra Pena, Massimo Pietropaolo.

Benaroya Research Institute, Seattle: Carla Greenbaum, Emily Batts, Tyler Brown, Jane Buckner, Angela Dove, Marissa Hammond, Deborah Hefty, Jani Klein, Kristen Kuhns, McKenzie Letlau, Sandra Lord, Marli McCulloch-Olson, Lisa Miller, Gerald Nepom, Jared Odegard, Mary Ramey, Elaine Sachter, Marissa St. Marie, Kimberly Stickney, Dana VanBuecken, Ben Vellek, Christine Webber. Past Members: Laurie Allen, Jenna Bollyk, Nicole Hilderman, Hebatullah Ismail, Steve Lamola, Srinath Sanda, Heather Vendettuoli, David Tridgell.

Children’s Hospital Los Angeles: Roshanak Monzavi, Meredith Bock, Lynda Fisher, Mary Halvorson, Debra Jeandron, Mimi Kim, Jamie Wood. Past Members: Mitchell Geffner, Francine Kaufman, Robertson Parkman, Christine Salazar.

Columbia University, New York: Robin Goland, Raphael Clynes, Steve Cook, Matthew Freeby, Mary Pat Gallagher, Rachelle Gandica, Ellen Greenberg, Amy Kurland, Sarah Pollak, Amy Wolk. Past Members: Mary Chan, Linda Koplimae, Elizabeth Levine, Kelly Smith, Jeniece Trast.

Indiana University, Indianapolis: Linda DiMeglio, Janice Blum, Carmella Evans-Molina, Robin Hufferd, Bonnie Jagielo, Christy Kruse, Vanessa Patrick, Mark Rigby, Maria Spall, Kim Swinney, Jennifer Terrell. Past Members: Lyla Christner, LeeAnn Ford, Sheryl Lynch, Martha Menendez, Patricia Merrill, Mark Pescovitz (late), Henry Rodriguez.

Joslin Diabetes Center, Boston: Cielo Alleyn, David Baidal, Steve Fay, Jason Gaglia, Brittany Resnick, Sarah Szubowicz, Gordon Weir. Past Members: Ronald Benjamin, Debbie Conboy, Andrea deManbey, Richard Jackson, Heyam Jalahej, Tihmar Orban, Alyne Ricker, Joseph Wolfsdorf, Hui H. Zhang.

Stanford University: Darrell Wilson, Tandy Aye, Bonita Baker, Karen Barahona, Bruce Buckingham, Kerry Esrey, Trudy Esrey, Garry Fathman, Radhika Snyder. Past Members: Beenu Aneja, Maya Chatav, Oralia Espinoza, Eliana Frank, Jenny Liu, Jennifer Perry, Rebecca Pyle, Alison Rigby, Kristin Riley, Adriana Soto.

University of California San Francisco: Stephen Gitelman, Saleh Adi, Mark Anderson, Ashley Berhel, Kathy Breen, Kathleen Fraser, Andrea Gerard-Gonzalez, Paula Jossan, Robert Lustig, Sara Moassesfar, Amy Mugg, David Ng, Priya Prahalod, Martha Rangel-Lugo, Srinath Sanda, Joshua Tarkoff, Christine Torok, Rebecca Wesch. Past Members: Ivy Aslan, Jeanne Buchanan, Jennifer Cordier, Celia Hamilton, Louise Hawkins, Thu Ho, Anjali Jain, Karen Ko, Theresa Lee, Shelly Phelps, Stephen Rosenthal, Taninee Sahakitrungruang, Lorraine Stehl, Lisa Taylor, Marcia Wertz, Jenise Wong.

University of Chicago: Louis Philipson, Rosemary Briars, Nancy Devine, Elizabeth Littlejohn. Past Member: Tiffany Grant.

University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora: Peter Gottlieb, Georgeanna Klingensmith, Andrea Steck, Aimon Alkanani, Kimberly Bautista, Ruth Bedoy, Aaron Blau, Betsy Burke, Laraine Cory, MyLinh Dang, Lisa Fitzgerald-Miller, Alex Fouts, Vicky Gage, Satish Garg, Patricia Gesauldo, Raymond Gutin, Cory Hayes, Michelle Hoffman, Kaitlin Ketchum, Nyla Logsden-Sackett, David Maahs, Laurel Messer, Lisa Meyers, Aaron Michels, Stesha Peacock, Marian Rewers, Perla Rodriguez, Flor Sepulbeda, Rachel Sippl, Andrea Steck, Iman Taki, Bao-Khan Tran, Tuan Tran, R. Paul Wadwa, Philip Zeitler. Past Members: Jennifer Barker, Sandra Barry, Laurie Birks, Leah Bomsburger, Terra Bookert, Leah Briggs, Patricia Burdick, Rosio Cabrera, Peter Chase, Erin Cobry, Amy Conley, Gabrielle Cook, Joseph Daniels, Dominic DiDomenico, Jennifer Eckert, Angelica Ehler, George Eisenbarth (late), Pamela Fain, Rosanna Fiallo-Scharer, Nicole Frank, Hannah Goettle, Michelle Haarhues, Sherrie Harris, Lauren Horton, John Hutton (late), Joy Jeffrrey, Rachael Jenison, Kelly Jones, Whitney Kastelic, Maria Amelia King, Debbie Lehr, Jenna Lungaro, Kendra Mason, Heather Maurer, Luy Nguyen, Allison Proto, Jaime Realsen, Kristina Schmitt, Mara Schwartz, San Skovgaard, Jennifer Smith, Brandon Vanderwel, Mary Voelmle, Rebecca Wagner, Amy Wallace, Philip Walravens, Laurie Weiner, Becky Westerhoff, Emily Westfall, Katina Widmer, Hali Wright.

University of Florida, Gainesville: Desmond Schatz, Annie Abraham, Mark Atkinson, Miriam Cintron, Michael Clare- Salzler, Jessica Ferguson, Michael Haller, Jennifer Hosford, Diane Mancini, Hank Rohrs, Janet Silverstein, Jamie Thomas, William Winter. Past Members: Gloria Cole, Roberta Cook,Ryan Coy, Elena Hicks, Nancy Lewis.

University of Miami: Jennifer Marks, Alberto Pugliese, Carlos Blaschke, Della Matheson, Alberto Pugliese, Natalia Sanders-Branca, Jay Sosenko. Past Members: Luz Arazo Ray Arce, Mario Cisneros, Samir Sabbag.

University of Minnesota, Minneapolis: Antoinette Moran, Carrie Gibson, Brian Fife, Bernhard Hering, Christine Kwong, Janice Leschyshyn, Brandon Nathan, Beth Pappenfus, Anne Street. Past Members: Mary Ann Boes, Sarah Peterson Eck, Lois Finney, Theresa Albright Fischer, Andrea Martin, Chenai Jacqueline Muzamhindo, Missy Rhodes, Jennifer Smith, John Wagner, Bryan Wood.

University of Pittsburgh: Dorothy Becker, Kelli Delallo, Ana Diaz, Barbara Elnyczky, Ingrid Libman, Beata Pasek, Karen Riley, Massimo Trucco. Past Members: Brian Copemen, Diane Gwynn, Frederico Toledo.

University of South Florida: Henry Rodriguez, Sureka Bollepalli, Frank Diamond, Emily Eyth, Danielle Henson, Anne Lenz, Dorothy Shulman.

University of Texas Southwestern, Dallas: Phillip Raskin, Soumya Adhikari, Brian Dickson, Erin Dunnigan, Ildiko Lingvay, Lourdes Pruneda, Maria Ramos-Roman, Philip Raskin, Chanhaeng Rhee, John Richard, Mark Siegelman, Daytheon Sturges, Kathryn Sumpter, Perrin White.

Past Members: Marilyn Alford, Jamie Arthur, M. Larissa Aviles-Santa, Erica Cordova, Renee Davis, Stefani Fernandez, Steve Fordan, Tauri Hardin, Aris Jacobs, Polina Kaloyanova, Ivanna Lukacova-Zib, Sasan Mirfakhraee, Alok Mohan, Hiroshi Noto, Oralenda Smith, Nenita Torres.

University of Toronto: Diane Wherrett, Diana Balmer, Lesley Eisel, Roze Kovalakovska, Mala Mehan, Farah Sultan. Past Members: Brenda Ahenkorah, Jose Cevallos, Natasha Razack, Mary Jo Ricci, Angela Rhode, Mithula Srikandarajah, Rachel Steger.

Vanderbilt University, Nashville: William E. Russell, Margo Black, Faith Brendle, Anne Brown, Daniel Moore, Eric Pittel, Alyssa Robertson, April Shannon, James W. Thomas.

Yale University, New Haven: Kevan Herold, Laurie Feldman, Robert Sherwin, William Tamborlane, Stuart Weinzimer.

International Clinical Center Staff involved in this Protocol:

Hospital District of Southwest Finland: Jorma Toppari, Tiina Kallio, Maarit Kärkkäinen, Elina Mäntymäki, Tiina Niininen, Birgitta Nurmi, Petro Rajala, Minna Romo, Sointu Suomenrinne.

Past Members: Kirsti Näntö- Salonen, Olli Simell, Tuula Simell.

San Raffaele Hospital (Italy): Emanuele Bosi, Manuela Battaglia, Eleonora Bianconi, Riccardo Bonfanti, Pauline Grogan, Andrea Laurenzi, Sabina Martinenghi, Franco Meschi, Matteo Pastore.

Past Members: Luca Falqui, Maria Teresa Muscato, Matteo Viscardi.

University of Bristol (United Kingdom): Polly Bingley, Harriet Castleden, Nicola Farthing, Sam Loud, Claire Matthews, Jennifer McGhee, Ann Morgan, Joanna Pollitt. Past Members: Rebecca Elliot-Jones, Carole Wheaton.

University of Helsinki: Mikael Knip, Heli Siljander, Heli Suomalainen.

Walter and Eliza Hall Institute of Medical Research (Australia): Peter Colman, Felicity Healy, Shelley Mesfin, Leanne Redl, John Wentworth, Jinny Willis. Past Members: Maree Farley, Leonard Harrison, Christine Perry, Fiona Williams.

TrialNet Online List of Affiliate Investigators

TrialNet Affiliates: Aberdeen, Scotland: A. Mayo, J. Paxton, V. Thompson; Ajo, AZ: L. Volin; Akron, OH: C. Fenton, L. Carr, E. Lemon, M Swank; Albany, NY: M.K. Luidens, M. Salgam, V. Sharma; Albuquerque, NM: D. Schade, C. King; Ames, IA: R. Carano, J. Heiden; Anchorage, AK: N.D Means, L. Holman; Ann Arbor, MI: I. Thomas, D. Madrigal, T. Muth, C.L. Martin, C. Plunkett, C. Ramm, R.J. Auchus; Asheville, NC: W. Lane, E. Avots, M. Buford, C. Hale, J. Hoyle, B. Lane; Atlanta, GA: A. Muir, S. Shuler, N. Raviele, E. Ivie, M. Jenkins, K. Lindsley, I. Hansen, D.O. Fadoju, E.I. Felner, B. Bode, R. Hosey, J. Sax; Auckland, NZ: C. Jefferies, S. Mannering, R. Prentis; Augusta, GA: J.X. She, M. Stachura, D. Hopkins, J. Williams, L. Steed, E. Asatapova; Austin, TX: S. Nunez, S. Knight, P. Dixon; Bakersfield, CA: J. Ching; Baltimore, MD: T. Donner, S. Longnecker, K. Abel, K. Arcara, S. Blackman, L. Clark, D. Cooke, L. Plotnick, P.A. Levin, L. Bromberger, K. Klein; Bangor, ME: K. Sadurska, C. Allen, D. Michaud, H. Snodgrass; Bartlett, TN: G. Burghen, S. Chatha, C. Clark; Baton Rouge, LA: J. Silverberg, C. Wittmer, J. Gardner, C. LeBoeuf; Belfast, Ireland: P. Bell, O. McGlore, H. Tennet, N. Alba; Bend, OR: M. Carroll, L. Baert, H. Beaton, E. Cordell, A. Haynes, C. Reed, K. Lichter, P. McCarthy, S. McCarthy, T. Monchamp, J. Roach, S. Manies; Billings, MT: F. Gunville, L. Marosok, T. Nelson, K. Ackerman, J. Rudolph, M. Stewart; Birmingham, AL: K. McCormick, S. May, T. Falls; Birmingham, UK: T. Barrett, K. Dale, L. Makusha, C. McTernana, K. Penny-Thomas, K. Sullivan, P. Narendran, J. Robbie, D. Smith; Boise, ID: R. Christensen, B. Koehler, C. Royal, T. Arthur, H. Houser, J. Renaldi, S. Watsen; Bonita, CA: P. Wu, L. Lyons, B. House, J. Yu; Bournemouth, UK: H. Holt, M. Nation, C. Vickers, R. Watling; Bronx, NY: R. Heptulla, J. Trast, C. Agarwal, D.J. Newell, R. Katikaneni; Brunley, UK: C. Gardner, A. Del Rio, A. Logan, H. Collier, C. Rishton, G. Whalley, A. Ali, S. Ramtoola; Buffalo, NY: T. Quattrin, L. Mastrandea, A.J. House, M. Ecker; Calgary, AB: C. Huang, C. Gougeon, J. Ho, D. Pacuad; Cambridge, UK: D. Dunger, J. May, C. O’Brien, C. Acerini, B. Salgin, A. Thankamony, R. Williams; Chapel Hill, NC- J. Buse, G. Fuller, M. Duclos, J. Tricome, H. Brown, D. Pittard; Charleston, SC: D. Bowlby, A. Blue, T. Headley; Charleston, WV: S. Bendre, K. Lewis, K. Sutphin; Charlottesville, VA: C. Soloranzo, J. Puskaric, H. Madison; Chattanooga, TN: M. Rincon, M. Carlucci, R. Shridharani, B. Rusk, E. Tessman, D.M. Huffman, H. Abrams, B. Biederman, M.D. Jones, V. Leathers; Chicago, IL: W. Brickman, P. Petrie, D. Zimmerman, J. Howard, L. Miller, R. Alemzadeh, D.V. Mihailescu, R. Melgozza-Walker, N. Abdulla, C. Boucher-Berry, D. Ize-Ludlow, R. Levy, C. Swenson Brousell; Christchurch, NZ: R. Scott, H. Heenan, H. Lunt, D. Kendall, J. Willis, B. Darlow; Cincinnati, OH: N. Crimmins, D. Edler, T. Weis, C. Schultz; Cleveland, OH: D. Rogers, D. Latham, C. Mawhorter, C. Switzer, W. Spencer, P. Konstantnopoulus, S. Broder, J. Klein; Colombia, MO: B. Bachrach, M. Gardner, D. Eichelberger; Columbia, SC: L. Knight, L. Szadek, G. Welnick, B. Thompson; Colombus, OH: R. Hoffman, A. Revell, J. Cherko, K. Carter, E. Gilson, J. Haines, G. Arthur, B. Bowen, W.B. Zipf, P. Graves, R.A. Lozano, D. Seiple, K. Spicer; Concord, CA: A. Chang, J. Fregosi, J Harbinson, C. Paulson, S. Stalters, P. Wright, D. Zlock; Cooperstown, NY: A.E. Freeth, J. Victory; Crystal Lake, IL: H. Maheshwari, A. Maheshwari, T. Holmstrom, J. Bueno; Danbury, CT: R. Arguello, J. Ahern, L. Noreika, V. Watson, S. Hourse; Dayton, OH: P. Breyer, C. Kissel, Y. Nicholson, M. Pfeifer, S. Almazan; Denver, CO: J. Bajaj, M. Quinn, K. Funk, J. McCance, E. Moreno, R. Veintimilla, A. Wells; Des Moines, IA: J. Cook, S. Trunnel; Detroit, MI: D. Transue, J. Surhigh, D. Bezzaire, K. Moltz, E. Zacharski; Downers Grove, IL: J. Henske, S. Desai, K. Frizelis, F. Khan; Duluth, MN: R. Sjoberg, K. Allen; Dunedin, NZ: P.P Manning, G. Hendry, B. Taylor, S. Jones; Edmonton, AB: R. Couch, R. Danchak,D. Lieberman; El Paso, TX: W. Strader, M.E. Bencomo; Escondido, CA: T. Bailey, L. Bedolla, C. Roldan; Exeter, UK: C. Moudiotis, B. Vaidya, C. Anning, S. Bunce, S. Estcourt, E. Folland, E. Gordon, C. Harrill, J. Ireland, J. Piper, L. Scaife, K. Sutton, S. Wilkins, M. Costelloe, J. Palmer; Fargo, ND: L. Casas, C. Miller, M. Burgard, C. Erickson, J. Hallanger-Johnson; Florence, SC: P. Clark, W. Taylor; Florissant, MO: J. Galgani; Fresno, CA: S. Banerjee, C. Banda, D. McEowen, R. Kinman; Garran, Australia: A. Lafferty, S. Gillett, C. Nolan, M. Pathak; Grand Folks, ND: L. Sondrol, T. Hjelle, S. Hafner, J. Kotrba, R. Hendrickson; Grand Rapids, MI: A.P. Cemeroglu, T. Symington, M. Daniel, Y. Appiagyei-Dankah, D.C. Postellon, M.S. Racine, L. Kleis; Greenville, NC: K. Barnes, S.E. Godwin, H. McCullough, K. Shaheen, G. Buck, L. Noel, M.L. Warren; Greenville, SC: S. Weber, S.M. Parker, I. Gillespie, B.A. Nelson, C. Frost, J. Amrhein, E.C. Moreland, A. Hayes, J. Peggram; Hackensack, NJ: J. Aisenberg, M.E Riordan, J. Zasa; Halifax, NS: E. Cummings, K. Scott, T. Pinto, A. Mokashi; Hamilton, ON: K. McAssey, E. Helden; Harrogate, UK: P. Hammond, L. Dinning, S. Rahman, S. Ray; Hartford CT: C. Dimicri, S. Guppy, H. Nielsen; Henderson, NV: C.K. Vogel, C. Ariza, L. Morales; Hershey, PA: Y.T. Chang, R.A. Gabbay, L. Ambrocio, L. Manley; Hollywood, FL: R. Nemery, W. Charlton, P. Smith, L. Kerr, B. Steindel-Kopp, M. Alamaguer; Honolulu, HI: E. Tabisola-Nuesca, A. Pendersen, N. Larson, H. Cooper-Olviver, D. Chan, D. Fitz-Patrick, T. Carreira, Y. Park, R. Ruhaak; Idaho Falls, ID: D. Liljenquist, G. Browning, T. Coughenour, M.B. Sulk; Iowa City, IA: E. Tsalikan, M. Tansey, J. Cabbage; Jackson, MS: N. Dixit, S. Pasha, M. King, K. Adcock, H. Atterberry; Jacksonville, FL: L. Fox, K. Englert, N. Mauras, J. Permuy, K. Sikes; Joliet, IL: T. Berhe, B. Guendling, L. McLennan, L. Paganessi, C. Murphy; Kalamazoo, MI: M.B. Draznin, M. Kamboj, S. Sheppard; Kalispell, MT: V. Lewis, L. Coates; Kansas City, MO: W. Moore, G. Babar, J. Bedard, D. Brenson-Hughes, J. Cernich, M. Clements, R. Duprau, S. Goodman, L. Hester, L. Huerta-Saenz, A. Karmazin, T. Letjen, S. Raman; Kingsport, TN: D. Morin, W. Bestermann, E.J. Morawski, J.L. White, A. Brockmyer, R. Bays, S. Campbell, A. Stapleton, N. Stone, A. Donoho, H. Everett. H. Hensley, M. Johnson, C. Marshall, N. Skirvin, P. Taylor, R. Williams, L. Ray, C. Wolverton; Knoxville, TN: D.A. Nickels, C. Dothard; Lake Success, NY: P.W. Speiser, M. Pellizzari, L. Bokor; Las Vegas, NV: K. Izuora, S. Abdelnour, P. Cummings, S. Paynor, M. Leahy, M. Riedl, S. Shockley, R. Saad, T. Briones; Lebanon, NH: S. Casella, C. Herz, K. Walsh; Leichester, UK: J. Greening, F. Hay, S. Hunt, N. Sikotra, L. Simons; Lexington, KY: D.G. Karounos, R. Oremus, L. Dye, L. Myers, D. Ballard, W. Miers, R. Sparks; Little Rock, AR: K.M. Thraikill, K. Edwards, J. Fowlkes, S. Kemp, A. Morales, L. Holland, L. Johnson; Liverpool, UK: P. Paul, A. Ghatak, K. Phelen, H. Leyland, T. Henderson; Livingston, NJ: D. Brenner, E. Oppenheimer, I. Mamkin, C. Moniz; London, ON: C. Clarson, M. Lovell; Los Angeles, CA: A. Peters, V. Ruelas, D. Borut, D. Burt, M. Jordan, S. Castilla, P. Flores, M. Ruiz, L. Hanson, J. Green-Blair, R.J. Sheridan; Lousiville, KY: K.A. Wintergerst, G. Pierce, A. Omoruyi, M. Foster, S. Kingery; Lubbock, TX: A. Lunsford, I. Cervantes, T. Parker, P. Price, J. Urben; Manchester, UK: I. Doughty, H. Haydock, V. Parker; Melbourne, Australia: P. Bergman, S. Duncum, C. Rodda; Memphis, TN: A.D. Thomas, R. Ferry, D. McCommon, J. Cockroft; Mesa, AZ: A. Perelman, R. Calendo; Miami, FL: C. Barrera, E. Arce-Nunez, Y. Martinez, M. De la Portilla, I. Cardenas, L. Garrido, M. Villar; Milan, Italy: R. Lorini, E. Calandra, G. D’Annuzio, K. Perri, N. Minuto, C. Rebora, R. Callegari; Milwaukee, WI: O. Ali, J. Kramer, B. Auble, S. Cabrera, P. Donohoue, R. Fiallo-Scharer, M. Hessner, P. Wolfgram, A. Kansra, N. Bettin, R. McCuller, A. Miller; Mineola, NY: S. Accacha, J. Corrigan, E. Fiore, R.L. Levine, T.A. Mahoney; Montreal, QC: C. Polychronakos, V. Gagne; Morristown, NJ: H. Starkman, M. Fox, D. Chin, F. Melchionne, L.A. Silverman; New Brunswick, NJ: I. Marshall, L. Cerracchio, J. Cruz, A. Viswanathan, J. Wilson; New Orleans, LA: S. Chalew, S. Valley, S. Layburn, A. Lala, P. Clesi, M. Genet, G. Uwaifo, A. Charron, T. Allerton, W. Cefalu, L. Melendez-Ramirez, R. Richards, C. Alleyn, E. Gustafson, M. Lizanna; New Port Richey, FL: J. Wahlen, S. Aleiwe, M. Hansen, H. Wahlen; New York, NY: C.J. Levy, A. Bonaccorso, R. Rapaport, Y. Tomer, D. Chia, M. Goldis, L. Iazzetti, M. Klein, C. Levister, L. Waldman, E. Wallach, M.O. Regelmann, Z. Antal, M. Aranda, C. Reynholds; Newcastle Upon Tyne, UK: N. Leech, D. Wake, C. Owens, M. Burns, J. Wotherspoon, A. Murray, K. Short, G. Curry, S. Kelsey, J. Lawson, J. Porter, S. Stevens, E. Thomson, S. Winship, L. Wynn; Newton, NZ: E. Wiltshire, J. Krebs, P. Cresswell, H. Faherty, C. Ross; Norfolk, VA: A. Vinik, P. Barlow, M. Bourcier, M.L. Nevoret; North Adelaide, Australia: J. Couper, S. Beresford; Norwich, UK: N. Thalagne, H. Roper, J. Gibbons, J. Hill, S. Balleaut, C. Brennan, J. Ellis-Gage, L. Fear, T. Gray, L. Jones, C. McNerney, L. Pointer, N. Price, K. Few, D. Tomlinson; Nottingham, UK: L. Denvir, J. Drew, T. Randell, P. Mansell, S.A. Bell, S. Butler, Y. Hooton, H. Navarra, A. Roper, G. Babington, L. Crate, H. Cripps, A. Ledlie, C. Moulds, R. Norton, B. Petrova, O. Silkstone, C. Smith; Oak Lawn, IL: K. Ghai, M. Murray, V. Viswanathan, M. Henegan, O. Kawadry; Oakland, CA: J.A. Olson, L. Patterson, T. Ahmad, B. Flores; Oklahoma City, OK: D. Domek, S. Domek, K. Copeland, M. George, J. Less, T. Davis, M. Short; Olympia Fields, IL: A. Dwarakanathan, P. O’Donnell; Omaha, NE: B. Boerner, L. Larson, M. Phillips, M. Rendell, K. Larson, C. Smith, K. Zebrowski, L. Kuechenmeister, M. Thevarayapillai; Orange, CA: M. Daniels, H. Speer, N. Forghani, R. Quintana, C. Reh, A. Bhangoo; Orlando, FL: P. Desrosiers, L. Ireland, T. Misla, C. Torres, S. Wells, J. Villar, M. Yu, D. Berry, D. Cook, J. Soder, A. Powell; Ormskirk, UK: M. Ng, M. Morrison, Z. Haslam; Ottawa, ON: M. Lawson, B. Bradley, J. Courtney, C. Richardson, C. Watson, E. Keely, D. DeCurtis; Palm Beach Gardens, FL: M. Vaccarcello-Cruz, Z. Torres, K. Sandberg; Pensacola, FL: H. Hsiang, B. Joy, D. McCormick, A. Powell, H. Jones, J. Bell, S. Hargadon, S. Hudson, M. Kummer; Peoria, IL: S. Sauder, E. Sutton, K. Gensel, R. Aguirre-Castaneda, V. Benavides Lopez, D. Hemp, S. Allen, J. Stear; Perth, Australia: E. Davis, T. Jones, A. Roberts, J.A Dart, N. Paramalingam; Philadelphia, PA: L.E. Levitt Katz, N. Chaudhary; K.M. Murphy, S.M. Willi, B. Schwartzman; Phoenix, AZ: C. Kapadia, D. Larson, D. McClellan, G. Shaibai, L.A. Kelley, G. Villa, C. Kelley, R. Diamond, M. Kabbani, T. Dajani, F. Hoekstra, M. Magorno; Pittsburgh, PA: J. Holst, V. Chauhan, N. Wilson, P. Bononi, M. Sperl; Plymouth, UK: A. Millward, M. Eaton, L. Dean; Portland, ME: J. Olshan, H. Renna, C. Milliard; Portland, OR: D. Snyder, S. Beaman, K. Burch, J. Chester, A. Ahmann, B. Wollam, D. DeFrang, R. Fitch, K. Jahnke, K. Hanavan, B. Klopfenstein, L. Nicol, R.W. Bergstrom, T. Noland; Poughkeepsie, NY: J. Brodksy, L. Bacon; Providence, RI: J.B. Quintos, L.S. Topor, S. Bialo, B. Bancroft, A.G. Soto; Raleigh, NC: W. Lagarde, H. Lockemer, T. Vanderploeg; Rancho Cucamonga, CA: M.A Ibrahim, M. Huie, V. Sanchez; Rapid City, SD: R. Edelen, R. Marchiando, J. Palmer, T. Repas, M. Wasson, P. Auker, J. Culbertson, T. Kieffer, D. Voorhees, T. Borgwardt, L. DeRaad; Reno, NV: K. Eckert; Richland, WA: E. Isaacson, H. Kuhn, A. Carroll, M. Schubert; Richmond, VA: G. Francis, S. Hagan, T. Le, M. Penn, E. Wickham; Rio Piedras, PR: C. Leyva, K. Rivera, J. Padilla, I. Rodriguez; Rochester, NY: N. Jospe, J. Czyzyk, B. Johnson; Sacramento, CA: U. Nadgir, N. Marlen, G. Prakasam, C. Rieger, N. Glaser, E.C. Heiser, B. Harris; Salt Lake City, UT C. Foster, H. Slater, K. Wheeler, D.L Donaldson, M. Murray; San Antonio, TX: D.E. Hale, R. Tragus, D.R. Word, J. Lynch, L. Pankratz, W. Rogers; San Diego, CA: R. Newfield, S. Holland, M. Hashiguchi, M. Gottschalk, A. Philis-Tsimikas, R. Rosal, S. Franklin, S.M. Guardado; San Francisco, CA: N. Bohannon, M. Garcia; San Jose, CA: T. Aguinaldo, J. Phan, V. Barraza, D. Cohen; Santa Barbara, CA: J. Pinsker, U. Khan, J. Wiley, L. Jovanovic; Santa Clara, CA: P. Misra, M. Wright, D. Cohen, K. Huang; Scottsbluff, NE: M. Skiles, S. Maxcy; Seattle, WA: C. Pihoker, K. Cochrane, J. Fosse, S. Kearns, M. Klingsheim; Sheffield, UK: N. Wright, L. Viles, H. Smith, S. Heller, M. Cunningham, A. Daniels, L. Zeiden, J. Field, R. Walker; Sioux Falls, SD: K.J. Griffin, L. Bartholow, C. Erickson, J. Howard, B. Krabbenhoft, C. Sandman, A. Vanveldhuizen, J. Wurlger, A. Zimmerman, K. Hanisch, L. Davis-Keppen; South Brisbane, Australia: A. Cotterill, J. Kirby, M. Harris, A. Schmidt; Spokane, WA: C. Kishiyama, C. Flores, J. Milton, W. Martin, C. Whysham, A. Yerka, T. Freels, J.M. Hassing, J. Webster; Springfield, IL: R. Green, P. Carter, J. Galloway, D. Hoelzer, S. Roberts, S. Said, P. Sullivan; Springfield, MA: H.F. Allen, E. Reiter, E. Feinberg, C. Johnson; St. John’s, NL: L.A. Newhook, D. Hagerty; St. Louis, MO: N.H. White, L. Levandoski; St. Paul, MN: J. Kyllo, M. Johnson, C. Benoit; St. Petersburg, FL: P. Iyer, F. Diamond, H. Hosono, S. Jackman, L. Barette, P. Jones; Syracuse, NY: I. Sills, S. Bzdick, J. Bulger, R. Weinstock; Taunton, UK: I. Douek, R. Andrews, G. Modgill, G. Gyorffy, L. Robin, N. Vaidya, S. Crouch, K. O’Brien, C. Thompson, N. Thorne; Toledo, OH: J. Blumer, J. Kalic, L. Klepek, J. Paulett, B. Rosolowski, J. Horner, M. Watkins; Topeka, KS: J.L. Casey, K. Carpenter, C. Burns, J. Horton, C. Pritchard, D. Soetaert, A.G. Wynne; Torrance, CA: K. Kaiserman, M. Halvorson; Tucson, AZ: C. Chin, O.Y. Molina, C. Patel, R. Senguttuvan, M. Wheeler, O. Furet, C. Steuhm; Tulsa, OK: D.H. Jelley, S. Goudeau, L. Chalmers, D. Greer; Vancouver, BC: C. Panagiotopoulos, D.L. Metzger, D. Nguyen, M. Horowitz; Walnut Creek, CA: M.P. Christiansen,. E. Glades, C. Morimoto, M. Macarewich, R. Norman, K. Patin, C. Vargas, A. Barbanica, A. Yu; Washington DC: P. Vaidyanathan, W. Osborne, R. Mehra; Wenatchee, WA: S. Kaster, S. Neace, J. Horner; Wilmington, DE: G. Reeves, C. Cordrey, L. Marrs, T. Miller, S. Dowshen, D. Doyle; Winnipeg, Manitoba: S. Walker, D. Catte, H. Dean; Winston-Salem, NC: M. Drury-Brown, B. Hackman; Worcester, MA: M.M.C. Lee, S. Malkani, K. Cullen, K. Johnson; Yuma, AZ: P. Hampton, M. McCarrell, C. Curtis, E. Paul, Y. Zambrano.

Additional Information

Disclosure Summary: The authors declare that there is nothing to disclose associated with this manuscript.

Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References