Comparison of autoantibody-positive and autoantibody-negative pediatric participants enrolled in the T1D Exchange clinic registry

Abstract

Objective

To compare characteristics of autoantibody (aAb)-positive and -negative cases of type 1 diabetes (T1D) <18 years old in the T1D Exchange clinic registry.

Methods

An aAb-positive status (n = 6239) required at least one of the aAbs to be positive; an aAb-negative status (n = 485) required negative results on testing of at least two different aAbs.

Results

The percentage of males was higher (58% vs 51%; P = 0.002) and total daily insulin dose lower (P = 0.003) in aAb-negative compared with aAb-positive groups, but both groups had similar distributions of race–ethnicity, diagnosis age, family history of T1D, ketoacidosis at diagnosis, body mass index at diagnosis and at most recent office visit, and current HbA1c.

Conclusions

Male gender and lower total daily insulin dose were more likely in aAb-negative than aAb-positive children with T1D, but no other distinguishing characteristics were identified. Further examination of characteristics of aAb-negative cases may help characterize the heterogeneous nature of T1D.

Introduction

Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing β-cells, leading to insulin deficiency.¹ Autoantibodies (aAbs) are markers of an autoimmune response, but in 10%–20% of cases of presumed T1D testing is negative.^2–5 There have been limited efforts to further understand the physiopathology behind this group of patients, with some data suggesting a higher incidence of aAb negativity among those of African or Asian ancestry.^5–8 Using the large T1D Exchange clinic registry database,⁹ the present study compared the characteristics of youth with T1D who were aAb-positive with those who were aAb-negative.

Methods

The T1D Exchange Clinic Network includes 67 US-based pediatric and adult endocrinology practices. A registry of individuals with T1D commenced enrollment in September 2010⁹ and, as of 1 August 2012, included 25 833 participants, with 14 592 aged <18 years. To be enrolled in the clinic registry, an individual must have a clinical diagnosis of presumed autoimmune T1D and either islet cell antibodies present or, if antibodies are negative or unknown, then insulin must have been started at or shortly after diagnosis and used continually thereafter (except in the case of a pancreas or islet cell transplant). Each clinic received approval from an institutional review board (IRB). Informed consent and assent from minors were obtained according to IRB requirements. Data were collected for the registry’s central database from the participant’s medical record and by having the participant or parent complete a comprehensive questionnaire, as described previously.⁹

Clinic registry participants <18 years old who had aAb measurements available were considered for the present analysis. Pancreatic aAb test results, which were obtained from the clinic’s medical records, included islet cell (ICA), glutamate decarboxylase (GAD), tyrosine phosphatase (IA-2 or ICA-512), and zinc cotransporter (ZnT8); insulin aAb results were not used because of uncertainty in determining the timing of assessment relative to the initiation of insulin therapy. Only the 6724 participants who met the criteria for either aAb-positive or aAb-negative, as described below, were included in the analysis. An aAb-positive status (n = 6239) required at least one autoantibody to be positive at any time relative to diagnosis; an aAb-negative status (n = 485) required negative results on testing of at least two different aAbs, at least one of them within 12 months after diagnosis (Tables 1–3 show the autoantibodies tested and the results for the aAb-positive and aAb-negative cases; Table S1, available as Supplementary Material to this paper, shows the timing of measurements relative to diagnosis.)

Table 1.

Cross-tabulation for combinations of autoantibodies tested and autoantibody positivity within the autoantibody-positive group (n = 6239)

		Autoantibody positive
	All	Anti-GAD	Anti-GAD/anti-IA2	Anti-GAD/anti-IA2/ZnT	Anti-GAD/ZnT	Anti-IA2	Anti-IA2/ZnT	ICA	ICA/anti-GAD	ICA/anti-GAD/anti-IA2	ICA/anti-GAD/anti-IA2/ZnT	ICA/anti-GAD/ZnT	ICA/anti-IA2	ICA/anti-IA2/ZnT	ICA/ZnT	ZnT
Autoantibody tested
Anti-GAD	633	633
Anti-GAD/anti-IA2	1825	395	1175			255
Anti-GAD/anti-IA2/ZnT	249	30	33	109	13	19	31									14
Anti-GAD/ZnT	19	8			10											1
Anti-IA2	47					47
Anti-IA2/ZnT	6						6
ICA	210							210
ICA/anti-GAD	2677	666						497	1514
ICA/anti-GAD/anti-IA2	300	42	79			20		7	25	104			23
ICA/anti-GAD/anti-IA2/ZnT	33	6	1	1	3	1	1	1		6	6			5		2
ICA/anti-GAD/ZnT	216	21			20			28	32			56			47	12
ICA/anti-IA2	19					6		2					11
ICA/ZnT	1														1
ZnT	4															4

Data show the number of individuals in each group.

GAD, glutamic acid decarboxylase; IA2, islet antigen 2; ZnT, zinc transporter; ICA, islet cell antibodies.

Table 3.

Frequency for testing of each autoantibody, within each antibody group

	Autoantibody positive (n = 6239)		Autoantibody negative (n = 485)
	No. tested	No. positive (%)	No. tested
ICA	3456	2575 (75)	342
GAD	5952	4988 (84)	482
IA2	2479	1939 (78)	169
ZnT8	528	342 (65)	62

GAD, glutamic acid decarboxylase; IA2, islet antigen 2; ZnT8, zinc transporter 8; ICA, islet cell antibodies.

Differences in clinical characteristics comparing aAbpositive and aAb-negative participants were assessed using Chi-squared tests for categorical variables and t-tests or Wilcoxon rank tests for continuous variables. When assessing the differences in current body mass index (BMI), HbA1c, and total daily insulin dose, participants with diabetes of <1 year duration were excluded from the analysis. All P-values are two-sided. Due to multiple comparisons, only P < 0.01 were considered to be potentially clinically meaningful. Analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA).

Results

As shown in Table 4, diagnosis age was similar in aAb-positive and aAb-negative cases. The aAb-negative cases were more likely than aAb-positive cases to be male (58% vs 51%, respectively; P = 0.002), but both groups had similar race–ethnicity distributions and a similar frequency of family history of T1D.

Table 4.

Characteristics of antibody-positive and antibody-negative participants

	Antibody positive (n = 6239)	Antibody negative (n = 485)	P-value*
Age at diagnosis (years)	7.8 ± 3.9	7.7 ± 4.2	0.770
Males (%)	3187 (51)	283 (58)	0.002
Race–ethnicity†			0.510
White non-Hispanic	4628 (74%)	347 (72%)
Black non-Hispanic	396 (6%)	35 (7%)
Hispanic–Latino	784 (13%)	66 (14%)
Asian	101 (2%)	12 (2%)
Other	300 (5%)	24 (5%)
Family history (first-degree relative) of T1D‡	741 (12%)	66 (14%)	0.250
BMI percentile at diagnosis§	47 (15, 83)	39 (12, 79)	0.130
No. normal/underweight (%)	2586 (77)	218 (78)
No. overweight (%)	373 (11)	25 (9)
No. obese (%)	396 (12)	35 (13)
Current BMI percentile§	77 (57, 91)	77 (54, 90)	0.320
No. normal/underweight (%)	2755 (63)	229 (65)
No. overweight (%)	974 (22)	71 (20)
No. obese (%)	666 (15)	51 (15)
DKA at diagnosis**	2029 (35%)	151 (33%)	0.360
Current HbA1c†† (%)	8.4 ± 1.5	8.4 ± 1.5	0.810
Current total daily insulin dose‡‡ (units/kg per day)	0.83 ± 0.38	0.77 ± 0.35	0.003

Unless indicated otherwise, data are given as either the mean ± SD or the number of subjects in each group, with percentages in parentheses.

^*P-values were calculated for categorical variables using a Chi-squared test and for continuous variables using either a t-test (when mean values are shown) or Wilcoxon’s rank test (when median values are shown).

^†Race/ethnicity data were unavailable for 31 participants.

^‡Family history data of type 1 diabetes (T1D) were unavailable for 224 participants.

^§Current body mass index (BMI) and BMI at diagnosis are given as the median, with 25th and 75th percentiles in parentheses. Data for BMI at diagnosis were unavailable for 3091 participants. Current BMI data exclude results for 1942 participants with a duration of diabetes <1 year (n = 1810 in the antibody-positive group and 132 in the antibody-negative group) and was unavailable in a further 36 participants. The results for current BMI were similar in both groups when the analysis included those with diabetes of <1 year duration.

^**Diabetic ketoacidosis (DKA) data at diagnosis were unavailable for 539 participants.

^††Current HbA1c data exclude results for 1942 individuals with diabetes of <1 year duration and was unavailable for a further 73 participants.

^‡‡Current total daily insulin dose data exclude results for 1942 individuals with diabetes of <1 year duration and was unavailable for a further 268 participants.

At the time of diagnosis, aAb-positive and aAb-negative cases were similar in terms of the proportion that presented with ketoacidosis (P = 0.36) and median BMI percentile (P = 0.13). At the time of registry enrollment, aAb-positive and aAb-negative cases had similar age and diabetes duration distributions (both with mean age 10.9 years and mean duration 2.7 years) and a similar proportion were using an insulin pump (41% vs 43%, respectively). Most recent HbA1c and BMI levels appeared similar between groups, whereas total daily insulin dose tended to be slightly higher among aAb-positive cases (P = 0.003; Table 4).

Discussion

Although one of the hallmarks of T1D is the presence of one or more aAbs, it is well recognized that there is a subset of presumed T1D patients who are aAb-negative at diagnosis.^3,5

In the present study, we found that characteristics of aAb-negative and aAb-positive cases were similar, with the exception that a higher proportion of aAb-negative participants were male and that the aAb-negative participants had a lower total daily insulin dose than the aAb-positive participants, associations that could be due to chance because we do not have plausible explanations. Of note, we did not find a difference in race–ethnicity distribution between positive and negative cases, in contrast with other studies reporting a higher frequency of negative cases among individuals with African or Asian ancestry.⁸ It is also of interest that the frequency of a family history of T1D was similar in aAb-positive and aAb-negative cases.

The main limitations of the present study are that all aAbs were not collected on all participants, particularly ZnT8, which was measured in a small percentage, and measurements were not made at a standardized time point from diagnosis or in a single reference laboratory. As a result, we cannot determine whether all those without aAbs present were indeed wholly aAb-negative.

There are several key questions that remain to be answered in aAb-negative patients, including whether they have a fundamentally different process leading to diabetes. Preliminary insights from the Hvidore Study Group, a cohort of children with T1D from Europe and Japan, suggested that GADA-, IA-2A-, and ICA-negative children have a slower decline in β-cell function and improved glycemic control 12 months after diagnosis.¹⁰ However, that study had a small number of participants, included wide ethnic backgrounds, and did not include ZnT8 aAbs. In our data, there was a suggestion of a lower total daily insulin dose among aAb-negative compared with aAb-positive individuals, which could be an indirect sign of greater β-cell function in aAb-negative subjects. An additional consideration is that the aAb-negative patients may have another form of diabetes, such as maturity onset diabetes of youth resulting from a monogenic defect, a mitochondrial defect, or other rare causes.^11,12 Further characterization of aAb-negative cases with presumed T1D may uncover novel defects regulating β-cell growth and differentiation. Whole exome sequencing or other analyses may help define such causes for diabetes.¹³

A better understanding of the disease process in aAb-negative cases may help to project the expected clinical course for aAb-negative individuals with diabetes and lead to alternative therapies, such as oral agents rather than exogenous insulin or new family screening practices. Furthermore, such aAb-negative patients are excluded from new onset T1D intervention studies that aim to preserve β-cell function. Further insight into their disease process may lead to therapies that help preserve β-cell function and that differ from therapies offered to those with aAb positivity.

Table 2.

Combination of autoantibody tested within the negative antibody group (n = 485)

	n
Autoantibody tested
Anti-GAD/anti-IA2/	114
Anti-GAD/anti-IA2/ZnT	28
Anti-GAD/ZnT	1
ICA/anti-GAD	284
ICA/anti-GAD/anti-IA2	22
ICA/anti-GAD/anti-IA2/ZnT	2
ICA/anti-GAD/ZnT	31
ICA/anti-IA2	3

GAD, glutamic acid decarboxylase; IA2, islet antigen 2; ZnT, zinc transporter; ICA, islet cell antibodies.

Significant findings of the study

The phenotype of non-autoimmune type 1 diabetes (T1D) patients was characterized in a large cohort. We noted differences consistent with a different pathopysiologic process. Further prospective studies are needed to characterize non-autoimmune T1D and could lead to the discovery of novel genes.

What this study adds

Significant information to current knowledge on the natural history and phenotype of non-autoimmune T1D. It adds valuable information on autoantibody trends, and stresses the importance of further studies to discover novel genes involved and to gain an understanding of the heterogeneity of T1D.

Appendix I. Staff of the Type 1 Diabetes (T1D) Exchange Clinic Network Coordinating Center and sites of the T1D Exchange Clinic Network

The T1D Exchange Clinic Network Coordinating Center staff are Roy Beck, Brian Becker, Christina Carpenter, Vincent Chen, Peiyao Cheng, Elizaveta Dolzhenko, Stephanie DuBose, Heidi Gillespie, Russell Guzzetta, Callyn Hall, Kellee Miller, Dan Raghinaru, Tricia Rampersad, Nicole Reese, Alysa Sampson, Ashleigh Saenz, Jeffrey Saunders, Heidi Strayer, and Dongyuan Xing.

The T1D Exchange Clinic Network sites with participating principal investigators (PI), co-investigators (I), and coordinators (C) ordered according to the number of participants recruited per site as of 1 August, 2012 are listed below.

Philadelphia, PA Children’s Hospital of Philadelphia (n = 1451)

Steven Willi (PI); Terri Lipman (I); Tammy Calvano (C); Olena Kucheruk (C); Pantea Minnock (C); Chau Nguyen (C)

Aurora, CO Barbara Davis Center for Childhood Diabetes (n = 1440)

Georgeanna Klingensmith (PI); Carolyn Banion (I); Jennifer Barker (I); Cindy Cain (I); Peter Chase (I); Rosanna Fiallo-Scharer (I); Sandy Hoops (I); Megan Kelsy (I); Georgeanna Klingensmith (I); David Maahs (I); Cathy Mowry (I); Kristen Nadeau (I); Marian Rewers (I); Arleta Rewers (I); Robert Slover (I); Andrea Steck (I); Paul Wadwa (I); Philippe Walravens (I); Philip Zeitler (I); Eric Cruz (C); Heidi Haro (C); Maria King (C)

Syracuse, NY SUNY Upstate Medical University (n = 1301)

Ruth Weinstock (PI); Roberto Izquierdo (I); Suzan Bristol (C)

New York City, NY Naomi Berrie Diabetes Center, Columbia University P&S (n = 1249)

Robin Goland (PI); Rachelle Gandica (I); Mary Chan (C); Ellen Greenberg (C); Amy Kurland (C)

Ann Arbor, MI University of Michigan (n = 927)

Joyce Lee (PI); Brigid Gregg (I); Meng Tan (I); Ashley Eason (C)

Aurora, CO University of Colorado/Denver, Barbara Davis Center for Childhood Diabetes (n = 897)

Satish Garg (PI); Aaron Michels (I); Audrey Morris (C); Haley Stewart (C); Sonya Walker (C)

Indianapolis, IN Riley Hospital for Children, Indiana University School of Medicine (n = 859)

Linda DiMeglio (PI); Tamara Hannon (I); Donald Orr (I); Stephanie Woerner (C)

Boston, MA Children’s Hospital Boston (n = 836)

Joseph Wolfsdorf (PI); Maryanne Quinn (I); Kayla Fitch (C)

Portland, OR Harold Schnitzer Diabetes Health Center at Oregon Health and Science University (n = 793)

Andrew Ahmann (PI); Jessica Castle (I); Farahnaz Joarder (I); Chris Bogan (C); Rebecca Fitch (C); Bethany Wollam (C)

Atlanta, GA Atlanta Diabetes Associates (n = 742)

Bruce Bode (PI); Katie Gazaway (C); RaShonda Hosey (C)

Buffalo, NY University Pediatric Associates (n = 673)

Kathleen Bethin (PI); Teresa Quattrin (I); Michelle Ecker (C)

Los Angeles, CA Children’s Hospital Los Angeles (n = 605)

Jamie Wood (PI); Lynda Fisher (I); Debra Jeandron (I); Francine Kaufman (I); Mimi Kim (I); Roshanak Monzavi (I); Pisit Pitukcheewanont (I); Anna Sandstrom (I); Marisa Cohen (C); Brian Ichihara (C); Megan Lipton (C)

Grand Rapids, MI Helen DeVos Children’s Hospital Endocrinology and Diabetes (n = 576)

Michael Wood (PI); Yaw Appiagyei-Dankah (I); Ayse Cemeroglu (I); Maala Daniel (I); Daniel Postellon (I); Michael Racine (I); Lora Kleis (C); Laura Wagner (C)

Seattle, WA University of Washington, Diabetes Care Center (n = 569)

Irl Hirsch (PI); Anthony DeSantis (I); DC Dugdale (I); R Alan Failor (I); Lisa Gilliam (I); Mary Janci (I); Peggy Odegard (I); Dace Trence (I); Brent Wisse (I); Jan Ginsberg (C); Dori Khakpour (C); Christina Peterson (C); Pam Thomson (C)

Idaho Falls, ID Rocky Mountain Diabetes & Osteoporosis Center, PA (n = 557)

David Liljenquist (PI); Mark Sulik (PI); Carl Vance (PI); Jean Halford (C); James Manning (C)

Morristown, NJ BD Diabetes Center at Goryeb Children’s Hospital (n = 542)

Harold Starkman (PI); Tymara Berry (I); Laurie Ebner-Lyon (I); Elaine Nussbaum (I); Christine Wagner (I); Marie Fox (C)

Stanford, CA Stanford University School of Medicine, Division of Pediatric Endocrinology (n = 525)

Bruce Buckingham (PI); Avni Shah (I); Breanne Harris (C)

Minneapolis, MN International Diabetes Center/Park Nicollet Adult Endocrinology (n = 514)

Richard Bergenstal (PI); Amy Criego (I); Greg Damberg (I); Glenn Matfin (I); Margaret Powers (I); David Tridgell (I); Beth Olson (C)

Boston, MA Joslin Diabetes Center- Pediatric (n = 451)

Sanjeev Mehta (PI); Lori Laffel (I); Camille Ratliff (C)

New Haven, CT Yale Pediatric Diabetes Program (n = 398)

Eda Cengiz (PI); William Tamborlane (I); Melody Martin-Fredericksen(C); Amy Steffen (C)

Los Angeles, CA University of Southern California–Community Diabetes Initiatives (n = 365)

Anne Peters (PI); Lucy Montoya (C); Valerie Ruelas (C)

Durham, NC Duke University Medical Center – Pediatric Endocrine Division (n = 364)

Robert Benjamin (PI); Juanita Cuffee (C); Jean Litton (C); Amber Spruill (C)

Minneapolis, MN International Diabetes Center/Park Nicollet Pediatric Endocrinology (n = 357)

Richard Bergenstal (PI); Amy Criego (I); Greg Damberg (I); Glenn Matfin (I); Margaret Powers (I); David Tridgell (I); Beth Olson (C)

Chicago, IL Northwestern University (n = 352)

Grazia Aleppo-Kacmarek (PI); Elaine Massaro (C); Kimberly Webb (C)

Charlottesville, VA University of Virginia Health System (n = 342)

William Clarke (PI); Christine Burt Solorzano (I); Mark DeBoer (I); Dianne Shifflett (C)

St. Louis, MO Washington University (n = 342)

Janet McGill (PI); Lori Buechler (C); Mary Jane Clifton (C); Stacy Hurst (C); Sarah Kissel (C); Carol Recklein (C)

Iowa City, IA University of Iowa Children’s Hospital (n= 327)

Eva Tsalikian (PI); Michael Tansey (I); Joanne Cabbage (C); Julie Coffey (C); Sarah Salamati (C)

Kansas City, MO Children’s Mercy Hospital (n = 323)

Mark Clements (PI); Sripriya Raman (I); Angela Turpin (I); Jennifer Bedard (C); Cyndy Cohoon (C); Aliza Elrod (C); Amanda Fridlington (C); Lois Hester (C); Terri Luetjen (C)

Detroit, MI Henry Ford Health System (n = 316)

Davida Kruger (PI); Andrew Hofmann (C)

Gainesville, FL University of Florida (n = 306)

Desmond Schatz (PI); Michael Clare-Salzler (I); Colleen Digman (I); Becky Fudge (I); Mike Haller (I); Henry Rohrs (I); Janet Silverstein (I); Sujata Wagh (I); David Weinstein (I); Tamara Wright (I); Erica Dougherty (C)

Orange, CA Children’s Hospital of Orange County (n = 305)

Mark Daniels (PI); Susan Clark (I); Timothy Flannery (I); Nikta Forghani (I); Ajanta Naidu (I); Christina Reh (I); Peggy Scoggin (I); Lien Trinh (I); Rebeca Quintana (C); Heather Speer (C)

Columbus, OH Central Ohio Pediatrics Endocrinology and Diabetes Services (n = 303)

William Zipf (PI); Diane Seiple (C)

Sioux Falls, SD Avera Research Institute (n = 281)

Brad Uhing (PI); Julie Kittelsrud (C); Ashley Stoker (C)

San Diego, CA University of California (n= 280)

Michael Gottschalk (PI); Marla Hashiguchi (C)

Tampa, FL University of South Florida Diabetes Center (n = 276)

Henry Rodriguez (PI); Craig Bobik (C); Danielle Henson (C)

Nashville, TN Vanderbilt Eskind Diabetes Clinic (n = 276)

Jill Simmons (PI); William Russell (I); Brooke Babington (C); Margo Black (C); Faith Brendle (C)

Cleveland, OH Case Western Reserve University (n = 251)

Rose Gubitosi-Klug (PI); Beth Kaminski (I); Susan Bergant (C); Wendy Campbell (C); Mary Beth Frohnapfel (C); Jennifer Haky (C); Catherine Tasi (C)

Oklahoma City, OK University of Oklahoma Health Sciences Center Dept. of Pediatric Diabetes and Endocrinology (n = 243)

Kenneth Copeland (PI); Joni Beck (I); Jill Schanuel (C); Jennifer Tolbert (C)

San Francisco, CA University of California, San Francisco Medical Center (UCSF) (n = 237)

Saleh Adi (PI); Andrea Gerard-Gonzalez (I); Stephen Gitelman (I); Nassim Chettout (C); Christine Torok (C)

Seattle, WA Seattle Children’s Hospital (n = 226)

Catherine Pihoker (PI); Susan Kearns (C)

Pittsburgh, PA Children’s Hospital of Pittsburgh of UPMC (n = 217)

Ingrid Libman (PI); Ana Diaz (C)

Minneapolis, MN University of Minnesota (n = 204)

Brandon Nathan (PI); Antoinette Moran (I); Melena Bellin (I); Shannon Beasley (C); Anne Kogler (C); Janice Leschyshyn (C); Jennifer Smith (C)

Greenville, SC Greenville Hospital System Pediatric Endocrinology (n = 196)

Bryce Nelson (PI); D’Anne Hannah (C)

Houston, TX Baylor College of Medicine/Texas Children’s Hospital (n = 187)

Morey Haymond (PI); Maria Redondo (I); Teresa Falk (C); Janette Gonzalez (C); Christina Lopez (C); Mariam Pontifes (C)

Ocean Springs, MS The Diabetes Center, PLLC (n = 187)

Kathleen Arnold (PI); Sharon Sellers (C)

Salt Lake City, UT University of Utah – Utah Diabetes Center (n = 181)

Vandana Raman (PI); Eric Garcia (C)

Worcester, MA University of Massachusetts Medical School (n = 179)

David Harlan (PI); Mary Lee (I); Lisa Hubacz (C)

Durham, NC University of North Carolina Diabetes Care Center (n = 179)

John Buse (PI); Michelle Duclos (C)

Sioux Falls, SD Sanford Research/USD (n = 178)

Verdayne Brandenburg (PI); Julie Blehm (I); Julie Hallanger-Johnson (I); Ryan Bosch (C); Jennifer Weiss (C)

Columbus, OH The Research Institute at Nationwide Children’s Hospital (n = 168)

Robert Hoffman (PI); Monika Chaudhari (I); David Repaske (I); Jesse Haines (C)

Billings, MT St. Vincent Healthcare/Internal Medicine and Diabetes (n = 165)

Justen Rudolph (PI); Charles McClave (I); Doris Biersdorf (C)

Bismarck, ND Medcenter One (n = 156)

Anthony Tello (PI); Donna Amundson (C); Rhonda Ward (C)

Philadelphia, PA University of Pennsylvania School of Medicine/Rodebaugh Diabetes Center (n = 156)

Michael Rickels (PI); Stan Schwartz (I); Cornelia Dalton-Bakes (C); Carissa Fuller (C); Nora Rosenfeld (C)

Cincinnati, OH Cincinnati Children’s Hospital Medical Center (n = 148)

Lawrence Dolan (PI); Jessica Kichler (I); Holly Baugh (C); Debbie Standiford (C)

Spokane, WA Rockwood Research Center, P.S. (n = 132)

Jeanne Hassing (PI); Jennifer Jones (I); Stephen Willis (I); Carol Wysham (I); Tammy Freels (C); Candice Garcia (C); Deann Rice (C)

Baltimore, MD Johns Hopkins University Pediatric Endocrinology (n = 120)

Scott Blackman (PI); Kimber-Lee Abel (C); Loretta Clark (C); Andrea Jonas (C); Ellie Kagan (C)

Miami, FL University of Miami, Diabetes Research Institute (n = 119)

Jay Sosenko (PI); Ramon Arce (C)

Rapid City, SD Regional Health Clinical Research (n = 118)

Rachel Edelen (PI); Denise Baldwin (C); Christina Conroy (C); Kelly DeGrote (C); Rod Marchiando (C); Michelle Wasson (C)

Jacksonville, FL Nemours Children’s Clinic (n = 116)

Larry Fox (PI); Nelly Mauras (I); Katie Black (C); Ligeia Damaso (C)

Cleveland, OH Cleveland Clinic Department of Endocrinology, Diabetes and Metabolism (n = 111)

Laurence Kennedy (PI); Michelle Schweiger (I); Pantelis Konstantinopoulos (C); Carolyn Mawhorter (C); Amy Orasko (C); Denise Rose (C)

Tallahassee, FL Tallahassee Memorial Diabetes Center (n = 108)

Larry Deeb (PI); Kim Rohrbacher (C)

Albany, NY The Endocrine Group, LLP (n = 107)

Jill Abelseth (PI); Carol Duma (C); Sara Duma (C)

Findlay, OH Blanchard Valley Medical Associates (n = 100)

Leroy Schroeder (PI); Amanda Roark (C)

Milwaukee, WI The Medical College of Wisconsin/ Children’s Hospital of WI (n = 99)

Omar Ali (PI); Joanna Kramer (C); Donna WhitsonJones (C)

Nashville, TN Vanderbilt Eskind Diabetes Clinic (n = 98)

Amy Potter (PI); Brooke Babington (C); Margo Black (C); Faith Brendle (C)

Vallejo, CA Kaiser Permanente (n = 74)

Heidi Gassner (PI); Sobha Kollipara (I); Vicky Bills (C)

Paterson, NJ St. Joseph’s Children’s Hospital (n = 53)

Katerina Harwood (PI); Vijaya Prasad (I)