A number of patients with type 2 diabetes are GAD antibody positive. A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind clinical trial in recently diagnosed drug-naïve patients with type 2 diabetes that allows for the evaluation of GAD positivity in the context of anthropometric and biochemical characteristics. Of the 4,134 subjects enrolled in ADOPT for whom GAD status was obtained, 174 (4.2%) were GAD positive, with the prevalence of GAD antibodies being similar in North America (4.7%) and Europe (3.7%). Although BMI and age were similar, GAD-positive patients had a lower fasting insulin level, compatible with them being more insulin sensitive. The lower fasting insulin concentration was accompanied by a decreased early insulin response to oral glucose. However, when this insulin response was corrected for the degree of insulin sensitivity, GAD-positive and -negative patients had similar β-cell function. Consistent with the difference in insulin sensitivity, GAD-positive patients had higher HDL cholesterol and lower triglyceride levels. In the GAD-positive individuals, the prevalence of the metabolic syndrome as defined by NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) was also lower (74.1 vs. 83.7%, P = 0.0009). These phenotypic differences may underlie a potential difference in the natural history of hyperglycemia and its clinical outcomes.
A number of patients with phenotypic type 2 diabetes are GAD antibody positive. These individuals have been referred to as having LADA (latent autoimmune diabetes in adults) or type 1.5 diabetes (1–4). However, there is limited information regarding the phenotypic and metabolic characteristics of these patients in comparison to the majority of patients with type 2 diabetes who are GAD antibody negative (5). In particular, there are little data on phenotypic characteristics of GAD-positive recently diagnosed drug-naïve patients with type 2 diabetes (6). Although the prevalence of GAD antibodies has been well studied in Europe, no data are available on large cohorts in North America, and there have been no evaluations of GAD antibody status between North American and European subjects with type 2 diabetes in a single study using a single assay.
There is heterogeneity in the relative importance of insulin resistance and β-cell dysfunction in the pathogenesis of type 2 diabetes (7). GAD positivity may contribute to this heterogeneity in the subset of patients who have this antibody marker because it is typically more commonly associated with type 1 diabetes (8), which is largely a disease of reduced β-cell function (9).
The phenotypic characteristics and natural history of GAD-positive patients have been incompletely characterized in adults with suspected type 2 diabetes and are of interest for two reasons. First, it is important to phenotypically characterize subjects who are GAD positive to determine whether they have a different presentation and can be identified clinically. Second, there may be differences in the natural history of diabetes and/or response to treatment in subjects who are GAD positive compared with those who are GAD negative. In this article, using A Diabetes Outcome Progression Trial’s (ADOPT’s) cohort of >4,000 recently diagnosed drug-naïve patients with type 2 diabetes from North America and Europe (10), we examine the first question and determine whether type 2 diabetic subjects who are GAD antibody positive or negative differ phenotypically.
RESEARCH DESIGN AND METHODS
The ADOPT cohort comprised 4,357 individuals with recently diagnosed (within 3 years) drug-naïve type 2 diabetes recruited in 488 centers in North America (U.S. and Canada) and 15 countries in Europe (Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Ireland, the Netherlands, Norway, Spain, Sweden, and the U.K.). From this cohort, GAD antibody status was available on 4,134 individuals (95%), and these subjects are the basis for this report. Institutional review boards at each center approved the protocol, and subjects gave written informed consent before participation in the study.
The design of the study has been described in detail previously (10). Briefly, it is a randomized double-blind parallel-group trial consisting of a screening period and a 4- to 6-year treatment period. Eligible individuals were aged 30–75 years and had to have an insufficiently controlled fasting plasma glucose concentration (between 7 and 10 mmol/l) with routine diet and exercise intervention during the screening period. Patients were randomized to receive double-blinded rosiglitazone, glyburide, or metformin, with the goal being to attain ADA (American Diabetes Association) glycemic control guidelines (11) by titrating as necessary up to maximal dosage of each agent.
At baseline, subjects had standard anthropometric measurements and blood pressure performed. Fasting samples for routine lipid measurements and HbA1c were taken before the performance of a 75-g oral glucose tolerance test (OGTT). The latter was performed to obtain estimates of insulin sensitivity and β-cell function and involved a fasting sample and a sample 30 min after commencing ingestion of the glucose load. The OGTT samples were used to measure plasma glucose and insulin levels.
Assays and calculations.
All assays were performed at a central laboratory as described previously (10). Fasting plasma glucose was measured using a hexokinase assay (Olympus America, Melville, NY) method, and HbA1c was determined using the Biorad Variant Hemoglobin A1c assay (Hercules, CA). Serum immunoreactive insulin was quantified using a double-antibody radioimmunoassay (Linco, St. Louis, MO). This assay is specific for insulin only and has negligible cross-reactivity with proinsulin and its major circulating conversion intermediate des 31,32 human proinsulin (intact human proinsulin <0.2%; des 31,32 human proinsulin <0.2%; des 64,65 human proinsulin 76%). Total cholesterol and triglycerides were measured by enzymatic methods (Olympus America). HDL cholesterol was determined using a precipitation method (Olympus America). Non-HDL cholesterol was calculated as the difference between total cholesterol and HDL cholesterol.
GAD antibodies were measured using a commercially available radioimmunoassay manufactured by RSR (Cardiff, Wales, U.K.) and distributed by Kronus (Boise, ID). The assay recognizes autoantibodies to GAD65 in serum and has a clinical cutoff of 1.0 units/ml with an intra-assay coefficient of variation (CV) of 3.1% and an interassay CV of 5.1%. This clinical cutoff was determined from samples from 100 individual healthy blood donors that gave a mean of 0.055 ± 0.22 units/ml with a range of 0–1.45 units/ml. A total of 91 sera gave values indistinguishable from 0 units/ml, and 95 samples contained <0.35 units/ml. Three sera gave values of ≥1.0 units/ml, and all three were reduced by incubation with unlabelled GAD, suggesting that they contained specific GAD antibodies. The assay was assessed in the recent Diabetes Antibody Standardization Program (12), with 1 unit in this assay being equivalent to 25 WHO (World Health Organization) units. In this program, the assay had a sensitivity of 84% and a specificity of 90%.
The insulin response to glucose was determined as the insulinogenic index, ΔI (0–30)/ΔG (0–30), which is the ratio of the incremental insulin (I) and glucose (G) responses from 0 to 30 min after commencement of glucose ingestion in the OGTT. To account for the effect of insulin sensitivity to modulate this response, this response was adjusted for the fasting insulin concentration (7), which is a well-established estimate of insulin sensitivity (13,14). Insulin sensitivity was also determined using the homeostasis model assessment for insulin resistance (HOMA-IR) index, calculated as [insulin (μU/ml)] × [glucose (mmol/l)]/22.5, with lower values being more insulin sensitive and higher values more insulin resistant (15).
NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) criteria for the metabolic syndrome were used to determine whether individuals did or did not have the syndrome (16). These criteria were blood pressure ≥130/85 mmHg, HDL cholesterol <1.0 mmol/l (men) or <1.3 mmol/l (women), triglycerides ≥1.7 mmol/l, waist circumference >102 cm (men) or >88 cm (women), and fasting plasma glucose ≥6.1 mmol/l. The diagnosis of the metabolic syndrome required individuals to have at least three of these five criteria. Because all of the subjects in this report had diabetes, they only had to have two of the remaining four criteria to meet the definition. Subjects with blood pressure <130/85 mmHg who were taking antihypertensive medications and reported a diagnosis of hypertension were considered to have met the blood pressure criterion. Furthermore, those individuals who had triglyceride levels <1.7 mmol/l but were taking a fibrate at baseline were deemed to have met the triglyceride criterion.
Statistical methods.
Comparisons between GAD antibody-positive and -negative subjects were performed by χ2 analysis for frequency of dichotomous variables, whereas continuous variables were compared using a two-sample t test. Variables were log-transformed when necessary to improve normality of distribution. Ratios were analyzed using the Wilcoxon’s rank-sum test. Data are presented as means ± SE unless otherwise specified. A two-sided P ≤ 0.05 was considered significant.
RESULTS
GAD antibody status and subject characteristics.
Of the 4,134 subjects, 174 were GAD antibody positive, which represents 4.2% of the cohort. In North America, 103 of 2,212 (4.7%) were GAD antibody positive, whereas in Europe 71 of 1,922 (3.7%) were GAD positive (P = 0.12).
The characteristics of the subjects based on GAD antibody status at baseline are shown in Table 1. The two groups did not differ with respect to age, sex, BMI, waist circumference, fasting glucose, non-HDL cholesterol, or HbA1c levels. In contrast, HDL cholesterol levels were higher and triglyceride levels were lower in GAD-positive individuals. We examined whether atypical type 2 diabetic subjects, i.e., younger and less obese subjects, had higher prevalence of GAD positivity. We found no relationship of GAD positivity with age (P = 0.37) (Fig. 1A). However, we did find that less obese subjects had a higher prevalence of GAD positivity (P = 0.01) (Fig. 1B).
Insulin sensitivity and β-cell function.
As illustrated in Fig. 2A, the GAD-positive patients had significantly lower fasting insulin levels (133 ± 9.9 vs. 150 ± 1.7 pmol/l, P = 0.045), suggesting that they were more insulin sensitive. Because fasting insulin and the HOMA-IR index are highly correlated (r = 0.959 in this study), it is thus not surprising that GAD-positive subjects similarly had a lower HOMA-IR index (Table 1).
The insulinogenic index, ΔI (0–30)/ΔG (0–30), represents the early insulin response during the OGTT, and this measure was decreased in the GAD-positive compared with the GAD-negative subjects: median (interquartile range): 25.9 (13.8–51.9) vs. 33.0 (18.8–58.2) pmol/mmol, P < 0.001 (Fig. 2B). To obtain a measure of β-cell function that accounts for the effect of insulin sensitivity, we adjusted the insulinogenic index by dividing it by the fasting insulin concentration. After this adjustment, β-cell function did not differ between the GAD-positive and -negative groups: 0.255 (0.150–0.397) vs. 0.276 (0.172–0.425) pmol2/mmol, P = 0.12 (Fig. 2C).
Metabolic syndrome.
Although highly prevalent in both groups, the prevalence of the metabolic syndrome was significantly lower in the GAD-positive individuals (74.1% compared with 83.7% in the GAD-negative subjects, P < 0.001). The prevalence of subjects satisfying the individual components of the metabolic syndrome is shown in Table 2. Interestingly, whereas there were no significant differences in the proportion of patients meeting the different metabolic syndrome criteria, the GAD-negative subjects tended to have a higher proportion meeting the different criteria, and this would explain the overall greater prevalence of the syndrome in this group.
DISCUSSION
Most reports of GAD positivity in type 2 diabetes are from Europe, with two studies examining cohorts of >1,000 subjects. In the U.K. Prospective Diabetes Study (UKPDS), the overall prevalence of GAD antibodies was 10% (6), whereas in the Botnia Study in western Finland, the prevalence of GAD positivity was 9% (3,5). Although there is a paucity of information regarding the prevalence of GAD antibodies in subjects with type 2 diabetes in North America, two smaller studies, each with <200 subjects, have found somewhat conflicting data in that the prevalence rate in one was 16% (17) and in the other was 3.4% (18). Based on these limited data, it is difficult to truly evaluate whether there is a difference in the prevalence of GAD positivity in type 2 diabetes between North America and Europe. ADOPT is the only study to evaluate this issue on these two continents using a common assay with standardized recruitment criteria. With this approach, we have found that in a drug-naïve population of type 2 diabetic subjects diagnosed within 3 years, the prevalence of GAD antibody positivity was 4.2%, and there was no difference in the prevalence of these antibodies in North America and Europe (4.7 and 3.7%, respectively). Based on these findings, we would conclude that the prevalence of LADA/type 1.5 diabetes is similar in North America and Europe.
Our finding of a prevalence of 3.7% in Europe is clearly lower than that found in the UKPDS and Botnia Study. This difference could have at least three possible explanations. First, there could be heterogeneity across populations. The European cohort in ADOPT is comprised of individuals from 15 European countries, whereas these other two studies examined subjects exclusively from either the U.K. or Finland. That this may be the explanation is supported by findings in a Sardinian population of 1,436 individuals with type 2 diabetes that demonstrated a GAD antibody prevalence of 5.1% (A. Lernmark, personal communication). Second, it is possible that the difference may be caused by assay variability. Possible assay differences have recently been the focus of an international group aiming to standardize GAD assay methodology and reference reagents (12). Third, it is also possible that the different inclusion and exclusion criteria for the different studies (e.g., duration of diabetes and glucose control) resulted in the selection of cohorts with slightly different phenotypic characteristics and levels of GAD positivity between studies. In this context, because subjects in ADOPT had to be drug naïve and could have had diabetes for up to 3 years, it is possible that some GAD antibody subjects may have had more rapid β-cell destruction resulting in initiation of therapy and thus exclusion from the current study’s cohort.
Type 2 diabetes is characterized by both insulin resistance and β-cell dysfunction, whereas type 1 diabetes is primarily a disease of the β-cell. Thus, one may anticipate that the GAD-positive individuals would have a phenotype more typical of type 1 diabetes. In the present cohort of subjects, we found that the GAD-positive individuals were more insulin sensitive based on both the fasting insulin concentration and HOMA-IR, two indirect but well validated measures of insulin sensitivity (13,15,19). In the GAD-positive subjects, the mean fasting insulin level was 11% lower than in the GAD-negative individuals, whereas the median insulin response to oral glucose, determined as the insulinogenic index, was 22% lower in these same subjects. Based on the known reciprocal relationship between insulin sensitivity and the insulin response as a determinant of glucose metabolism (13), when this insulin response was adjusted for insulin sensitivity to provide a measure of β-cell function, we found that β-cell function was not different between the two groups. Insulin sensitivity and the insulin response have also been evaluated in GAD-positive subjects and individuals with MODY (maturity-onset diabetes of the young) (20). This study similarly demonstrated the heterogeneity of the phenotype and the value of assessing both of these variables that are important in the pathogenesis of hyperglycemia in type 2 diabetes.
The metabolic syndrome has been defined by a number of groups, most recently in 2001 by the National Cholesterol Education Panel (16). It was previously demonstrated in the NHANES III (Third National Health and Nutrition Education Survey) that the prevalence of the metabolic syndrome in subjects with type 2 diabetes aged ≥50 years was 86% (21). We found a similar overall prevalence of the syndrome in our cohort. However, in GAD-positive individuals, we found the prevalence of this syndrome to be significantly lower, consistent with their lower prevalence of insulin resistance. When examined as continuous variables, subjects who were GAD positive had both significantly lower triglycerides and higher HDL cholesterol levels compared with their GAD-negative counterparts. Thus, the GAD-positive subjects, although anthropometrically similar to the GAD-negative subjects, have a biochemical profile suggesting a lower cardiovascular risk. These findings are consistent with those made in the Botnia Study (5,22). Additional phenotypic and clinical outcome differences may become apparent with further clinical follow-up.
In summary, our findings indicate that patients with type 2 diabetes who are GAD positive are distinguishable in that despite similar levels of overall adiposity, they have lesser degrees of insulin resistance and as a consequence have a lower probability of the metabolic syndrome. These phenotypic differences could relate to differences in visceral adiposity that are not readily apparent by standard clinical assessments, such as waist circumference or waist-to-hip ratio. Furthermore, these differences may underlie a potential difference in the natural history of hyperglycemia and clinical outcome independent of glucose. Because ADOPT is a prospective clinical trial, it may afford the opportunity to determine the effect of different treatment modalities on GAD positivity and clinical outcome in recently diagnosed drug-naïve type 2 diabetic subjects.
APPENDIX
List of ADOPT Investigators and Committees
Austria.
Prof. Dr. Rudolf Prager, Dr. Heidemarie Abrahamian, Prof. Dr. Bernhard Ludvik, Dr. Reinhard Lober, Nicole Scharf.
Belgium.
Prof. E. Muls, Prof. C. Mathieu; Dr. G. Watté; Dr. G. Vileyn; Dr. G. Mehuys; Dr. R. Leliaert; Dr. P. Roelands; Dr. S. Bresseleers; Dr. F. Heyvaert; Dr. W. Van Peer, Dr. J. Verelst; Dr. R. Wouters; Dr. G. Vandistel; Dr. G. Dedeyne, H. Morobé; M. Carpentier; A. Ceusters.
Canada.
Ronnie Aronson, MD, Cathy Halyk; Gordon Bailey, MD, Audrey Hollingshead; André Bélanger, MD, Marie-Claire Meilleur; Joseph Berlingieri, MD, Fern Petrie; Makram Boctor, MD, Meena Pole; William Booth, MD, Florence Landry; Jacques Bouchard, MD, Linda Morin; Raphael Cheung, MD, Denise St. Louis; Gary Costain, MD, Douglas Tweel, MD, Maggie Ferguson; Keith Dawson, MD, Joyce Lewis; Jean-Marie Ékoé, MD, Josée DesCormiers; Pierre Filteau, MD, Guylaine Janelle; Pierre Fournier, MD, Louise Piuze; Claude Garceau, MD, Lyne Kelly; Daniel Gaudet, MD, Patrice Perron, MD, Lyne Côté; Ronald Goldenberg, MD, Sharon Code, Tara Coady-MacKinnon; Irving Gottesman, MD, Donna Hasler; Jean Pierre Hallé, MD, Aline Toupin; Philip Hardin, MD, Beverly Sternberg; Robyn Houlden, MD, Tish LaVallee; Irene Hramiak, MD, Sharon Powers; Christopher Kovacs, MD, Bernadette Rowe; Christopher Lai, MD, Suzanne Galandzy; René LaMontagne, MD, Huguette LaMontagne; David Lau, MD, Mary Ann Clearwaters; Lawrence Leiter, MD, Danielle Bedard; Sora Ludwig, MD, Sharon Erickson-Nesmith; Mary MacSween, MD, Beth Cole; Pierre Maheux, MD, Patrice Perron, MD, Mireille Luc; Suba Mann, MD, Sheila Brown; Liam Murphy, MD, Lori Berard; T.C. Ooi, MD, Colette Favreau; André Parent, MD, Monique Blais; Malvinder Parmar, MD, Myra Marsh; Edmond Ryan, MD, Mary Pick; Daniel Shu, MD, Sylvie Prieur; Ehud Ur, MD, Tabitha Palmer; Lucretia van den Berg, MD, Renza Brown; Timothy Zmijowskyj, MD, Roy-anne Poirier.
Czech Republic.
Prof. MUDr. Terezie Pelikánová, Doc. MUDr. Alexandra Jirkovská; Doc. MUDr. Milan Kvapil, MUDr. Dagmar Bartášková; MUDr. František Pátek, MUDr. Nad’a Shorná; Prof. MUDr. Jaroslav Rybka, MUDr. Lubomír Švestka; MUDr. Marek Honka, Anna Navrátilová.
Denmark.
Dr. Henning Beck-Nielsen, Dr. Iben Brock Jacobsen; Dr. Klaus Koelendorf.
Finland.
Johan Eriksson MD, PhD, Tom Forsén MD, PhD; Mauno Vanhala MD, PhD, Jarmo Starck MD; Jouko Saramies MD, Tuija Hurskainen; Juha Saltevo MD, Ulla Venesmaa MD; Tina Hellsten, MD, Maria Söderlund-Sarpoma.
France.
Dr. Phillippe Blanchard, Dr. Jacques Leclaire; Dr. Gérard Lalanne, Dr. Jean Claude Gaube; Dr. Françoise Leroy-Duroure, Dr. Regis Soullard; Dr. Christian Faugere, Dr. Raphael Moreno; Dr. Yves Mercey, Dr. Raphael Moreno, Dr. Bruno Pellenq, Dr. Philippe Roche; Dr. Jean-Noël Nal, Dr. Remi Fonteny; Dr. Didier Sacareau, Dr. Michel Bismuth; Dr. Gilles Sorbé; Dr. Pierre Causse; Dr. Christian Scellier; Dr. Didier Cadinot; Dr. François Lacoin, Dr. Jean-Louis Rose, Dr. Lucien Esquerre; Dr. Salam Farhat; Dr. Nicolas Breton; Dr. Nathan Abenhaim; Dr. Francois Spilthooren, Dr. Bernard Pairin; Dr. Alain Boye, Dr. Luc Formagne; Dr. Dominique Lejay, Dr. Marc Herent; Dr. Jacques Marty, Dr. Serge Faligot; Dr. Bernard Chagnoux; Dr. Alain El Sawy, Dr. Jean-Pierre Allamanno; Dr. Alain Duplan, Dr. Marc Fleury; Dr. Loic Boucher, Dr. Denis Marin; Dr. Gilles Faugas, Dr. Jean-Jacques Vanpraet; Dr. Eric De Sainte Lorette, Dr. Jean-Claude Mouchet; Dr. Thierry Latte, Dr. Denis Diard; Dr. Philippe Esteve, Dr. Bernard Lafaurie; Dr. Alain Dyan, Dr. Michel Braud; Dr. Jacques Dupouy, Dr. Michel Chay; Dr. Jean-Marie Letzeltzer, Dr. Michel Arnould; Dr. Leon Grynsztejn, Dr. Christian Hereng; Pr Bernard Charbonnel; Dr. Alain Queguiner; Dr. Jean-Pierre Champin, Dr. Pierre Livet; Dr. Didier Rabaud; Dr. Christian Ravier.
Germany.
Dr. Karl Streier; Dr. Gebhard Weber; Dr. Andreas Trieb; Dr. Wolfgang Schmidt, Dr. Margarete Schmidt; Dr. Michael Simonsohn; Dr. Helmut Anderten; Dr. Stephan Maxeiner; Dr. Günter Petig; Dr. Johannes Heidemann; Dr. Ulrich Engels; Dr. Holger Menke; Dr. Karlheinz Hehemann; Dr. Michael Orlowski; Dr. Ulrich Buschmann; Dr. Hans-Georg Leonhardt; Dr. Gerhard Klausmann; Dr. Hans-Joachim Herrmann; Dr. Ulrich Wendisch, Dr. Andreas Klinge; Dr. Gero Stumpf; Dr. Joachim Sauter, Dr. Gerard Tangerding; Dr. Andor Schmidt; Dr. Jochen Schaller; Dr. Waldemar Fischer; Dr. Hubert Wübbolding; Dr. Godehard Woywod; Dr. Joachim Minnich, Dr. Christiane Klein; Dr. Suleinam Kaspari; Dr. Michael Leidert; Dr. Thomas Block, Dr. Jochen Lind; Dr. Doris Böhme; Dr. Ali Boustani; Dr. Roland Braun; Dr. Armin Buerk; Dr. H.M. Frick; Dr. Heinz Gerbatowski, Dr. Josef Grosskopf; Dr. Heino Hebbeln; Dr. Klaus Hess; Dr. Karl-Heinz Hey; Dr. Christine Kosch; Dr. W.A. Kratschmann; Dr. Wolfgang Lieske; Dr. Irmgard Maier-Bosse; Dr. Sylvia Mantz; Dr. Michael Möckesch, Dr. Beate Möckesch; Dr. Otmar Müller; Dr. Lutz Partenheimer; Dr. Wilgard Pohl; Dr. Andreas Preusche; Dr. Hans-J Olejnik; Dr. Peter de Faber, Dorothea de Faber; Dr. Norbert Purr; Dr. Holger Samer Dipl. Med; Christine Schindler; Dr. Gerhard Scholz; Dr. Uwe Speier; Dr. Jürgen Wachter; Prof. Dr. Peter Weisweiler; Dr. Thomas Jung, Dr. Nikolaus Jung; Dipl. Med. Kerstin Steinbach; Dr. Muwafeg Abdel Qader; Dr. Heinrich Proba.
Hungary.
József Fovényi, Erzsébet Thaisz; Mihály Tarkó, Barna Bakó.
Ireland.
Prof. Michael Cullen, Mary Ryan; Dr. Donal O’Halloran, Dr. Aoife Brennan; Dr. Richard Firth; Dr. Joseph Sweeney; Dr. Alan Byrne, Karen Canning; Dr. Kevin Kelly, Kathy O’Brien; Dr. Seamus Sreenan, Sandra McAteer; Prof. T.J. McKenna, Dr. James Gibney; Dr. Chris Kyle, Gillian Glasgow; Dr. Roy Harper, Shirley Edgar, Dr. Declan Byrne, Dr. Faud Al-Saraj.
Italy.
Prof. Fausto Santeusanio, Dr. Gabriele Perriello; Prof. Emanuele Bosi, Dr. Piermarco Piatti; Dr. Giovanni Cicioni; Prof. Carlo Coscelli, Dr. ssa Maria Christina Calderini; Dr. Lamberto DeGiorgio, Dr. Stefano Carro; Prof. Aldo Galluzzo, Dr. Giuseppe Amato; Dr. Stefanogenovese; Prof. Mario Maioli, Dr. Pietro Fresu; Dr.ssa Gabriela Monesi, Dr. ssa Giovanna Lisato; Dr. Claudio Noacco, Dr. Claudio Taboga; Prof. Gianfranco Pagano; Prof. Carlo Rotella; Dr. Giacomo Vespasiani, Dr. Illidio Meloncelli; Dr. Alfonso Basso, Dr.ssa Maria Simoncini; Prof. Francesco Cannata, Dr. Paolo DiBarotolo; Prof. Riccardo Scardapane; Dr. Franco Tomasi; Dr. Corrado Campenelli, Dr. Roberto Norgiolini; Dr. Gianni Formoso, Dr. Mario Nuzzo.
The Netherlands.
E.H.R. Wins; M. Blok; Jacqueline Huizer; Vivienne van de Walle; W.A. de Backer; V. van Dongen; H.F.C.M. van Mierlo; C. Gieskes; M.J.C. Osinga-Meek; L.I. van Haeften-van Hoedel; P.A. Meurs; J.S.M. van den Hoven-Burink; A.J.M. Boermans.
Norway.
Dr. Knut Risberg, Lise Fracke; Dr. Arne Skag, Snorre Øfjord; Dr. Johannes Arnesen.
Spain.
Dr. Juan García Puig, Dr. Teresa Sancho Bueso; Dr. Juan Custardoy Olavarrieta, Dr. J. Manuel Ortín Arraniz; Dr. Alberto Martín Hidalgo, Dr. Maribel Pérez Soto; Dr. José Ramón Domínguez Escribano, Dr. Leticia Armán Alvarez-Buylla; Dr. Ignasi Castells Fusté, Dr. MŞ Teresa Rodellar Oncins; Dr. MŞ Luisa Ramírez Muñoz, Dr. Rosa Cañas Angulo; Dr. Andrés Nubiola Calonge, Dr. Rosa Rosado Muñoz; Dr. José Bueno Gómez , Dr. Javier Tisaire Sánchez; Dr. Francisco Pasquau Liaño, Dr. Victor Martínez López; Dr. Soledad Serrano Corredor, Dr. Sonia Fuentes Luri; Dr. Vicente Estopiñán García; Dr. José Manuel Pascual Izuel, Dr. Enrique Rodilla Sala; Dr. Soledad Ruiz de Adana, Dr. Victor Martín Hurtado de Mendoza; Dr. Tomás Martín González, Manuela Vaquero Martín; Dr. Pedro Checa Zornoza, Mercedes Enrique Rodríguez; Dr. Antonio Hernández Martínez, Dr. Francisco Javier Tébar Masó; Dr. Nieves Alonso Sánchez, Ana Fabregat Hidalgo; Dr. Antonio Hernández Mijares, Leonor Alcover Sorlí; Dr. Pablo Fernández Catalina, Dr. Isabel Alonso Troncoso; Dr. Wilfredo Ricart Engel; Dr. Patricio Arribas Arribas, Dr. Mónica Recasens Sala, Dr. Francisca Fernandez Fernandez; Dr. Rafael Arjona Mateos, Dr. Coral Montalbán Carrasco, Dr. Charo de la Pedraja Murgoitio; Dr. Agueda Muñoz Jiménez, Dr. M. Angeles Brito Pérez; Dr. Mónica Marazuela Azpíroz; Dr. Juan Parra Barona; Dr. Almudena Vicente Delgado, Dr. Amparo Marco Martinez, Dr. Julia Sastre Marcos; Dr. Pedro Jiménez Roset, Dr. M. Angeles Argente Gómez; Dr. Ricardo Arocas Pérez, Dr. José Antonio Durá García; Dr. J. Luis Lafuente Gutiérrez, Dr. Froilán Sánchez Sánchez; Dr. Francisco Valls Roca; Dr. José Luis Llisterri Caro, Dr. Salvador Baixauli Navarro; Dr. Teresa Amoros Barber, Graciela Alcaide Montoliú; Dr. Tomás Sánchez Ruiz, MŞ Carmen Ramos Díaz; Dr. Vicente Meneu Montolín, Dr. Juan Manuel Pilar Claramonte, Dr. Vicent Cerdá Alfonso; Dr. Concepción Terroba Larumbe, Dr. Olatz Izaola Jáuregui; Dr. Luis de Teresa Parreño, Dr. Ana García Herola, Dr. Julio Cesar Blázquez Encinar.
Sweden.
Dr. Ingrid Linnarsson; Dr. Bo Karlson, Christina Holmgren; Dr. Bengt Littorin; Dr. Ola Strömstedt, Ulla Winnberg; Dr. Dick Larsson, Anita Helgesson.
U.K.
Dr. Sion Edwards, Dr. Hadyn Mayo; Dr. Emyr Davies, Janet Reece; Dr. Paula Chattington, Sue Donough; Dr. Susan Taylor, Dr. Helen Parry; Dr. Jean Fraser, Pat Green; Dr. J. Maroni, Helen Anderson; Dr. Tom Cahill, Ms Cherry Browne; Dr. A Cooper, Sarah Brew; Dr. Wendy Gatling, Dr. Brenda Howarth; Dr. P. Goozee, Brigid Lenanton; Dr. Jonathan Hamling, Helen Talbot; Dr. John Hole, Jill Wood; Dr. Jeremy Simmons, Jeanette Plummer; Dr. G.C. Viberti, Dr. A. Smith, Jane Fry; Dr. D. Kerr, Dr. Sandra Egan and The Research Team; Dr. R. Abraham, Hannah Ward; Dr. Huw Charles, Melanie Davies; Dr. R. Gadsby, Pam Gadsby; Dr. Corinne Rees-Jones, Dr. Richard Evans; Dr. Ann Weaver, Penny Bowden; Dr. J. Ham, Anne Mills; Dr. P.N. Kulkarni; Dr. Meurig Williams, Lynne Thomas; Dr. M. Baker, Linda Warboys; Dr. Anne Connolly, Chris Portz; Dr. Simon Fearns, Linda Lambley; Dr. J. Trayner, Teresa Baxter; Dr. Graham, Helen Pinder; Dr. Martin Johnson, Hilary Wood; Dr. G. Martin, Chris Smith; Dr. R. Falk, Dr. Dexter; Dr. Dinesh K. Nagi, Miriam Khalifa; Dr. Hall; Dr. E. Montague, Kate O’Brien; Dr. J.U. Weaver, Dr. Akeel Syed; Dr. J. Andrews, Muriel Andrews; Dr. A. Harrower, Katrina Gallacher; Dr. D. McKeith, Dr. F. Doig; Dr. J. Milne; Dr. J.D. Walker, Alison McCallum; Dr. R.S. Gray, Maureen McKay; Dr. J. Repper, Caroline McNiff; Dr. S.J. Gallacher, Joyce Robson.
U.S.
Andrew Ahmann, MD, Vicki Craig; Cesar Albarracin, MD, Dion Avila; Michael Alderman, MD, Mary Jo Sanguily; Nadine Alex, MD, Amy Bertucci; James Allison, MD, Peggy Johnson; James Anderson, MD, Ruth Oremus; Robert Anderson, MD, Carla Danielson; Richard Arakaki, MD, Robin Yamamoto; Stephen Aronoff, MD, Satanya Brooks; David Baldwin, MD, Nahla Hasabou; Arnaud Bastien, MD, Dawn Linneman; Carolyn Becker, MD; Andrew Behnke, MD; David Bell, MD, Melanie Smith, Robin Noles; Barry Benowitz, MD, Shelly Turner, Coleen Alge; Richard Bernstein, MD, Jeannie Fontanalla; Mark Berntsen, MD; Jeffrey Boggess, MD, Cindy Cunningham; Charles Booras, MD, Barbara Maluchnik; William Bowden, DO, Julie Milano; Bruce Bowling, MD, Sandra Lindsey, Susan Owens; Seth Braunstein, MD, Barbara Duffy; Humberto Bruschetta, MD, Laura Stephens; Geoffrey Burgess, MD, Bernice Burgess; Leroy Byrd, MD, Alicia Sullivan, David Cragg; Nancy Campbell, MD, Patty Mendoza; Robert Capodilupo, MD, Gail Bailargeon; David Carter, MD, Beth Breazeale; Harold Cathcart, MD, Kami Halsey; George Chao, Stephanie Edmondson; Bruce Chertow, MD, Amy Music; Joyce Chung, MD, Diane Falcon; Joshua Cohen, MD, Mary Ellen Wolf; Louis Cohen, MD, Janie Coffman; Frank Cole, MD, Amber Brooks-Wolfe; Lydia Corn, MD, Janie Coffman; George Dailey, MD, Charlotte Sanborn; Gregory Damberg, MD, Susan List; Jaime Davidson, MD, Donna Flanders; Mayer Davidson, MD, Selena Alvarez; Harry Delcher, MD, Adrian Dobs, MD, Ann Munson; Edward Domurat, MD, Sheri Loke; Daniel Donovan, MD, Carlos Lopez; Laurie Edelman, MD, Nicky O’Connor; Charles Eil, MD; Samer Eldeiry, MD, Michael Kane; Philip Emrie, MD, Ann Muldrow; John Evans, MD, Karen Anderson; Mark Feinglos, MD, Jennifer English; Robert Ferraro, MD; Anthony Firek, MD, Grace Ding; Ira Fishman, MD; Charles Fogarty, MD, Sherry Yeisley; Leon Fogelfeld, MD, Shilpa Shah; Bruce Francis, MD, Candace Idso, Beth Miller; Miguel Franco, MD, Nanette Carr; Almena Free, MD, Patti Alexander; Robert Gabbay, MD, John Gilbert, MD, Karie Nguyen; Barry Goldstein, MD, Lori Conley; G.M. Gollapudi, MD, Vimal Tanega; Stephen Grubb, MD, Holly Blackwood; George Grunberger, MD, Carmen Licavoli; Burritt Haag, MD, Celeste Silva; Steven Haffner, MD, Arlene Martinez; Michael Hagan, MD, Connie Hamilton; Kathleen Hall, MD; Bruce Hamilton, MD, Greg Kuzbida; Israel Hartman, MD, Nikki Lindsey; Joseph Hawkins, Jr. MD, Carolyn Okamoto; Andrea Hayes, MD, Cheryl Glass, Heather Tarrant; Amy Meiers, William John Henry, MD, Sharon Van Patton; Bruce Henson, MD, Lauren Gray; Thomas Higgins, MD, Eileen Milton; Robert Hippert, DO, Angie Raker; Irl Hirsch, MD, Pam Thomson; Pricilla Hollander, MD, Sue Shor; Jennifer Hone, MD, Cheri Casey; Peter Honig, MD, Laurie Jameson; E. Walter Hood, MD, Lani Mogilevich; Randall Huling, MD, Kerry Moore; Ali Iranmanesh, MD, Christy Florow; Stephanie Jackson, MD; Adesh Jain, MD; Rajeev Kumar Jain, MD, Debra Kasprzak; John Jennings, MD, Anthony Firek, MD, Grace Ding; Stephaine Jocums, MD, Connie Spiller; Lisa Johnson, MD, Amy Campbell; Jann Johnston, MD; Steven Kahn, MB ChB, Brenda Montgomery; Charkravarthy Kannan, MD, Sini Koshy-Hunt; Stuart Kauffman, MD; Robert Kaufmann, MD, Shirley Wiley; Todd Kaye, MD, Paula Whited; William Kaye, MD, Nelly Delgado; Howard Kerstein, MD, Judy Recht; Boris Kerzner, MD, Thin Thin Mencarini; Rashid Khairi, MD, Brenda Shultz; Ellen Kim, MD, Janey Troy; Murray Kimmel, MD, Ruth Holt; Michael Kleerekoper, MD, Barbara Lloyd; Thomas Knecht, MD, Jeannie Farnsworth, Golnush Sharafsaleh; Mark Kutner, MD, Maria Soto; Fernando Larach, MD, Kim McCown; Anne Leddy, MD, Mary Carter; Philip Levin, MD, Karen Klein; Ronald Lewis, MD, Colleen Stutes; Angelo Licata, MD, Mary Corl; Daniel Lorber, MD, Maria Patruno; Catherine Lowder, MD, Beth Stenger; Antoinette Mangione, Kathy Tranauskis; David Mansfield, MD, Matt Bullock; Thomas Marbury, MD; Eric Marks MD, Matt Bullock; Umesh Masharani, MD; Ramesh Mathur, MD; Ronald Mayfield, MD; R. Eric McAllister, MD; Dennis McCluskey, MD, Margie McCormick, Patti Schisler; Janet McGill, MD, Sarah Kissel; Luigi Fernando Meneghini, MD, Olga Machado; Mellisa Meredith, MD, Connie Trantow; John Merenich, MD, Deanna Kurz; Nicholas Messina, III, MD, Dale Adams; B. Robert Meyer, MD, Cassia Charles; Edward, Meyer, MD; Alan Miller, MD, Jessica Tapia; David Morin, MD, Amy Dye; Anthony Morrison, MD, Anne Howley; Lawrence Mulmed, MD, Mary Steele; Daniel Nadeau, MD, Ronda Beyers; Jerry Nadler, MD, Harriette Wheatley; Margarita Nunez, MD, Pam Strong; Leann Olansky, MD, Bettie Burton; Philip Orlander, MD; R. Zorba Paster, MD; Andre Patron, DO, Eric Serfer; Samuel Peeples, MD, Suzanne Griffith; Mahfooz Peshimam, MD, Connie Hill; Lawrence Phillips, MD, Peggy Jenkins; David Podlecki, MD, Marsha Hibberd; Leonid Poretsky, MD, Marina Krymskaya; Matthew Portz, MD, Suzanne Holback; Manuel Quinones, MD, Dr. Eriniquez; Phillip Raskin, MD, Soma Abraham; Robert Ratner, MD, Evelyn Robinson; Charles Reasner, MD, Magda Ortiz; Marc Rendell, MD, Dave Gleeson; Jane Reusch, MD, Alicia Mattson; Stephen Richardson, MD, Halia Melnyk; Deborah Richmond, MD, Elizabeth Spencer; Julio Rosenstock, MD, Lisa Mize; Lance Rudolph, MD, Sheri Romero; Joseph Salvatore, MD; Andrew Savin, MD, Laura Cunningham; Timothy Schmidt, MD, Yvonne Chase; Sherwyn Schwartz, MD, Cindy Rivali; Marc Seltman, MD; Gregory Serfer, DO, Eric Serfer; Morali Sharma, MD, Debra Nichols, Madonna Pool; John Sheehan, MD, Margaret Ulchaker; Leslie Sheeler, MD; Henry Sideropoulos, MD, Shameema Ahmed; William Smith, MD, Terry McCormick; James Snyder, MD, Amy Spencer; Norman Soler, MD, Kelly Powel; Craig Spellman, MD, Enisa Arslanagic; Evan Stein, MD, Dessy Dimova; Martin Stevens, MD, Justin Schoeder; John Stokes, MD; Lisa Stone, MD, Joan Horner; Larry Stonesifer, MD, Heather Perdue; Mark Strauss, MD; Isaac Tam, MD, Billie Courtney; Joanna Tan, MD, Christian Araya; Ileana Tandron, MD, Michelle Fernandez; Andrew Thieneman, MD, Sheryl Davis; Stephen Thomson, MD, Laura Hulse; Raymond Tidman, MD, Deborah Allen; Stuart Topkis, DO, Cheryl Collins; David Van Sickle, MD, Michelle Manhart; Jack Wahlen, MD, Bonnie Wahlen; Mervyn Weerasinghe, MD, Lydia St. Hilaire; Richard Weinstein, MD, Sally Crain; Ruth Weinstock, MD, Susan Carusone; Jeffrey Whitmer, MD, Patti Krotchen; Steven Wittlin, MD, Mary Kelly; Carol Wysham, MD, Lynn Maxwell; Jose Yanez, MD, Jean Gaddis; Franklin Zieve, MD, Ann Grimsdale; Randall Zusman, MD, Beverly Buczynski; Alan Zweben, MD, Sandy Happy, Deborah Dougherty.
ADOPT Steering Committee.
Steven Kahn, MB, ChB, Giancarlo Viberti, MD (co-chairs), Martin Freed, MD, Steven Haffner, MD, William Herman, MD, Rury Holman, MD, Nigel Jones, MA, John Lachin, ScD, Bernard Zinman, MDCM.
ADOPT Data Safety Monitoring Board.
Marian Fisher, PhD, Alan Garber, MD, PhD (co-chairs), Professor John Fuller, Professor Henry Dargie, Daniel Levy, MD, Ellen Roecker, PhD.
ADOPT Study Team.
Caroline Aitken, Deborah Andrew, Rosemary Fowler, Mark Heise, Karen Huckel, Josephine Koskinas, Barbara Kravitz, Leslie Nosek, Colleen O’Neill, Lisa Porter, Jacqueline Richards, Yijun Sun, Doreen Woodward, Samantha Wright, Dahong Yu.
Effect of age (A) and BMI (B) on the prevalence of GAD positivity in 174 GAD antibody-positive recently diagnosed drug-naïve patients with type 2 diabetes. There was no significant difference in the incidence of GAD positivity between age categories, whereas the incidence was significantly different based on BMI (P < 0.05).
Effect of age (A) and BMI (B) on the prevalence of GAD positivity in 174 GAD antibody-positive recently diagnosed drug-naïve patients with type 2 diabetes. There was no significant difference in the incidence of GAD positivity between age categories, whereas the incidence was significantly different based on BMI (P < 0.05).
![FIG. 2. A: Insulin sensitivity determined by fasting insulin. B: Insulin response to oral glucose as the insulinogenic index (ΔI/ΔG [0–30]). C: β-Cell function as ΔI/ΔG [0–30]/fasting insulin from an OGTT in 174 GAD antibody-positive () and 3,960 GAD antibody-negative (□) recently diagnosed drug-naïve patients with type 2 diabetes. Data are expressed as the means ± SE for fasting insulin and as median and interquartile range for the insulin response and β-cell function.](/view-large/figure/2276492/zdb0120436370002.jpeg)
A: Insulin sensitivity determined by fasting insulin. B: Insulin response to oral glucose as the insulinogenic index (ΔI/ΔG [0–30]). C: β-Cell function as ΔI/ΔG [0–30]/fasting insulin from an OGTT in 174 GAD antibody-positive (
) and 3,960 GAD antibody-negative (□) recently diagnosed drug-naïve patients with type 2 diabetes. Data are expressed as the means ± SE for fasting insulin and as median and interquartile range for the insulin response and β-cell function.
A: Insulin sensitivity determined by fasting insulin. B: Insulin response to oral glucose as the insulinogenic index (ΔI/ΔG [0–30]). C: β-Cell function as ΔI/ΔG [0–30]/fasting insulin from an OGTT in 174 GAD antibody-positive () and 3,960 GAD antibody-negative (□) recently diagnosed drug-naïve patients with type 2 diabetes. Data are expressed as the means ± SE for fasting insulin and as median and interquartile range for the insulin response and β-cell function.
Baseline characteristics by GAD antibody status
| GAD positive | GAD negative | P | |
|---|---|---|---|
| n | 174 | 3,960 | — |
| Age (years) | 57.0 ± 0.799 | 56.5 ± 0.159 | 0.524 |
| Male (%) | 55.8 | 57.7 | 0.605 |
| BMI (kg/m2) | 31.4 ± 0.466 | 32.0 ± 0.091 | 0.231 |
| Waist circumference (cm) | 103.9 ± 1.17 | 105.5 ± 0.233 | 0.178 |
| Waist-to-hip ratio | 0.942 ± 0.007 | 0.948 ± 0.001 | 0.391 |
| Fasting plasma glucose (mmol/l) | 8.49 ± 0.105 | 8.39 ± 0.022 | 0.357 |
| HbA1c (%) | 7.49 ± 0.070 | 7.35 ± 0.015 | 0.066 |
| Fasting plasma insulin (pmol/l) | 133 ± 9.89 | 150 ± 1.73 | 0.045 |
| HOMA-IR ([μU/ml]/[mmol/l]) | 5.36 (4.83–5.95) | 6.38 (6.25–6.51) | 0.0005 |
| Systolic blood pressure (mmHg) | 131.2 ± 1.19 | 132.9 ± 0.25 | 0.144 |
| Diastolic blood pressure (mmHg) | 78.6 ± 0.71 | 79.7 ± 0.14 | 0.132 |
| HDL cholesterol (mmol/l) | 1.26 (1.22–1.31) | 1.21 (1.20–1.22) | 0.035 |
| Non-HDL cholesterol (mmol/l) | 3.83 (3.68–4.00) | 3.97 (3.94–4.00) | 0.091 |
| Triglycerides (mmol/l) | 1.67 (1.52–1.83) | 1.86 (1.83–1.90) | 0.011 |
| GAD positive | GAD negative | P | |
|---|---|---|---|
| n | 174 | 3,960 | — |
| Age (years) | 57.0 ± 0.799 | 56.5 ± 0.159 | 0.524 |
| Male (%) | 55.8 | 57.7 | 0.605 |
| BMI (kg/m2) | 31.4 ± 0.466 | 32.0 ± 0.091 | 0.231 |
| Waist circumference (cm) | 103.9 ± 1.17 | 105.5 ± 0.233 | 0.178 |
| Waist-to-hip ratio | 0.942 ± 0.007 | 0.948 ± 0.001 | 0.391 |
| Fasting plasma glucose (mmol/l) | 8.49 ± 0.105 | 8.39 ± 0.022 | 0.357 |
| HbA1c (%) | 7.49 ± 0.070 | 7.35 ± 0.015 | 0.066 |
| Fasting plasma insulin (pmol/l) | 133 ± 9.89 | 150 ± 1.73 | 0.045 |
| HOMA-IR ([μU/ml]/[mmol/l]) | 5.36 (4.83–5.95) | 6.38 (6.25–6.51) | 0.0005 |
| Systolic blood pressure (mmHg) | 131.2 ± 1.19 | 132.9 ± 0.25 | 0.144 |
| Diastolic blood pressure (mmHg) | 78.6 ± 0.71 | 79.7 ± 0.14 | 0.132 |
| HDL cholesterol (mmol/l) | 1.26 (1.22–1.31) | 1.21 (1.20–1.22) | 0.035 |
| Non-HDL cholesterol (mmol/l) | 3.83 (3.68–4.00) | 3.97 (3.94–4.00) | 0.091 |
| Triglycerides (mmol/l) | 1.67 (1.52–1.83) | 1.86 (1.83–1.90) | 0.011 |
Data are means ± SE or geometric mean (95% CI).
Prevalence of NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) metabolic syndrome criteria by GAD antibody status
| GAD positive | GAD negative | P | |
|---|---|---|---|
| n | 174 | 3,960 | — |
| Metabolic syndrome positive | 74.1 | 83.7 | <0.001 |
| Fasting glucose >6.1 mmol/l | 100 | 100 | — |
| Waist circumference >102 cm (male), >88 cm (female) | 66.7 | 70.0 | 0.335 |
| Blood pressure ≥130 systolic or diastolic ≥85 mmHg | 77.0 | 78.6 | 0.627 |
| Triglycerides ≥1.7 mmol/l | 57.5 | 65.2 | 0.054 |
| HDL cholesterol <1.0 mmol/l (male), <1.3 mmol/l (female) | 33.3 | 39.3 | 0.144 |
| GAD positive | GAD negative | P | |
|---|---|---|---|
| n | 174 | 3,960 | — |
| Metabolic syndrome positive | 74.1 | 83.7 | <0.001 |
| Fasting glucose >6.1 mmol/l | 100 | 100 | — |
| Waist circumference >102 cm (male), >88 cm (female) | 66.7 | 70.0 | 0.335 |
| Blood pressure ≥130 systolic or diastolic ≥85 mmHg | 77.0 | 78.6 | 0.627 |
| Triglycerides ≥1.7 mmol/l | 57.5 | 65.2 | 0.054 |
| HDL cholesterol <1.0 mmol/l (male), <1.3 mmol/l (female) | 33.3 | 39.3 | 0.144 |
Data are percent unless otherwise indicated.
*A complete list of the ADOPT Study Group members can be found in the appendix.
B.Z., S.E.K., and S.M.H. have received honoraria, consulting fees, and grant/research support from GlaxoSmithKline.
Article Information
The study was supported by funds from GlaxoSmithKline.
The study was overseen by the ADOPT Steering Committee (Steven Kahn and Giancarlo Viberti [co-chairs], Martin Freed, Steven Haffner, William Herman, Rury Holman, Nigel Jones, John Lachin, and Bernard Zinman) and day-to-day operations were conducted under the auspices of the ADOPT Study Team (Caroline Aitken, Deborah Andrew, Rosemary Fowler, Mark Heise, Karen Huckel, Josephine Koskinas, Barbara Kravitz, Leslie Nosek, Colleen O’Neill, Lisa Porter, Jacqueline Richards, Yijun Sun, Doreen Woodward, Samantha Wright, and Dahong Yu).
We thank the study participants and study staff, without whom these analyses would not have been possible.
