The Willingness to Participate in Pediatric Type 1 Diabetes Studies

Since July 2017 (as a pilot study from September 2016) parents in Saxony have had the option to have neonates tested for an increased risk of type 1 diabetes by means of genetic testing. To this end, blood is extracted from the heel in the context of the usual neonatal screening, and this is analyzed separately. This “Freder1k Study” is an initiative by the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) and is funded by the US foundation Helmsley Charitable Trust.

BOX. Freder1k and POInT study team.

• Collaborators: GPPAD-Coordinating Center (CC):

  M. Gündert, F. Haupt, S. Arnolds, C. Barz, K. Blasius, N. Friedl, C. Gezginci, A. Gomez- Bantel, J. Hasford, M. Heigermoser, B. Höfelschweiger, M. Jolink, N. Klein, R. Lickert, C. Matzke, R. Riewöhner, M. Bißbort, M. Scholz, K. Schütte-Borkovec, L. Vogel, G. Göppel, F. Voß, A. Weiß, J. Maria Zapardiel Gonzalo, P. Sifft, L. Wendel, H. Kapfelsberger, M. Vurucu, K. Sarcletti, S. Jacobson

• Dresden

  Clinical Center: E. Bonifacio, R. Berner S. Dietz, G. Gemulla, S. Kowal, F. Lander, R. Morgenstern, M. Weigelt, N. Zubizarreta, S. Arabi, R. Hoffmann, R. Blechschmidt, F. Ehrlich, M. L. Zielmann

• Munich

  Clinical Center: A. G. Ziegler, P. Achenbach, M. Bunk, S. Färber- Meisterjahn, W. Grätz, I. Greif, H. Kaltenecker, M. Herbst, A. Hofelich, A. Kölln, V. Vollmuth, B. Marcus, A. Munzinger, J. Ohli, C. Ramminger, F. Reinmüller, T. Welzhofer, M. Kaiser, E. Karapinar, C. Winkler

• Collaborating screening laboratories

  Institut für Klinische Chemie und Laboratoriumsmedizin Screeninglabor, University Hospital Carl Gustav Carus Dresden (P. Mirtschink); University Hospital Carl Gustav Carus Dresden (P. Mirtschink), University of Leipzig Medical Center (U. Ceglarek)

• Maternity hospitals

  Rof the maternity hospitals: K. Nitzsche, P. Wimberger, M. Ruediger, R. Bergert, A. Zirkel, G. Heubner, A. Gatzweiler, P. Bießlich, U. Winkler, U. Schramm, R. Andretzky, U. Dziambor, P. Jesche, A. Bachouri, U. Förster, H. Reck, S. Kahleyss, K. N. Pargac, D. Stadthaus, K. Haffner, F. Störmer, A. Süße, K. Praedicow, S. Pötzsch, G. Teichmann, K. Groeger, D. Wolff, U. Zügge, C. Fichtner, J. Wünsche, M. Krenz, E. Bieck, H. Thome, W. Kiess, H. Stepan, L. Kaltofen, A. Hübler, E. Gusenberg, A. Huster, M. Hofmann, A. Popiela, H. Sirb, K. Wagner, U. Rahm, E. Helwig, C. Daescu, W. Hessel, G. Adamiak-Brych, F. Schlemmer, C. Huster, B. Gebhardt, B. Strika-Pavlovic, G. Kemper, L. Hempel, G. Günther

Methods

Analyzing known diabetes risk genes (single nucleotide polymorphisms, SNPs) can indicate an increased risk of diabetes. An increased risk means a risk higher than 10% of developing multiple diabetes specific autoantibodies by the 6^th birthday and a 7.6% higher risk of developing manifest type 1 diabetes by the 10th birthday (1, 2).

The aims of early screening are:

• Identifying the increased risk

• Early education about risk increase and symptoms of illness, in order to prevent severe ketoacidosis at the time of manifestation, and

• Invitation to participate in a prevention study or alternatively to follow-up regarding the development of type 1 diabetes autoantibodies.

For the purpose of prevention, participation in the POInT (Primary Oral Insulin Trial) study was offered from February 2018 to March 2021. This Europe wide multicenter double blinded trial investigates whether daily administration of oral insulin versus placebo from the 7^th month of life to the 3rd birthday can delay or prevent the disease (3, 4).

Results

In total, 42 804 children attended the Freder1k screening in Saxony between July 2017 and June 2020 (figure).

Figure.

Willingness to participate in the Freder1k and POInT study in Saxony and Thuringia between 2017 and 2021; 471 children at increased risk for type 1 diabetes. 317 of the 471 families invited took up the offer of an initial consultation in the study center (“screening visit“, SV). Of these 317, 151 subsequently participated in the intervention study POInT.

*All Freder1k invitations were reported back only until 6/2020, from 7/2020 to 11/2021 only positive results were reported back. For this reason, the consent rate in this time period cannot be determined with any certainty.

In 2019 alone, 22 873 parent couples in Saxony received the invitation to attend the Freder1k screening via cooperating maternity clinics. This means that with a total number of 34 491 live births*, 66% of babies born in Saxony were reached (*Statistical Office of the Free State of Saxony, Kamenz, 2021). 67% of parents contacted agreed to participate.

Since 2019, parents in Thuringia also received an invitation to participate in Freder1k screening. From July 2017 to November 2020, an increased genetic risk (>10%) for developing type 1 diabetes was confirmed in 471 neonates under study (1.1% of all babies studied). Of these 471 children, 131 (27.8%) were directly related (parents or siblings) to a family member affected by type 1 diabetes (figure).

After being informed by telephone about the finding of an increased risk (ethics approval Technical University Dresden EK440112017), 317 of the affected pairs of parents (67.3%) took up the invitation to an initial personal consultation. For the remaining 32.7%, a possible reason for turning down the invitation may have been in particular a not sufficiently convincing management of explanation and education regarding the effort involved in and benefit conferred by participating in screening. In the initial consultation, parents received detailed information regarding type 1 diabetes, the risk of ketoacidosis, and the opportunity to participate in the prevention study POInT. Almost half (151/317) of the families agreed to participate in the study (47.6%) in spite of the effort involved (numerous and time-intensive follow up appointments, regular venipuncture, daily intake of a study drug, in some cases covering long distances to attend, etc).

The offer of several follow-up examinations for the development of diabetes specific autoantibodies (without intervention) was taken up by 61 of the 317 families (19.2%). 105 of the 317 pairs of parents (33%) declined any further measures.

Discussion

The willingness to participate of the families affected by type 1 diabetes was almost twice that of those not affected (48.1% v 25.9%), which is easily explained with prior awareness of everyday burdens and possible complications. This discrepancy in participation could also been interpreted as an indicator of the fact that the disease is little known in the general population. In general, the willingness to participate corresponded to our expectations (50% in those affected versus 30% in those not affected) (3).

The Freder1k screening has been continued after the end of the recruitment period for the POInT study. Since April 2021, parents of children at increased risk have had the option of participating in a prevention study of oral probiotics, the SINT1A study (Supplementation with B. Infantis for Mitigation of Type 1 Diabetes). On the basis of daily administration of the probiotic Bifidobacterium infantis in the first year of life the study will investigate whether the gut microbiota and immune system are beneficially affected and whether the development of insulin autoantibodies can be prevented (5).

In dependently of the results that POInT and SINT1A will yield, the date are showing already that many pairs of parents are willing to participate with their newborns in screening and prevention studies. This is also the case when the study is associated with a genetic test—which is often regarded with skepticism— and when the individual benefit is uncertain, while the individual effort in participating in the study can be great for families.

These findings indicate that laborious prevention and intervention projects can be implemented as early as in the neonatal period if they are relevant in ways that parents can understand and if they are accompanied by detailed and easy access consultation services.

A further increase in the awareness level of the disease type 1 diabetes and its associated consequences (health restrictions, complications, reduced quality of life, etc) as a result of more intensive information and educational work would be highly desirable.