The Profile of Articles on AXIN2 Mutations,Oligodontia, and Ethical Statements in Dental Research

Abstract

Purpose:

Editors often require ethical statements in research publications. This is particularly important with genetic data where discrimination may occur upon data disclosures. The purpose of this research is to determine if there was a positive trend of publishing ethical statements in dental genetic research. The study is limited to AXIN2 mutations which may be associated with oligodontia and cancer.

Methods:

A MEDLINE search of 2011–2021 articles concerning AXIN2, oligodontia, and ethical statements was conducted. Reviews, nonhuman subject research, abstracts, and articles not written nor translated into English were excluded.

Results:

Forty-four studies were found; 10 excluded. There were 25 (75.8%) with ethical statements, and 25 (75.8%) with participant consent statements. There was no significant difference by year in ethical statements over the ten years (p = 0.094).

Conclusion:

There is a need to encourage more ethical statements in publications especially for genetically sensitive topics to reassure readers of ethical practices.

Genetic data are becoming more available due to the rapid decrease in cost for the processing of genetic sequences. Genetic data provide possibilities for early interventions to improve health and wellness in personalized medicine. When aggregated, the data also provide possibilities for rapid advancement in public health. Nevertheless, there are ethical questions that have arisen in the past about tissue use or reuse without the consent of donors (Nascutiu and Lupu, 2020), as well as current concerns about genetic articles retracted due to research misconduct (Dal-Re and Ayuso, 2019). In this climate, many authors are providing ethical statements with their research in which they state that the research had been reviewed by an institutional review board. Some authors are also including statements that participants provided informed consent and children provided assent for the research.

In dentistry, there are many genetic variations that have been associated with important oral-craniofacial conditions. For example, amelogenin (AMELX) is associated with amelogenesis imperfect 1, SH3 Domain-binding protein 2 (SH3BPS) is associated with cherubism, and AXIN2 is associated with the absence of six or more teeth (Gettig and Hart, 2003). Having such information held confidentially and handled ethically is important to all stakeholders, especially when the data involve children, or include genetic alleles that may be associated with more than one disease or condition.

One such dental concern that involves children and a gene mutation that may be associated with more than one condition is oligodontia. Oligodontia is the absence of six or more (but not all) teeth excluding the wisdom teeth. It is a relatively rare condition with a prevalence proportion from 0.16% (Rolling and Poulsen, 2009) to 0.3% (Shakra and Alqaqaa, 2008). Some cases are part of a syndrome (oligodontia with cleft lip/palate; oligodontia with ectodermal dysplasia, etc.) and some cases have milder deficiencies limited to tooth development; although the line between syndrome and non-syndrome is often blurred. (Bock, et al., 2017). Several genes have been identified as being involved with nonsyndromic oligodontia. These are: AXIN2, ectodysplasin-A (EDA), Muscle Segment Homebox 1 (MSX1), Paired Box 9 (PAX9), and WNT10A. (Liu, et al., 2015; Wong, et al., 2014; Zhou, et al., 2021).

However, if a mutation in EDA is expressed at high levels, syndromic oligodontia with ectodermal abnormalities occurs (Liu et al. 2015; Worsaae, et al., 2007; Zhou, et al., 2021). If a mutation in MSX1 is expressed at high levels, syndromic oligodontia with cleft lip/palate occurs. Similarly, overexpression of a mutation in AXIN2 results in cleft lip/palate in syndromic oligodontia; however, there is also a potential link with gastrointestinal polyposis, colorectal cancer, and breast cancer (Weitzel, et al., 2011). This potential connection could lead to harm to a research participant through stigmatization, insurance/ employment issues, etc. if the if the study lacks ethical oversight and confidentiality is broken. Often oligodontia research participants (probands) are children who have been identified clinically with more than six missing permanent teeth. They may be asked to participate in dental research as well as cancer risk research aimed toward interceptive prevention measures (Bock, et al., 2017). Ethical recruitment and data security are particularly important when children are involved in research.

To underscore the importance of research integrity and research ethics, many journal editors are requiring ethical statements to be included in their journal’s publication. The level to which this practice is being conducted has been evaluated in dental research with humans and animals in 2006 (Navaneetha, 2011); concerning Indian dental journals from 2008–2011; and for pediatric dental journals (Walia, et al., 2022), for example; however, recent dental research specifically related to genetic dental research and ethical statements has not been previously reported. The purpose of this research is to determine if there was a positive trend of publishing ethical statements in dental genetic research articles from 2011–2021. The articles examined were those with research on AXIN2 mutations and oligodontia. This selection of AXIN2 research was made as a representative sample of dental genomic research.

Methods

Ethical Statement

The West Virginia University Institutional Review Board evaluated this research as non-human subject research (protocol 2201503679).

Study Design

The research on oligodontia and AXIN2 ethical statements was from January 1, 2011 to December 31, 2021. This decade was selected as the period following the September 22, 2010 Singapore Statement on Research Integrity for an international effort in promoting and following principles of research integrity. Articles concerning oligodontia were identified in MEDLINE (PubMed) using the following key words for the search: “AXIN2”AND “oligodontia.” MEDLINE (PubMed) was selected as it is a comprehensive, biomedical database maintained by the U.S. National Library of Medicine with approximately 25 million citations (Williamson and Minter, 2019). There is quality control in the maintenance and functioning of the database (Williamson and Minter, 2019) as a source. Forty-three titles were returned. Exclusion criteria were abstracts rather than full articles, articles that were literature reviews (narrative, meta-analyses, or systematic reviews), articles not written in English or not having an English translation, and articles that did not include human participants (animal, cell culture, or in silico research). The inclusion criterion was the article was either written in English or had an English translation available. Each title and abstract was read. Included articles were read for the following features: year of publication, location of research, presence or absence of a statement of ethics committee approval, and presence or absence of a statement of consent or assent.

Statistical Analysis

Data were analyzed for frequency determination and linear regression on year of publication. The alpha level was set, a priori, to ≤0.05. The software for the analyses was IBM SPSS Statistics® Version 26, Armonk, NY: IBM Corp.

Results

Table I has the descriptions of the 33 results concerning AXIN2 mutations and oligodontia that were returned from the MEDLINE (PubMed) search and all were either written in English or had English translations. Ten articles were excluded from the initial search: six were review articles (not requiring consent); one was an abstract written in English, but the full manuscript was only available in Chinese; one was an animal study; one was a cell culture study; and, one was an in silico study. The complete list is available in the supplemental materials.

Table I.

MEDLINE (PubMed) returned results on AXIN2 mutations and oligodontia.

	Author, year	Title	Citations	Location	Study type/study design	Number in study/age	Ethics Committee approval statement	Consent or assent	Journal guidance in reporting consent or ethical statement
1	Mu YD, Contreras Cl, McDaniel JS, Donly KJ, Chen S. 2013	Mutational analysis of AXIN2, MSXI, and PAX9 in two Mexican oligodontia families 10.4238/20l3,October.l0.10 Genetics and Molecular Research	7	U.S. (Families attended Texas Health Science Center)	Phenotypic and genotype description of the cases Bioinformatics analysis DNA sequencing analysis Primary data collection Case examined for descriptives with AXIN2 variation	8 pediatric patients Ages not provided (2 families with oligodontia)	Not stated	Assumed and not stated (NIH grant funding requirement)	Not mentioned
2	Bergenda B, Klar J, Stecksen-Blicks C, Norderyd J, Dahl N. 2011	• Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSXI, and PAX9 genes 10.1002/ajmg.a.34045 American Journal of Medical Genetics	44	Sweden	Correlation genotype-phenotype with family. Mutation analysis Primary data collection Case examined for descriptives with AXIN2 variation	93 with oligodontia participated Ages 17–30 years	yes	Yes consent	Requires written statements of ethics committee approval and written statement of consent obtained
3	Beard C, Purvis R, Winship IM, Macrae FA, Buchanan DD. 2019	Phenotypic confirmation of oligodontia, colorectal polyposis, and cancer in a family carrying an exon 7 nonsense variant in the AXIN2 gene 10.1007/s10689-019-00120-0 Familial Cancer	9	Australia	Case report Primary data collection Report of association with polyposis or colorectal neoplasia	4 (1 family) Probond age 67 years Family members 40–48 years	no	Yes, verbal consent	Member of COPE. Journal requires written statement of compliance with ethical standards; documentation of compliance must be available upon request.
4	Wang J, Jian F, Chen J, Wang H, Lin Y, Yang Z, Pan X, Lai W. 2011	Sequence analysis of PAX(, MSXI and AXIN2 genes in a Chinese oligodontia family 10.1016/j.archoralbio.2011.03.023 Archives of Oral Biology	13	China	Phenotypic and genotype description of the family Sequence analysis Primary data collection Case examined for descriptives with AXIN2 variation	6 (1 family) Probond age 1 1 Family members were adults	yes	Adult consent and child assent	Requires written statement of following ethical code (Declaration of Helsinki, etc.) and written informed consent was obtained.
5	Koskinen S, Keski-Filppula RK, Alapulli H, Nieminen P, Anttonen V 2019	Familial oligodontia and regional odontodysplasia associated with a PAX9 initiation condon mutation 10.1007/s00784-019-02849-5 Clinical Oral Investigations	1	Finland	Phenotypic and genotype description of the family Mutation analysis Primary data collection Case examined for descriptives with AXIN2 variation	1 family Probond age 6 years Family members were adults	yes	yes	Member of COPE. Journal requires written statement of compliance with ethical standards; documentation of compliance must be available upon request.
6	Liu H, Ding T, Zhan Y, Feng H. 2015	A Novel AXIN2 Missense Mutation is Associated with Non-Syndromic Oligodontia 10.1371/journal.pone.0138221 PLoS One	38	China	Comparison of wild and proband Structural and Conservation analysis Mutation analysis Primary data collection Comparative study of probond and controls	1 probond, age 8 years 100 controls, ages not provided	yes	yes	Member of COPE. Journal requires a written Ethics Statement concerning risks.
7	Wong S, Liu H, Bai B, Chang H, Zhao H, Wang Y, Han D, Feng H. 2014	Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia 10.1016/j.archoralbio.2013.12.009 Archives of Oral Biology	11	China	Phenotypic and genotype description Structure and Conservation analysis Mutation analysis Primary data collection Comparative cross sectional case-control study of those with oligodontia and those without	96 with oligodontia 200 without Ages not provided, however recruitment from prosthodontic clinic	yes	yes	Requires written statements of following ethical code (Declaration of Helsinki, etc.) and written informed consent was obtained.
8	Jensen JM, Sakakkebaek A, Gaustadness M, Sommerlund M, Gjorup H, Ljungmann K, Lautrup CK, Sunde L 2021	Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes? 10.1007/s10689-021-00280-y Familial Cancer	1	DENMARK	Phenotype and genetics Primary data collection Cases examined for association with colorectal cancer	1 family studied Probands, brothers, ages 58 and 56 years 8 carriers 39 in the pedigree	Stated in the article that ethics approval was not needed for the case report	yes	Member of COPE. Journal requires written statement of compliance with ethical standards; documentation of compliance must be available upon request.
9	Chan JM, Clendenning M, Joseland S, Georgeson P, et al. 2021	Rare germline variants in the AXIN2 gene in famiies with colonic polyposis and colorectal cancer 10.1007/s10689-021-00283-9 Familial Cancer	0	AUSTRALIA	Phenotyping Transcriptional analysis Mutational analysis Primary data collection Cases examined for association with polyposis	130 4 families genetics described Mean age 52.5 years	no	no	Member of COPE. Journal requires written statement of compliance with ethical standards; documentation of compliance must be available upon request.
10	Lee KE, Ko J, Shin TJ, Hyun HK, Lee SH, Kim JW. 2014	Oligodontia and curly hair occur with ectodysplasin-mutations 10.1177/0022034514522059 Journal of Dental Research	7	Korea	Mutational analysis Primary data collection Primary data collection Case examined for descriptives with AXIN2 variation	2 families Probonds ages 6 years and 3 years	yes	yes	Requires written statements of ethics committee approval and informed consent.
11	Qin H, Xu H, Xuan K. 2013	Clinical and genetic evaluation of a Chinese family with isolated oligodontia 10.1016/j.archoralbio.2013.04.007 Archives of Oral Biology	1	China	Phenotype Mutation Analysis Primary data collection Case examined for descriptives with AXIN2 variation	1 family Probond age 1 1 years 2 adult family members also affected 6 not 100 unaffected controls	yes	yes	Requires written statement of following ethical code (Declaration of Helsinki, etc.) and written informed consent was obtained.
12	Lindor NM, Win AK, Gallinger S, Daftary D, Thibodeau SN, Silva R, Letra A. 2014	Colorectal cancer and self-reported tooth agenesis. 10.1186/1897-4287-12-7 Heredity Cancer in Clinical Practice	7	US	Survey of colon cancer family registry for missing teeth Assay of 2 probands with colon cancer, tooth agenesis and family members Survey data collected PI had available germline secondary data from recruitment site Cross sectional observational study colorectal cancer v oligodontia	1636 self-reported cases and 2788 self-reported not affected Ages not provided	Not reported But NIH	Not reported But NIH	Requires written statement of ethics committee approval, details that research followed Declaration of Helsinki principles.
13	Arzoo PS, Klar J, Bergendal B, Norderyd J, Dahl N. 2014	WNT10A mutations account for 1/4 of population-based isolated oligodontia and show phenotypic correlations 10.1002/ajmg.a.36243 American Journal of Medical Genetics Part A	23	Sweden	Mutation Analysis Phenotype analysis Primary data collection Cases examined for descriptives with AXIN2 variation	94 families (104 patients) Ages 19–32 years	yes	Yes	Requires statements of ethics committee approval and participant consent.
14	Marvin ML, Mazzoni SM, Herron CM, Edwards S, Gruber SB, Petty EM. 201 1	AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome 10.1002/ajmg.a.33927 American Journal of Medical Genetics Part A	33	US	Case report Mutation analysis Primary data collection Case examined for descriptives with AXIN2 variation	Proband, age 35 years Plus adult family (ages 35 to 97 years) N = 5	yes	yes	Requires statements of ethics committee approval and participant consent.
15	Kantaputra PN, Hutsadaloi A, Kaewgahya M, Intachai W, German R, Koparal M, Leethanakul C, Tolun A, Cairns JRK 2018	WNT1 OB mutations associated with isolated dental anomalies. 10.1111/cge.13218 Clinical Genetics	7	Thailand	Mutation analysis Whole genome sequencing Protein modeling Primary data collection Case examined for descriptives with AXIN2 variation and other variations	256 with various tooth agenesis Ages not provided. (Radiographic images indicated adults)	yes	yes	Requires written statement of ethical committee approval. Authors confirm consent was obtained but no requirement for a written statement in the journal
16	Sery O, Bonczek O, Hlouskova A, Cernochova P, Vanek J, Misek 1, Krejci P, Holla LI 2015	A screen of a large Czech cohort of oligodontia patients implicates a novel mutation in the PAX9 gene 10.1111/eos.12170 European Journal of Oral Sciences	2	Czech Republic	DNA analysis Mutation analysis Primary data collection Case examined for descriptives with AXIN2 variation and other variations	270 with oligodontia 30 controls Ages 9 to 23 years	Yes	yes	Requires statement of independent review, consent obtained, and research conducted following Declaration of Helsinki
17	Kimura M, Machida J, Yamaguchi S, Shibata A, Tatematsu, et al. 2013	Novel nonsense mutation in MSXI in familial nonsyndromic oligodontia: subcellar localization and role of homeodomain/MH4 10.1111/eos.12170 European Journal of Oral Sciences	12	Japan	Mutation analyses Primary data collection Case examined for descriptives with AXIN2 variation and other variations	6 familial and 7 sporadic cases Ages not provided. (Radiographic images indicated adults)	Yes	no	Requires statements of independent review, consent obtained, and research conducted following Declaration of Helsinki
18	Yue H, Liang J, Yang K, Hua B, Bian Z. 2016	Functional analysis of a novel missense mutation in AXIN2 associated with non-syndromic tooth agenesis 10.1111/eos.12273 European Journal of Oral Sciences	7	China	Conservation analysis Mutation analysis Primary data collection Case examined for descriptives with AXIN2 variation and other variations	1 proband and 6 family members (3 generations) Age of proband not provided (Radiographic image indicates adult) 500 controls	Yes	yes	Requires statements of independent review, consent obtained, and research conducted following Declaration of Helsinki
19	Yang L, Liang J, Yue H, Bian Z. 2020	Two novel mutations in MSXI causing oligodontia 10.1371/journal.pone.0227287 PLoS One	1	China	Mutation analysis Primary data collection Case examined for descriptives with AXIN2 variation and other variations	2 probands (ages 16 years and 21 years) and family 300 controls	yes	yes	Member of COPE. Journal requires a written Ethics Statement concerning risks.
20	Mazzoni SM, Petty EM, Stoffel EM, Fearon ER 2015	An AXIN2 Mutant Allele Associated with Predisposition to Colorectal Neoplasia Has Contex-Dependent Effects on AXIN2 Protein Function 10.1016/j.neo.2015.04.006 Neoplasia	8	US	Mutation analysis in cell line and with one heterozygous carrier Primary data collection Gene activity studied	1 blood draw Age not provided	Not reported	yes	Requires written statements of ethics committee approval, informed consent, compliance with Declaration of Helsinki
21	Bock NC, Lenz S, Ruiz-Heiland G, Ruf S. 2017	Nonsyndromic oligodontia: Does the Tooth Agenesis Code (TAC) enable prediction of the causative mutation? 10.1007/s00056-016-0056-y Journal of Orofacial Orthopedics/ =Fortschritte der Kieferothopadie	4	Germany	Mutation gene vs oligodontia Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	20 Ages 7–16 years	yes	yes	Member of COPE. Journal requires written statement of compliance with ethical standards; documentation of compliance must be available upon request.
22	Chu K, Wang Y, Chou Y, Chen, J Wang Y, Simmer JP, Hu J, Wang. 2021	Synergistic Mutations of LRP6 and WNTI0A in Familial Tooth Agenesis. 10.3390/jpml1111217 Journal of Personalized Medicine	0	Taiwan	Mutational analysis Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	4 families Proband ages: 7 years; 6 years; 1 1 years; and 10 years	yes	yes	Requires written statements of ethics committee approval, informed consent, compliance with Declaration of Helsinki.
23	Keskin G, Karaer K, Gundogar ZU 2021	Targeted next-generation sequencing (NGS) analysis of mutations in nonsyndromic tooth agenesis candidate genes: Analysis of a Turkish cohort 10.1007/s00056-021-00284-4 Journal of Orofacial Orthopedics/ Fortschritte der Kieferothopadie	1	Turkey	Genetics sequencing analysis Primary data collection Cases examined for descriptives with AXIN2 variation and other variations and associations	49 with agenesis Ages 6–13 years	Yes	yes	Member of COPE. Journal requires written statement of compliance with ethical standards; documentation of compliance must be available upon request.
24	Yuan Q, Zhao M, Tandon B, Maili L, Liu X, et al. 2017	Role of WNT10A in failure of tooth development in humans and zebrafish 10.1002/mgg3.332 Molecular genetics and genomic medicine	7	US	Genetic sequencing Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	Proband, age 9 years	yes	yes	Requires written statement of ethics committee approval. Collects information that consent was obtained but does not require statement. Must follow Declaration of Helsinki.
25	Qin H, CaiJ 2015	Axis inhibition protein 2 polymorphisms may be a risk factor for families with isolated oligodontia 10.3892/mmr.2014.2900 Molecular Medicine Reports	2	China	Mutation analysis Primary data collection Case examined for descriptives with AXIN2 variation	Proband, age not reported, but radiographically has second molars in bell stage, and 8 family members 60 others	Yes	Not mentioned	Requires written statement of ethics committee approval. Must follow Declaration of Helsinki. Editor may request supporting information.
26	Vierra 2021	Prophylactic subtotal colectomy in a patient with an AXIN2 mutation 10.1093/jscr/rjab470 Journal of surgical Case Reports	0	US	Case study Genetic testing for AXIN2 was positive, multiple polyps. Case	1, age 50 years	Not mentioned	Not mentioned	Requires written statements of ethics committee approval, informed consent, compliance with Declaration of Helsinki.
27	Arte S, Parmanen S, Pirinen S, Alaluusua S, Nieminen P. 2013	Candidate gene analysis of tooth agenesis identifies novel mutations in six genes and suggests significant role for WNT and EDA signaling and allele combinations 10.1371/journal.pone.0073705 Plos one	38	Finland	Mutation analysis Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	127 probands, ages 6–54 years	Yes	yes	Member of COPE. Journal requires a written Ethics Statement concerning risks.
28	Alfawaz S, Fong F, Plagnol V, Wong FSL, Fearne J, Kelsell DP. 2013	Recessive oligodontia linked to a homozygous loss-of-function mutation in the SMOC2 gene 10.1016/j.archoralbio.2012.12.008 Archives of Oral Biology	11	Pakistan	Mutation analysis Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	3 siblings ages 8, 10, 16 years	yes	yes	Requires written statements of following ethical code (Declaration of Helsinki, etc.) and written informed consent was obtained.
29	Mastouri MH, DeCoster P, Zaghabani A, et al. 2018	Genetic study of non-syndromic tooth agenesis through the screening of paired box 9, msh homeobox 1, axin 2, and Wnt family member I0A genes: a case series 10.1111/eos.12391 European Journal of Oral Sciences	5	Tunisia	DNA sequencing Analysis of mutations (insilico poly Ph en database) Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	28 with oligodontia and 9 family members 88 others Ages not provided	Yes	Not mentioned	Requires statements of independent review, consent obtained, and research conducted following Declaration of Helsinki
30	Bonczek O, Bielik P, Krejci P, Zeman T, et al. 2018	Next generation sequencing reveals a novel nonsense mutation in MSXI gene related to oligodontia 10.1371/journal.pone.0202989 PLoS One	19	Czech Republic	Molecular modeling Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	60 with agenesis, ages 13 to 17 years.	Not mentioned	Not Mentioned	Member of COPE. Journal requires a written Ethics Statement concerning risks.
31	Jobbagy-Ovari G, Paska C, Stiedl P, Trimmei B, et al., 2014	Complex analysis of multiple single nucleotide polymorphisms as putative risk factors of tooth agenesis in the Hungarian population 10.3109/00016357.2013.822547 Acta Odontologica Scandinavica	8	Hungary	Genotyping Primary data collection Chi-Square analysis of differences among groups of variation vs group	469 192-hypodontia mean age and SD 18.9 ± 7.7 years 17-Oligodontia mean age and SD 21 ±6.1 years 260-Control mean age and SD 26.2 ± 13.4 years	Yes	yes	Member of COPE. Journal requires written statement of compliance with ethical standards; documentation of compliance must be available upon request.
32	Liang J, Qin C, Yue H, He H, Bian Z 2016	A novel initiation condon mutation of PAX9 in a family with oligodontia 10.1016/j.archoralbio.2015.10.022 Archives of Oral Biology	23	China	Mutation analysis Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	1 family Proband, age 12 years 100 controls	Yes	yes	Requires written statement of following ethical code (Declaration of Helsinki, etc.) and written informed consent was obtained.
33	Sarkar T, Bansal R, Das P 2014	Whole genome sequencing reveals novel non- synonymous mutation in ectodysplasin A (EDA) associated with non-sydromic X-linked dominant congenital tooth agenesis 10.1371/journal.pone.0106811 Plos One	19	India	DNA sequencing Primary data collection Cases examined for descriptives with AXIN2 variation and other variations	1 family (6 people) Proband, age 6 years Also affected 2 family members ages < 12 years and mother	Yes	yes	Member of COPE. Journal requires a written Ethics Statement concerning risks.

Abbreviation: COPE, Committee on Publication Ethics; PI, principle investigator.

There were 21 different journals. From their author guidelines reviewed in 2022, there were 20 journals that specifically indicated that the research had to be conducted ethically. Thirteen had a specific requirement for a written statement of ethic committee approval, and eight had a specific requirement for a written statement of informed consent.

In the 33 articles, 25 (75.8%) had ethic committee approval statements. One case report had a specific statement that ethic committee approval was not needed. There were 25 (75.8%) articles with statements that informed consent was obtained. One publication had a specific notation of child assent; one reported that the consent was provided verbally. Table 2 has the distribution by year.

Table 2.

Distribution of Ethic Committee Approval and Written Consent Statements in 33 MEDLINE (PubMed) Articles on AXIN2and Oligodontia Between 201 I and 2021.

	2011 (3 articles)	2012	2013 (5 articles)	2014 (6 articles)	2015 (4 articles)	2016 (2 articles)	2017 (2 articles)	2018 (3 articles)	2019 (2 articles)	2020 (1 article)	2021 (5 articles)	Total statements
Ethics committee approval statement reported	3 (12.0%)	0	4 (16.0%)	5 (20.0%)	3 (12.0%)	2 (8.0%)	2 (8.0%)	2 (8.0%)	1 (4.0%)	1 (4.0%)	2 (8.0%)	25
Written consent statement reported	3 (12.0%)	0	4 (16.0%)	5 (20.0%)	3 (12.0%)	2 (8.0%)	2 (8.0%)	1 (4.0%)	1 (4.0%)	1 (4.0%)	4 (12.0%)	25

Note: 2011 was the only year with a specific report of an assent among the articles reviewed.

In linear regression of publications with ethics committee approval statements on year, there were no significant differences for the ten years (standardized beta, 0.56; p = 0.094). Similarly, for publications with statements of informed consent, there were no significant differences for the ten years (standardized beta, −0.39; p = 0.260).

Discussion

In this 2011–2021 analysis of the presence of ethics committee approval statements and consent statements in MEDLINE (PubMed) articles searched for genetic research on AXIN2 mutations and oligodontia, there were 75.8% of authors who reported ethics committee approval and 75.8% who reported consent was obtained. The trend for increased reporting over the ten years failed to reach significance and remained stable with approximately three-fourths of articles including statements of ethics committee approval and consent statements over the decade. These results are similar to other studies on ethical reporting statement in journal articles. In a MEDLINE search for ethical reporting involving genetics and stroke conducted between January 2000 and January 2002, of the 41 studies returned, 63% had ethics committee approval statements and 71% had informed consent statements (Meschia and Merino, 2003). Similarly, in a study of articles from the first issue of nine selected dental journals in 2018, 69.8% had written statements of ethics approval, and 60% mentioned obtaining informed consent (Preoteasa, et al., 2018). However, in a study of 702 articles from 10 dental journals published in India, from 2008 to 2011, ethics committee approval was reported in 9.8% of the articles and obtaining informed consent was reported in 6.1% (Janakiram and Porter, 2016).

All articles in this study involved primary data collection with human participants. Three articles that did not include ethics committee approval statements were from two journals, both of which belonged to the Committee on Publication Ethics (COPE), but did not have specific requirements in their authors’ guidelines to include a statement of ethics committee approval. One of the other five articles that did not include ethics committee approval statements was from a journal which did not mention reporting ethics committee approval, while the other four, which were from different journals, did require such a statement in their 2022 guidelines. Similarly, of the eight articles that did not have written informed consent statements, five were from four journals that had such requirements in their 2022 guidelines, two COPE members and the one remaining did not have specific wording for such requirements. Although 19 of the studies involved children less than age 18 years, only one specifically stated that assent was obtained.

Most of the other research involving ethics and genetics has primarily focused upon creating and providing researchers with guidelines in conducting genetic research. This is the first article, to the author’s knowledge, that evaluated international articles for reporting institutional review board approval and participant consent in dental journal articles concerning genetic research. Ethical guidelines and authors’ guidelines for journals vary across the world. For example, some institutional review boards in the US consider case studies or limited case series as not requiring research approval and half of the articles in this research were case studies or case series. The authors of one case study, conducted in Denmark, specifically noted that in an institutional review board approval was not necessary for their case report in a journal article (Jensen, et al., 2021). Another case report article (conducted in Australia) indicated that consent was provided verbally (Beard, et al., 2019). With genetic research, there are considerable risks of identifying a proband when a case report is published. It is generally assumed that appropriate ethical approval and appropriate consent has occurred for all publications. A limitation of this research is that journal editors may not specifically instruct authors to report ethic committee and consent approvals; and, without the instruction, the authors may not feel the need to report IRB/REC approval, informed consent and/assent. Having the authors verifying that protection is important.

In the US, researchers must protect against inadvertent disclosure of sensitive, or health-related information as per the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Protected health information is stringently protected and breaches in disclosure have severe consequences. The U.S. Genetic Information Nondiscrimination Act (GINA) of 2008 was also created to protect against disclosures with severe punishment for data release. However, it is controversial as to if a genetic sequence is protected health information. Discussions for secondary use of sequences and specimens have evolved as has the ethics associated with broader use. With the rapid advances in personalized medicine, it is more important than ever that research participants understand what is being asked of them when they provide consent, particularly consent involving their genome.

Conclusion

In a ten-year review of articles related to a specific genetic mutation in AXIN2 and oligodontia and ethics, there were 75.8% of authors reporting an ethics’ committee approval statement and a statement that consent was obtained in the articles published from 2011–2021.

Educational Implications

Ethical research in dental genomics, as ethical principles in every area of research, involve the principles outlined in the Belmont Report: respect (autonomy), justice, and beneficence. Dental curricula must be innovative in explaining how these principles relate to genetic data, confidentiality, and risk. Students need to have opportunities to explore cases with ethical dilemmas in research and disclosures of findings, and how attitudes differ world-wide. This research was meant to stimulate conversations about the need to have ethical statements and statements about consent in peer-reviewed research. Dental curricula must address all areas of research, particularly ethics, so that the students not only understand research results, statistical analyses, and techniques presented in the articles, but also are assured the participants were respected and that the participants provided consent to the researcher.

Best Practices

Researchers should know and follow the best practices in working with human participants; namely respect, justice, and beneficence. Statements of ethical review and participant consent/assent should be presented in peer-reviewed journal articles and journal editors should carefully check that such information is provided before articles are published.

Research Agenda

Many journal authors’ guidelines require statements of ethics committee approval for publication. Consent and assent statements should also be included given the sensitivity of genetic disclosures. Although all the articles in this study had primary data collections and three-fourths of the articles had statements of ethics committee approval and consent statement, there is a need for improvement. Research into the reasons that 25% of the publications did not have the statements may require further study about the awareness of authors, reviewers, and journal editors about publication policies.