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Attitudes of the Lithuanian public and experts towards the return of IGF

The results of the quantitative study revealed a high level of interest of the Lithuanian population in obtaining information relevant to their health from the biobank. Our survey results align with the attitude surveys of the public and biobank participants from some other countries [14], the overall rate of those interested is substantially high.

The findings from our study as well as from some other countries reveal that people desire various health-related insights, including information on the risk of untreatable monogenic diseases like Huntington’s disease (PAG approach), the risk of monogenic diseases in offspring (such as possessing a pathogenic variant associated with cystic fibrosis) (PAG approach), and even slight genetic risks for multifactorial diseases like type 2 diabetes (DTC GT approach) [1, 3]. For instance, in the U.S. study, 95% of the 4,659 respondents agreed that they would like to know about health risks related to treatable diseases (e.g., asthma), and 90% expressed interest in learning about risks related to untreatable diseases (e.g., Alzheimer’s disease) [3]. Similarly, in a Japanese study, more than 80% of the population biobank participants expressed a desire to receive information encouraging lifestyle changes, a number even higher than those who wished to receive clinically significant findings (over 50%) [1].

Despite the expressed willingness of the general population to know the information related to their individual health, which was revealed during the biobanking activities, it is important to underline that the results of the qualitative research carried out by the authors revealed a less than uniform attitude of the experts regarding the appropriateness of returning these findings. While experts unanimously agreed that biobank participants should be informed about findings indicating an increased risk of a treatable monogenic disease like Lynch syndrome (MAG approach), they held varying opinions regarding the disclosure of other findings, such as those related to Huntington’s disease (PAG approach), possession of a pathogenic variant associated with cystic fibrosis (PAG approach), and type 2 diabetes (DTC GT approach). The experts, regardless of their professional field, presented arguments both for and against returning findings like possession of pathogenic variant associated with Huntington’s disease or cystic fibrosis to the biobank participants. They highlighted the challenges in establishing a clear policy for informing biobank participants about these findings and changed their views on the appropriateness of returning them accordingly during the interviews. This undoubtedly reflects the complexity of the issue and the need for a debate on the return of IGF. A slightly clearer division of opinion between the domains was observed with regard to the return of the type 2 diabetes finding. When discussing this finding, the most significant differences of opinion were found between the experts according to their area of expertise. Medical geneticists, natural scientists and ethicists considered it inappropriate to return such a finding to a biobank participant. This reflects more a concern that findings that may not be sufficiently informative may cause misunderstanding and confusion for the biobank participant. Conversely, legal and data protection experts considered the return of such a finding to the biobank participant to be appropriate. The latter experts’ position is more reflective of the public’s view.

Similar findings regarding the divergence between public and expert opinions on other findings than the MAG approach suggests, have been observed in contexts unrelated to biobanking. For example, a study on the Danish population in the context of clinical genome sequencing reveals that the general public’s preferences for reporting differ significantly from those of professionals, as indicated in the ACMG guidelines. The general population places greater importance on findings from the PAG approach, which includes severe but clinically non-actionable findings, compared to the MAG approach favored by professionals. This may suggest the need for a new policy that combines elements of both the MAG and PAG approaches to better align with public preferences while maintaining professional standards [15].

The general public and the experts in Lithuania agreed that the finding indicating an increased risk of developing a treatable monogenic disease (Lynch syndrome), discovered during the biobanking activity, should be offered/returned to the biobank participant. However, it is important to note that the Lynch syndrome case scenario within our research study involved a pathogenic variant with relatively high penetrance, which is not always the case and may depend significantly on family history [16]. Therefore, it would still be valuable to explore how both experts and the public perceive low-penetrance monogenic variants, as this is crucial for understanding how opportunistic screening can lead to false positives, overdiagnosis, unnecessary surveillance, and distress.

Lithuanian experts also emphasized the need to validate findings in an accredited laboratory and assess their clinical validity, even though this criterion was not explicitly mentioned in the interview guide. The reason for raising this point is that it poses a significant challenge to both the findings and their practical application, given the substantial resource demands involved in validating all potentially relevant variants in a biobank before they can be returned.

Both issues—the agreement on the disclosure of high-penetrance, serious monogenic diseases and the importance of clinical validity—are already, to some extent, reflected in the current Lithuanian strategy for the return of health-related findings to a biobank participant. Nevertheless, the analysis of the empirical data leads to a number of points to be addressed and improved. Firstly, as the results have shown the disagreements may arise between experts on the assessment of specific findings against the established strategy. However, it may be even more difficult for biobank participants to understand what health information they can obtain from a biobank. In other words, once a biobank participant has been informed of a finding, he or she may still be surprised that he or she has agreed to be aware of the finding. Secondly, Lithuanian experts and citizens considered other criteria not set out in Lithuanian legislation (e.g. invasiveness of the preventive measure) to be important in the decision to know/return a particular finding. Thirdly, experts and the public highlighted that while all the criteria discussed (severity of disease, likelihood of disease, effectiveness of the preventive measure and invasiveness) may be relevant when considering whether to return/know a particular finding, each of these criteria may have a different weight in this decision. It is therefore important to consider the interplay between all criteria when deciding whether to know/offer a particular finding.

Measures to improve the IGF strategy in Lithuania

Based on the results of empirical research, as well as the discussion of these findings, the authors of this paper believe that specifying the current strategy for returning IGF to biobank participants in Lithuania—while still following the MAG approach—should be considered the primary goal for improving the return of IGF from biobanks. This could be done in at least two ways.

Development and use of a list of genes and diseases

The genes and diseases included in this list should be selected based on criteria deemed important by Lithuanian experts and the public. The advantages and challenges of using such a list in biobank activities are presented in Table 8.

The list of genes and diseases is recommended and/or applied in several scientific clinical projects in other European countries that aim to integrate genome sequencing into clinical practice [17, 18]. In recent years, this method has also been adopted in biobanks [19, 20]. One of the advantages of using a gene and disease list is that it makes it easier for all individuals involved in biobank activities (e.g., biobank administrators, participants, and funders) to understand which findings might be detected and returned to biobank participants. For participants, reviewing the gene and disease list can be helpful in reducing unrealistic expectations about the information they might receive, such as avoiding the misconception that not finding any results means they are in good health. For biobank administrators and researchers, this list is a convenient tool for limiting the number of findings that may be returned during biobank operations. Moreover, it simplifies the process for those managing and funding the biobank to calculate and plan the necessary human and financial resources to effectively implement the return of findings [21]. It is also worth noting that the adaptation and application of a gene and disease list require minimal changes to the legal regulations in Lithuania.

Despite the advantages of applying a gene and disease list, there are also challenges associated with its implementation. First, creating and regularly updating such a list requires expert knowledge, time, and financial resources, which are very limited for conducting biobank activities in Lithuania. One possible solution to this challenge is to use existing gene and disease lists. For example, this approach has been adopted by the Estonian Biobank, which uses the gene and disease list prepared and continuously updated by the American College of Medical Genetics and Genomics (ACMG) [22,23,24,25,26] as one of the methods for evaluating findings. However, it is important to note that while the ACMG gene and disease list is becoming a standard for the return of findings in various scientific projects, the specific needs of a biobank—considering factors such as the focus of planned research, the characteristics of the biobank’s participant population, the intensity of communication with participants, and the resources available for implementing a return of findings strategy—might make a narrower or broader list of genes and diseases more appropriate [21].

A further challenge in applying a gene and disease list lies in the limited capacity of researchers to curate and interpret findings. Gene lists may indicate which results warrant consideration for return, but they do not determine which policy should be implemented. For example, policies may require researchers to actively screen all listed genes for pathogenic variants—an approach that may prove unfeasible in many research contexts—or to report such findings only if they are incidentally discovered in the course of research, which could be a more practical approach.

One more complication in applying a gene and disease list concerns the assumptions regarding clinical responsibilities. In the article we referred to duties such as the duty to rescue or obligations that apply when the researcher is also a medical doctor. However, it is important to clarify that many genomics researchers are not clinicians and have no direct relationship with participants. As a result, they may not bear the same ethical or professional responsibilities as healthcare providers. This may complicate the application of clinical norms in research settings. One way to address this gap is by integrating clinical team members into the research team from the outset, thereby ensuring that appropriate expertise is available and responsibilities are clearly defined where needed.

Another challenge related to the use of a gene and disease list is that researchers might discover other findings (not included in the list) that they consider significant for the participant’s health. This challenge could be mitigated by establishing an advisory body for the biobank, which would be responsible for reviewing new cases of findings not included in the list.

Use of guidelines for evaluating criteria for returning IGF

These guidelines can serve as an alternative to the previously discussed gene and disease list or as a supplementary tool to help determine which genes and diseases should be included in the list. One example of such guidelines is the five-criteria scale proposed by Berg and colleagues for assessing the clinical significance of specific genetic conditions. This scale was developed by an interdisciplinary group of experts, including not only clinical geneticists but also specialists from other fields (e.g., cardiology, neurology, primary care), clinical laboratory professionals, and ethics experts. The criteria in this scale include the severity of disease outcomes, the probability of disease occurrence, the effectiveness of interventions, the burden of interventions, and the level of evidence, with scores for these criteria ranging from 0 to 15 in total. A higher total score across these five criteria indicates greater clinical significance of the genetic variant [27].

The scale proposed by Berg and colleagues for determining the clinical significance of findings might be appealing to those involved in biobank activities (Table 9). This is primarily because the scale provides a rationale for why a particular finding is or isn’t returned to a biobank participant. Using this tool could also contribute to a more transparent and consistent evaluation of findings. Additionally, it is easily adaptable to different return-of-findings strategies and contexts. For example, while Berg and colleagues suggest focusing solely on genes associated with monogenic health disorders, the tool can be readily adapted to evaluate genes associated with complex diseases if needed. It is also worth noting that, like the gene and disease list, integrating this scale into the return-of-findings strategy in Lithuania would require only minimal legal adjustments.

One of the major challenges with using this scale is that the interpretation of its criteria and the assignment of scores might vary among experts from different fields. Therefore, it would be advisable to establish an interdisciplinary advisory body for the biobank to assist in evaluating specific findings using this scale.

Given the significant variation in Lithuanian experts’ opinions regarding the return of non-clinically actionable health information and the high level of willingness expressed by the general population, the residents to receive such information, it is important to continue developing discussions and conducting empirical research on this topic. For instance, understanding why the Lithuanian public wants non-clinically actionable health information and the psychological aspects of returning such information could be valuable. This issue, along with the broader question of IGF returning, could be examined not only within the context of biobanks but also in the broader context of healthcare.

Study limitations

We recognize that the empirical study outlined above has certain limitations. One significant limitation of the qualitative study is that many scientists involved in the research, who work with samples and health data stored in the biobank, also hold additional roles related to the biobank, such as founders or managers. While the perspectives of these experts are particularly valuable, their views on the investigated aspects may differ from those of scientists who do not have an inter-dependent relationship with the biobank. Therefore, it would be essential to explore the viewpoints of this other group of researchers in future studies.

The quantitative study also presents several limitations. Firstly, the survey was conducted among members of the Lithuanian population who voluntarily agreed to participate, resulting in a relatively low response rate of 22.7%. While this outcome was anticipated, we aimed to enroll as large as possible sample from the invited ones. However, it remains uncertain if the views of those who chose not to participate might have affected the study results.

Secondly, the study focused on hypothetical scenarios rather than actual human behavior. It is important to note that individual behavior may vary based on contextual factors, such as personal experiences with the healthcare facility associated with the biobank or the specific circumstances under which they were invited to participate.

Thirdly, since this study involved the general population in Lithuania than biobank participants and most surveyed individuals reported their health as fair or good, the findings may be more applicable to population-based biobanks rather than disease focused ones.

Finally, while the sample was designed to be representative concerning gender, age, place of residence, and education, there were challenges in ensuring the participation of older adults (65+) and those with lower education levels (e.g., primary education). These groups tend to be less technologically literate and less likely to use computers, resulting in their underrepresentation in the survey, and data weighting did not help to overcome this problem.

Although most referrals to the specialized vulva clinic were made by specialists, little more than half of the suggested diagnoses could be confirmed, which is in line with other results and represents a major potential for improvement in diagnostic approaches [8, 12]. While the overall correctness of suggested diagnosis was disappointingly low, there were marked differences among specific vulvar disorders and the clinical background of referring specialists. Significant inconsistencies in vulvar diagnosis were also found between referring physicians and dermatologists in a recent study [13]. The higher diagnostic accuracy observed in dermatologists may be attributable to the referral bias where mainly complex or refractory cases are referred and not the straightforward vulvar cases. A referral bias is also reflected by the difference referrals with a diagnosis or a suspected diagnosis (68.5% from gynecologists vs. 91.7% from dermatologists). Further, most vulvar pathologies are dermatoses, which are familiar to dermatologists as they also appear on other areas of the body. Dermatologists typically conduct a full body examination, including the oral cavity, and at least inquire about any genital involvement. Many dermatoses, such as eczema or psoriasis, can affect the vulva, but they are usually not limited to the genitalia, which generally provides the dermatologist with a clue for the diagnosis. In contrast, gynecologists have significantly less exposure to vulvar and gynecologic dermatology, as vulvar diseases are addressed only at a limited number of specialized centres in Switzerland.

There is a potential referral bias: dermatologists might be confident with their dermatological diagnoses but not with the exclusion of an underlying gynecological disease, whereas gynecologists are confident with their exclusion of a genital pathology but not so with their dermatological diagnoses. The learning objectives of the Swiss OB/GYN specialty program include the detection, prevention and treatment as well as the follow-up of diseases of the female genital organs, however there is no specific emphasis in vulvar dermatology. The inclusion of learning objectives in vulvar dermatology should be implemented in the National OB/GYN specialty programs (Fig. 2).

For lichen sclerosus the concordance between referral and final diagnosis was high, which is likely due to the characteristic clinical signs of this disease [14] and supports the claim that both clinical expertise and experience in vulvar disorders play an important role in diagnostic outcome. However, in line with further results [8, 14,15,16,17,18], the frequent fear of dysplasia/vulvar cancer in suspected lichen sclerosus cases, likely motivated referral for re-evaluation in a tertiary center. In addition, reluctance to use strong topical steroids for a prolonged period is a well-known reason to refer women with lichen to a specialist clinic [8, 19, 20]. The suspicion of dysplasia, eczema, and lichen planus also proved to be most often correct, which should probably be attributed to their clear diagnosis, either by biopsy or by specific characteristics of clinical presentation [14]. However, eczema had relatively often been mistaken for lichen sclerosus, which was the most frequently corrected diagnosis through histopathological evaluation of biopsies. The great variety of other inflammatory diseases and subtle differences in their classification probably explain the considerable difference between suspected and final diagnoses in this group [2, 9, 21]. Although these diseases are commonly seen in gynecologists’, dermatologists’, and general practitioners’ daily clinical routines [10, 18, 22, 23], infectious diseases were often falsely diagnosed, which is likely also a consequence of the broad spectrum of clinical symptoms [1, 14, 24, 25]. Vulvodynia is an exclusion diagnosis, i.e. all relevant diagnostic tests have to be completed before the final diagnosis can be made [26, 27]; this was often not the case before the patient was referred. Unspecific symptom descriptions likely also contributed to the underestimation of this diagnosis [26,27,28].

With only 44% of patients reporting similar key symptoms when they saw a referral physician as at the first consultation in the specialized center, the agreement between symptoms on the two occasions was relatively vague. Although some of the discrepancy may be a result of reporting bias, symptoms or their intensity may also have changed and consequently have been reported differently at the two appointments. In addition, physicians will likely have explored symptoms in many ways, ranging from no direct question on symptoms at all to a highly complex exploration via a predefined symptom list. A guideline as to what and how information on symptoms should be collected might help to improve diagnostic quality [10, 12, 29].

While it took a long time after onset of symptoms for patients to be referred to the specialized vulva clinic, the tests needed to permit final diagnosis were completed rather quickly. The mean time between symptom onset and final diagnosis in our study was 46.1 months, with 1.0 month from the 1st consultation in the vulva clinic until final diagnosis, which is in line with other findings [18].

Differences in the time to diagnosis might be due to a deliberate, partial investigation of vulvar disease prior to referral, with the final diagnosis—especially when more sophisticated approaches such as vulvar colposcopy, dermoscopy, or biopsies are needed—being left to the specialized vulva clinic [8, 9, 29]. However, if gynecologists consider themselves to be specialists supporting women with vulvar complaints, it would be beneficial to improve their expertise to allow more reliable diagnoses or early pre-defined referral to a center offering the diagnostics tools and experience needed. The high number of vulva disorders that are a manifestation of a skin disease accords with their frequent correct initial diagnosis by referring dermatologists [18].

One reason for the limited diagnostic quality of the initial evaluation of vulvar diseases might be based on the variety, how different diagnostic tests are used in clinical practice. While bacterial/mycosal smears were frequently made, biopsies were only rarely taken, and no patterns could be detected in the performance of such biopsies among referring physicians. While some physicians, tended to steer the diagnostic process to a clear diagnosis, others referred women at some point of the diagnostic process to the tertiary vulva care center. Here, either a clear definition of how tertiary centers could ideally cooperate with primary caregivers, or better training in when, how and where biopsies should be taken would be helpful in improving diagnostic success in vulvar diseases.

In line with this finding, the cotton swab test, which, in addition to excluding other causes of vulvar pain [2, 26, 30], is mandatory for the diagnosis of vulvodynia, was only carried out in about 15.4% of women before they were referred to the tertiary center. As vulvodynia is among the most frequent vulvar disorders [31] the systematic realization of this test would help to increase diagnostic accuracy in a large proportion of vulvar diseases. As vulvar pain can also be a comorbidity of other vulvar diseases [26, 32, 33], it is important to exclude any other pain-inducing disease.

In agreement with the literature, the almost 4 years’ latency from symptoms to referral was seen more often in diseases with a fluctuating character, such as eczema and lichen sclerosus [14]. A delayed diagnosis of a dermatoses can lead to significant physical, psychological, and medical complications, depending on the specific condition. A long delay often of several years in diagnosing lichen sclerosus and lichen planus can result in progressive scarring, atrophy, and adhesions, which may lead to functional impairment and distress (e.g., narrowing of the vaginal or urethral opening) as well as an increased risk of the development of squamous cell carcinoma [34]. Furthermore, misdiagnosis can lead to unnecessary treatments, potentially worsening the patient’s condition or causing irreversible changes to the vulva appearance.

Latency was also high in diseases such as vulvodynia and other inflammatory diseases. Time from initial symptoms to final diagnosis was shortest for infectious diseases, which might be a result of sudden strong clinical symptoms, which motivated both patients and physicians towards an early solution. In contrast, the time from the onset of the first symptoms to the diagnosis of lichen sclerosus was the longest in our cohort, averaging nearly 7 years, which is longer than the 4 years reported in a survey study by Krapf et al., where women indicated they received the correct diagnosis after this duration [35].

In 225 women a diagnosis could already be formulated at the first consultation by confirming or rejecting the suspected diagnosis of a referring doctor, with 90.4% of the women receiving a final diagnosis after a maximum of two consultations. These data show that when the right approach is chosen, most vulvar diagnoses can be made very straightforwardly. While physicians can only influence patients to seek medical support to a rather limited extent, they can use this resource to facilitate earlier diagnosis and, consequently, earlier treatment.

The most common pitfalls in the diagnosis of vulvar diseases and solutions for overcoming challenges to correct diagnosis are summarized in Fig. 2 [1, 14, 28, 36]. To guarantee best diagnostic quality, if histopathological evaluation is required it should be performed by a dermato-histopathologist with experience in vulvar pathology [37]. Specific immunohistochemical markers for neuroproliferative vestibulodynia might offer future options in the classification and patho-etiology of vulvar pain [38]. Specialists supporting women who have vulvar diseases should also follow well-defined approaches to treating vulvar disorders, for example, approaches to managing vulvovaginal symptoms [29] or vulvar disorders [14]. For a standardized diagnostic method, health professionals should adhere to existing diagnostic protocols, such as the European Guideline for the Management of Vulval Conditions [14].

Shame and hesitancy to seek medical support, possibly also due to cultural background are factors hampering timely diagnosis on the patient’s side [39]. Active investigations of vulvar complaints in an atmosphere facilitating discussion of delicate topics should therefore be a standard component of taking a gynecological history [12]. Specific attention has to be paid to multiple conditions.

Strengths and limitations

The strengths of our study are the large study group and the inclusion of study participants over a period of 4 years in a real-life setting. Limitations include the retrospective data collection based on a type of documentation that was not expressly designed for the present evaluation. Despite the presence of multiple symptoms, only the leading symptom was used to compare the initial situation and the situation in the tertiary center. The intensity of several important symptoms might have changed over time and consequently have resulted in an overestimation of discrepancies. Although there was no systematic internal quality assessment of the diagnosis, we considered final diagnoses from the tertiary center to be correct. As referring physicians individually decided which information should be included in the referral letter, individual effort invested in the correctness and completeness of reports might have varied strongly and not all details of investigations occurring before referral might have been brought to the attention of the tertiary center. Another limitation is the comparison of correct diagnoses of gynecologists compared to dermatologists as the vast majority, nearly 70%, of the referrals were from gynecologists and only 7.4% from dermatologists.

However, this first systematic evaluation of suspected diagnoses before patients were referred to a tertiary hospital vulva clinic and later outcomes of additional diagnostic steps provides valuable targets for the improvement of diagnoses in primary health support.