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Abstract
Hereditary breast and ovarian cancer syndrome is an autosomal dominant cancer susceptibility syndrome mainly due to variants in BRCA1 or BRCA2 genes. Patients presenting with BRCA1 or BRCA2 gene mutations have a lifetime risk of developing breast or ovarian cancer (80% and 40%, respectively). Genetic testing to explore the predisposition to develop cancer represents a pivotal factor in such cases, and this review wants to explore the main implications in terms of medicolegal liability and insurance issues. Medicolegal issues related to these diagnostic processes include: (a) failure to recommend the test; (b) failure to properly interpret the test; (c) failure to correctly translate results into clinical practice; (d) lack of informed consent; and (e) failure to refer patients to specialized genetic counseling. Such errors may lead to compensation since the legal burden inherent in the efficacy of prophylactic interventions is a proof that requires the so-called ‘preponderance of the evidence’. Concerning insurance issues, the carriers of such alleles without cancer are healthy because the genetic predisposition is not a disease per se but represents a (relevant) health risk. However, disclosure of these conditions can be impelled by insurers. It can lead to so-called ‘genetic discrimination’ because insurance companies might use genetic information to limit insurance options or increase their costs. Many private and public healthcare funders do not cover risk reducing surgeries, even when recommended as part of a risk reduction management plan for BRCA gene mutation carriers. Here, positions on these matters from different high income countries are discussed, stressing the importance of a common supranational or international regulatory framework to reach a trade-off between the economic interests of insurers and the rights of carriers not to disclose extremely sensitive information.
- BRCA1 Protein
- BRCA2 Protein
- Ovarian Cancer
- Neoplasms
- Gynecology
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Introduction
Hereditary breast and ovarian cancer syndrome is an autosomal dominant cancer susceptibility syndrome clinically defined by family history criteria, and molecularly characterized by the presence of germline pathogenic variants in clinically validated hereditary breast and ovarian cancer genes.1 2 Most hereditary breast and ovarian cancer cases are caused by certain mutations in BRCA1 or BRCA2 genes, which represent the most frequent cause of high penetrance among hereditary breast and ovarian cancers and affect all ethnic groups and races. Approximately 1 in 400 to 1 in 500 persons in the general population are born with an inherited mutation in one of these two genes.3 4
Germline variants with a pathogenic or likely pathogenic significance in BRCA1 and BRCA2 genes strongly predispose to breast cancer (most specifically to early onset, triple negative, or bilateral breast cancer) in both men and women.5 Patients presenting with a BRCA1 or BRCA2 gene mutation have a high lifetime risk of developing breast cancer or tubo-ovarian cancer of up to 80% and 40%, respectively.6 Carriers of these alleles, when mutated, also have a higher risk of cancer of the peritoneum, pancreas, prostate, and skin (melanoma).7 All patients who may be at risk for carrying a gene mutation must be referred for genetic counseling and testing in the oncology care context according to European and American guidelines.2 8 There are different published criteria to identify patients at risk, including but not limited to a diagnosis made at an early age (≤50 years), number of relatives with breast cancer, two breast cancer primaries, triple negative disease, male breast cancer, and previously identified BRCA gene mutation in the family, but people with a history of epithelial ovarian, fallopian tube, or peritoneal cancer are also recommended for appropriate referrals in individuals with a personal or family history of breast cancer. Referral factors may include ethnic origin, small family size and structure, and existence of additional malignancies linked to BRCA in the family.8
Unlike breast cancers, ovarian cancer is relatively rare, and is the fifth leading cause of death among women;9 it represents the most lethal gynecologic cancer, with a 5 year-survival of 50%.10 Regarding ovarian cancer risks, women with a BRCA1 gene mutation have a 48% lifetime risk of developing ovarian cancer (95% confidence interval (CI) 38.8% to 57.9%), whereas BRCA2 gene mutation carriers experience disease by age 70 years in about 20% of cases (95% CI 13% to 33%).8 In contrast with breast cancer, ovarian cancer patients harboring a BRCA1 or, particularly, a BRCA2 gene mutation have significantly longer overall survival and progression free survival compared with the BRCA wild type population.11 12
When a diagnosis of BRCA1 or BRCA2 gene mutation is obtained, there is a shift towards a proactive approach to screening and risk reducing strategy to achieve concrete prevention and effective reduction in cancer development. According to the National Comprehensive Cancer Network guidelines, breast screening in women with a definitive diagnosis of a BRCA1/BRCA2 gene mutation should include annual breast magnetic resonance imaging from ages 25–29 years, with annual mammograms from ages 30–75 years.8 The European Society for Medical Oncology advises intensive screening at least once a year from the age of 30 years, or 5 years earlier than the youngest relative already affected by breast cancer, with particular attention paid to BRCA1 carriers who need to be screened every 6 months. Additional imaging techniques, such as ultrasound for ages 30–39 years and mammography from age 40 years are recommended during the semi-annual screening.2
All international guidelines agree regarding the risk reducing strategy and suggest that bilateral risk reducing mastectomy should be discussed as it remains the most effective option, which can reduce the breast cancer risk by 90%13 in BRCA gene mutation carriers.14 Due to the well known lack of efficient screening for ovarian cancer,15 16 risk reducing salpingo-oophorectomy represents the most effective strategy for ovarian cancer risk reduction in BRCA1/2 gene mutation carriers and should be performed in women who have completed their maternity desire, when aged between 35 and 40 years for BRCA1 carriers and between 40 and 45 years for women with BRCA2 pathogenic variants.2 Risk reducing salpingo-oophorectomy is the most effective method of prevention, reducing epithelial ovarian cancer occurrence by up to 90%.15 Nevertheless, despite a significant reduction, the risk of developing peritoneal carcinomatosis persists, particularly in patients found with a serous tubal intraepithelial carcinoma at the final histologic examination.16 This review aims to identify and discuss the main medicolegal and insurance issues related to BRCA1 and BRCA2 gene tests, in the light of national and international regulations.
Methods
We used PubMed and Google Scholar to perform subjective assessment of the available literature, including studies published over the past 30 years in the medicolegal and gynecologic oncology area, aiming to produce a narrative overview of the current state of the art and knowledge of issues regarding BRCA1 and BRCA2 tests in ovarian and breast cancers, focusing on the perspectives of high income countries. The search was implemented with medical search headings terms using the following keywords: 'BRCA1 gene', 'BRCA2 gene', 'ovarian cancer', 'breast cancer', and 'medicolegal aspects' in combination with terms specific to each subtopic ('BRCA1 mutation', 'BRCA2 mutation', 'genetic testing', 'genetic discrimination', and 'insurance discrimination').
All studies included in this review were thoroughly examined by all co-authors to critically include or exclude them. To restrict the number of references in which various articles addressed the same topic, one publication was selected unless multiple references were required to enhance the analysis of the issue. Finally, international and supranational initiatives on the topic, together with the main regulatory systems regarding the use of genetic information in insurance coverage, were examined. This study is not intended to be a comprehensive review of insurance policies in individual countries worldwide; it is rather an international overview and comparison of different viable solutions.
Results
Medicolegal Issues
To date, more than 30 international guidelines are available on BRCA testing.6 7 Genetic counseling is a critical step in this process, aiming to (i) assess the risk of carrying a gene mutation in healthy patients and families, (ii) explain the benefits and limitations of genetic testing, (iii) help to understand the test results, and (iv) propose prophylactic strategies.7 Information and informed consent are essential because the risks and benefits in such cases must be carefully balanced as the trade-off between them is highly variable.
Women with a higher risk of breast cancer or ovarian cancer may achieve the maximum benefit, because the prophylactic strategies in such cases are often lifesaving, whereas patients with a lower risk may have only small benefits or even possible harm. Indeed, women who undergo prophylactic surgery (bilateral risk reducing mastectomy and risk reducing salpingo-oophorectomy) or chemoprevention to reduce their risk of cancer may be exposed to short term and long term adverse events related to the surgical or pharmacological induction of menopause.17 18 However, a remaining risk of developing breast cancer and ovarian cancer after risk reducing surgery has been reported. Indeed, after bilateral risk reducing mastectomy, there is a residual risk of 5% due to the permanence of in situ or ectopic glandular tissue,19 and after risk reducing salpingo-oophorectomy, the reported incidence of peritoneal cancer is 4.3% at 20 years after surgery.20 As a result, the increase in life expectancy (due to reduced neoplastic risks) and the deterioration in quality of life (due to prevention strategies) should also be carefully balanced during the clinical evaluation of BRCA carriers. From a quality of life standpoint, the main symptoms reported by patients before undergoing risk reducing surgery are reported to include stress, anxiety, and depression, the levels of which were observed to decrease immediately after the intervention.21
Consequently, combining these aspects and the complex psychological and social factors surrounding this issue, an informed choice is also a key factor from both clinical and legal perspectives. Indeed, the liability of healthcare professionals associated with current advances in genetic testing to identify individuals with an increased risk of developing breast or ovarian cancer may concern the following: (a) failure to recommend the test; (b) failure to properly interpret the test; (c) failure to correctly translate results into clinical practice; (d) lack of informed consent; and (e) failure to refer patients to specialized genetic counseling (Table 1).22 For example, when a missed diagnosis is claimed at the gene test, if the patient has been correctly informed, it is of paramount importance to prove that she would have preferred to undergo a prophylactic intervention. This issue is particularly relevant from a legal standpoint if the legal principle of the 'preponderance of the evidence' (a standard legal proof used for medical malpractice litigations, which deems a probability >50% that the claim is true23) is accomplished, because recent studies reported that approximately 64.7% of these patients choose to undergo prophylactic oophorectomy.24 Consequently, because this surgery has been associated with a reduction of up to 77% in all cause mortality, a missed genetic diagnosis could be considered a legally relevant error.
Issues in BRCA mutated patients
Insurance Coverage Issues and Reimbursement Policies
The main issue is that carriers of such alleles without cancer are in a state of good health because the genetic predisposition is not a disease per se but merely represents a (relevant) health risk. The results of clinical or direct to consumer genetic testing can be used for non-clinical and even unethical goals, and disclosure of the results might jeopardize some fundamental individual rights. For example, insurance companies and (potential) employers might use this sensitive information for discriminatory purposes. Genetic discrimination is usually defined as unequal or unethical conduct based on actual or assumed genetic characteristics (such as the risk for genetic disorders) carried by asymptomatic individuals (or their relatives).25 26 A genetic predisposition to breast cancer and ovarian cancer, for example, could strongly limit insurance options or increase their costs. Hence the misuse of genetic information may endanger fundamental rights (eg, healthcare and employment) of the individual, and as a result, in recent years, many countries have enacted regulatory frameworks to prevent genetic discrimination.14
Also, when patients harboring BRCA1/BRCA2 gene mutations are finally counseled for prophylactic options, such as bilateral risk reducing mastectomy or risk reducing salpingo-oophorectomy, two legally equivalent scenarios from a coverage perspective, they may start to face new difficulties. In Europe, some inappropriate reimbursement and funding rules and regulations disincentivize the best prophylactic surgery.27 Many private and public healthcare funders do not cover risk reducing surgeries, even when they are recommended as part of a risk reduction management plan for BRCA gene mutation carriers.27 Payers may argue that this condition is not a disease, subsequently refusing reimbursement. In the UK, the National Health Service fully covers risk reducing surgeries thanks to the recommendations of the National Institute for Health and Care Excellence. In the US, Ha et al analyzed insurance coverage for prophylactic bilateral or contralateral mastectomies in non-cancerous or 'high risk' patients, showing a coverage of 39%. All policies covered prophylactic surgery for BRCA1/2 gene mutations whereas other indications had more variable coverage.28 In Japan, prophylactic surgeries (mastectomy and salpingo-oophorectomy) for BRCA1/BRCA2 patients are not covered by health insurance, although some authors proved their cost-effectiveness.29
The European Society of Plastic, Reconstructive, and Aesthetic Surgery recently published the results of a survey regarding the status, current trends, and differences in the practice of breast reconstruction in Europe.30 The reported rate of breast reconstruction was relatively low across Europe, superimposable to larger countries, such as North America. Although breast reconstruction is reported by 91% of respondents to be covered by public health insurance across Europe, there is a low number of immediate and delayed breast reconstructions compared with the total number of mastectomies. As a result, homogeneous European guidelines are strongly needed to avoid disparities at supranational and national levels. For example, in Italy, bilateral risk reducing mastectomy is not currently considered among the so-called national essential levels of assistance, which are the services that the national health system must provide. Additionally, immediate breast reconstruction is not covered, although it is recommended by the 2020 Breast Cancer Guidelines of the Italian Association of Medical Oncology.31 Consequently, in Italy, this intervention is economically sustainable for the public finances only in regions where reimbursements for mastectomies are higher.31
In the US, breast reconstruction coverage is guaranteed by the Women’s Health and Cancer Rights Act of 1998 when the lump or mastectomy is related to breast cancer, as well as in cancer prevention. This act requires employer sponsored and private health insurance policies to cover all stages of breast reconstruction on which the mastectomy has been performed, including implants, surgery, and reconstruction of the contralateral breast for a symmetrical appearance, and finally treatment of physical complications (lymphedema). According to the Canada Cancer Society and the Cancer Council Australia, in these respective countries, breast reconstruction after breast cancer surgery is covered by the majority of provincial and territorial health insurance plans, and the amount and type of coverage may vary across the country.32 33
Regulations
International and Supranational Initiatives
In 1997, the United Nations Educational, Scientific, and Cultural Organization released the Declaration on the Human Genome and Human Rights, stating that fundamental freedoms and human dignity should not be violated based on genetic profile. In 2003, the United Nations Educational, Scientific, and Cultural Organization reiterated the importance of protecting these sensitive personal data, to protect them from possible misuse for non-ethical purposes.14
To date, there is still some legislative heterogeneity among countries regarding their approach to the use of genetic data in the insurance field, and in some countries, there are currently no specific regulations (G7 countries’ regulations are summarized in Table 2). Current regulatory solutions range from legislative bans, moratoriums, and restrictions as to when insurers may use information, to industry self-guidance.34
Impact on carriers of pathogenic mutations and on insurers in G7 nations
Europe
Since 2016, in the European Union, privacy protection has been guaranteed by the General Data Protection Regulation (GDPR), which applies when personal data are processed by a processor or controller. GDPR allows some flexibility for adaptation by individual member states. This regulatory framework concerns information about a patient’s health status, allowing the use of personal data to the extent that is strictly relevant and needed for the purposes for which it is processed. Consequently, European countries strictly limit the use of genetic information, and results may only be used for medical and scientific purposes.
People cannot be (at least always) compelled to disclose genetic test results to employers or insurance companies. The disclosure is voluntary and is valid by the acquisition of written, free, and informed consent from the consumer. As a result, in some European countries (France and Portugal), there is an outright ban on the use of genetic information by insurers.35 For example, in France, genetic tests can be performed only for medical purposes, genetic discrimination is prohibited by a 2002 law (Loi du 4 mars 2002 relative aux droits des maladies), and using genetic information for other purposes (eg, for insurance policies) is considered a criminal offense.36 37 This approach is the most protective one for the patient although it may be disruptive of insurers’ economic interests.14 On the other hand, other non-European Union and European Union countries have adopted a laissez-faire approach, where the use of genetic information is only forbidden below a certain financial ceiling.
In the UK, according to the Code on Genetic Testing and Insurance (an open ended agreement between the government and the Association of British Insurers), insurers should not require disclosure of the results of a predictive genetic test if the test was performed when the insurance coverage was active, in the case of a blood relative testing, and when the test was performed for scientific purposes. However, they may request the results of Huntington’s disease only, if the consumer requires coverage for life, critical illness, or income protections above a specific financial limit (£500 000, £300 000, and £30 000, respectively).14
In Switzerland, insurance companies must obtain the consent of individuals to perform a test (or to use the results of previously performed tests), which may not be used to determine the health or life insurance policy or for disability coverage below 400 000 Swiss francs per year.14 In the Netherlands, insurers request to disclose genetic information only if a specific economic threshold limit is exceeded and they can process genetic data if needed to implement an insurance policy. The Dutch Authority for the Financial Markets has advised against the use of genetic information for pricing.35 38 In Germany, genetic tests for risk prediction can be performed only by physicians specialized in human genetics (Genetic Diagnosis Act) and, even though genetic discrimination is explicitly prohibited with specific provisions for insurers and employers, the Human Genetic Examination Act regulates specific exclusions for insurers when the indemnity is >€300 000 or the annual indemnity is >€30 000.37
The respective approach of these countries aims to balance the interests of consumers and insurers. In Italy, an insurance policy can be annulled if the insured fails to disclose conditions that, if known, would have brought the insurer to refuse the contract or to propose different terms (eg, higher premiums or specific insurance exclusions, Article 1892 of the Italian Civil Code). However, in general, data protection is regulated through a relatively flexible approach, and the National Data Protection Authority regularly updates the circumstances under which health data can be processed, after consultation with political and institutional scientific authorities. More particularly, data regarding genetic predispositions can be currently processed only for health purposes, for scientific research, and to support reproductive choices.37
North America
In the US, the use of genetic information and genetic discrimination are mainly regulated by US Congress Acts and by state laws.39 In the US, the collection, storage, and disclosure of personal health information (including genetic data) have been regulated by the Health Insurance Portability and Accountability Act (HIPAA) since 1996.40 41 The HIPAA privacy rule applies to four entities: healthcare providers, health plans (eg, health insurers), public and private entities that process health information for billing purposes, and business associates of these entities.39 The main limitations of this regulation are regulated by these few entities and by the fact that protection can be enforced only by the Office for Civil Rights of the US Department of Health and Human Services.39
HIPAA does not specifically address the use of genetic information. In 2008, the US Congress then adopted the Genetic Information Nondiscrimination Act (GINA) to protect genetic data as a form of health information.42 43 GINA prevents health insurers from using genetic results to determine eligibility or premiums, and from requiring genetic testing to underwrite policies. In addition, it prevents employers from requesting, requiring, or purchasing genetic information.44 However, GINA protects individuals with a genetic predisposition to a disease but does not cover individuals already affected (eg, breast cancer patients).45 In addition, GINA does not protect against genetic discrimination for life, disability, and long term care insurance. It also does not cover military members and small businesses.43 As a result, participants in genomic testing research may have to disclose their data as part of the underwriting process for such types of insurance and may be exposed to pay higher premiums or being denied insurance coverage.14
The US has local laws about the use of genetic information and against genetic discrimination, and they vary greatly in terms of scope (often limited), definitions, and terminology.45 In Canada, the Genetic Non-Discrimination Act severely prohibits requiring an individual to undergo a genetic test or to disclose its results (and, if required, to penalize the individual who refuses to comply) as a condition of providing goods or services, entering, or continuing a contract or agreement or offering/continuing specific items or conditions in a contract.
Asia
Japan currently lacks specific laws which penalize genetic discrimination, and some Japanese authors reported a relatively low recognition of concerns about the misuse of genetic information in the national population. In Japan, local insurers also tend not to consider genetic discrimination as a topic of human rights.46–48 In South Korea, the 2004 Bioethics and Safety Act explicitly prohibits the use of genetic information against the interests of the patients in employment and insurance.48
In Singapore, genetic laboratories cannot disclose genetic information to third parties without consent. However, this consent is often required to entitled parties by the insurers.48 However, similar to the UK, there is a moratorium (an agreement between the local Ministry of Health and Life Insurance Association) that prohibits the request to disclose genetic data to underwrite insurance policies, but it is allowed for the subscription of a life insurance, for the recognition of total permanent disability, the need for long term care, and the management of a critical illness.49 In these latter cases, the request is legitimate if the pay-out exceeds a financial limit specified in the moratorium and if the patient underwent specific genetic testing.
Oceania
In Australia, the genetic predisposition to a disease is considered to be a form of disability and the Disability Discrimination Act then applies. It prohibits genetic discrimination unless there is a high economic risk for the insurer according to statistical or actuarial data.45 Australian life insurers decided to prohibit the use of genetic information for coverages <$500 000.45
Discussion
Summary of the Results
In this review, we described medical and legal issues associated with BRCA related malpractice, such as scenarios where patients face either false negative tests, which compromise their opportunity to undergo lifesaving prophylactic treatment, or false positive results which may drive a healthy woman to undergo unnecessary treatment.22 Furthermore, this review underscore the complexities surrounding insurance coverage and reimbursement policies, as well as the regulatory frameworks implemented at international and national levels to address genetic discrimination and protect individual rights.
Results in the Context of Published Literature
To date, genetic predisposition to cancer is considered differently in different countries, ranging from a disability protected by the laws against disability discrimination45 to a simple condition that exposes individuals to a risk, where genetic data are considered a privileged form of health information to be legally protected. In the commercial field, genetic discrimination can be seen as a legitimate form of premium differentiation (adjusting the insurance premium to the risk that the insured generates), a method that is fundamental for the economic performance of these companies. However, a trade-off between commercial interests and legal and social values should be considered. Hindering access of carriers of pathogenic variants to insurance coverages and employment or penalizing them with unfavorable conditions due to a potential, relatively frequent and fortuitous risk, can be considered to contravene some of the core social and ethical values (equity and solidarity), human rights texts (United Nations Educational, Scientific, and Cultural Organization Universal Declaration on the Human Genome and Human Rights, European Convention on Human Rights and Biomedicine), and relevant international recommendations.45
A specific regulation for genetic counseling and genetic data processing is currently missing, and common laws for general medical information are applied. This latter legislative trend embraces the so-called 'genetic exceptionalism', the idea that genetic information should be treated differently from other medical and personal data.42 As a result, the distinction between 'genetic' and 'non-genetic' information is not always clear in insurance policies.40 Clear definitions of these terms are subsequently required for proper use by policy holders and insurance providers. In addition, only clinically validated genetic tests (and not genetic susceptibility tests performed in research) should be used for insurance purposes.35 Regarding only the insurance aspects, it is legally relevant that at the time when the policy is subscribed, the individual may not be aware that they are carrying a pathogenic variant of BRCA1 or BRCA2 (even with a well known family history of breast cancer or ovarian cancer). It is still debated whether these individuals should undergo genetic testing to benefit from insurance services and whether known carriers of these BRCA1 and BRCA2 variants, with a very high risk of developing hereditary breast and ovarian cancer, should declare this information to the insurance company.43
In this study, while shedding light on the disparities in coverage across different countries and implications for patient access to preventive measures, we have given a global overview of international and supranational initiatives for the regulation of genetic information use and genetic discrimination prevention adopted by various countries. Finally, differences in the regulatory initiatives adopted by individual countries may be observed and two underlying assumptions can be identified. The first one concerns 'genetic privacy' (the confidentiality of genetic information that can only be disclosed with explicit consent). The second one concerns a 'non-discrimination approach' based on preventing the use of genetic information for discriminatory purposes. In addition, international organizations have also promoted regulations that, although non-binding, call on individual countries to adhere to such principles.41
Implications for Practice and Further Research
Our results highlight the need for physicians to prioritize informed consent, comprehensive genetic counseling, and adherence to legal and ethical principles in genetic testing and counseling practices. Practitioners must ensure proper interpretation and translation of test results into clinical practice, safeguarding patient rights and autonomy. Future research prompted by this study will be focused on the evaluation of the effectiveness of regulatory initiatives and patient outcomes related to the impact of insurance coverage disparities. The development of standardized guidelines to address disparities in accessing risk reducing surgeries and preventive interventions across different regions is needed.
Strengths and Weaknesses
To the best of our knowledge, this review represents the first study in the literature which addresses the medicolegal controversies regarding BRCA1 and BRCA2 testing, with particular attention focused on high income countries. We have shed light on the knowledge and legislative gaps existing in many different countries regarding a pivotal issue that affects ovarian cancer and breast cancer patients with the aim of driving public interest to solving it. The intrinsic limitation of this review lies in the fact that it was not possible to systematically analyze all high income countries due to the paucity of public translated legislation and/or pertinent scientific literature. A further limitation of this study was the lack of analysis regarding all countries of possible interest due to the heterogeneity and unavailability of sources (even only up to date ones) on medicolegal insurance aspects in the scientific literature.
Conclusions
Frequent genetic testing to predict the risk of breast and ovarian cancers is associated with the growing awareness of the possible discrimination deriving from disclosing genetic risk profiles, particularly for employment and health insurances. There is extreme heterogeneity in the regulatory approaches of different countries, varying from absolute prohibition of request to disclose data for non-health purposes to a substantial absence of specific laws.
While genetic discrimination for employment is often prohibited with no exemption, many countries are oriented towards a differentiated approach, allowing the request to disclose data only if the economic value of the coverage is greater than a set value, as far as health insurance is concerned. Because diverging values (ethical and social core principles, economic interests of private companies) are involved in such issues and human rights concerned by this issue are universal, a trade-off between individual protection and legitimate interests of third parties should be considered in the context of an international effort for a common perspective.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
References
Footnotes
X @annafagottimd
RO and SG contributed equally.
Contributors RO and SG contributed equally and are joint first authors. Conception of study: AF and GS. Guarantor: AF and GS. Design and development: RO, SG, CM, and AF. Data collection: RO, SG, CM, FC, and RM. Data analysis: RO, SG, CM, FC, and RM. Preparation of tables: SG and FC. Initial draft of the manuscript: RO, SG, CM, FC, and RM. Manuscript writing, review, and approval: all authors.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.