reflexion-thematique-du-comite-d-ethique). The gender perspective is often neglected in biomedical research in France, as opposed to Anglo-American and other European countries. One of the objectives of this Group is to conduct ethical reflection on the influence of social and cultural factors on the differences and inequalities between the sexes in health and medical research practices.

It is important to encourage physicians to take the differences between men and women into account, not as a simple dichotomy between male and female, but as the result of intricate links between sex and gender (Fausto-Sterling 2000, 2012[START_REF] Springer | Beyond a catalogue of differences: A theoretical frame and good practice guidelines for researching sex/gender in human health[END_REF][START_REF] Krieger | Genders, sexes, and health: What are the connections-and why does it matter?[END_REF]. Such an approach can improve research practices and consequently increase knowledge about the origins of differences between women and men in health.

In the first part of this document, and in order to use concrete examples, we suggest some thoughts and recommendations for the consideration of gender in three disciplines:

-MRI neuroimaging (Catherine Vidal) -Cardiovascular diseases (Jennifer Merchant) -Assisted reproductive technologies (Mylène Botbol-Baum) [3] These thoughts constitute the beginning of the debate and have already elicited responses from the Committee that will be useful for future versions of this document which, like all Committee Memos, remains open to further development.

The second part includes a report on the Group's activities for 2014/2015, followed by its projects for 2015/2016. In the following sections, we will present some principles that may be useful when considering the relationship between sex and gender, and give examples of how this approach is likely to improve the practices of MRI brain research in both women and men. We will also propose recommendations for the design, analysis and interpretation of experiments (see Rippon 2014 for a detailed review of theoretical and practical issues in MRI research comparing female and male subjects).

The interaction between sex and gender

For more than 10 years, MRI studies on brain plasticity have accumulated to

show how experience and learning shape the brains of both children and adults [START_REF] May | Experience-dependent structural plasticity in the adult human brain[END_REF][START_REF] Vidal | Le cerveau évolue-t-il au cours de la vie ? Paris, Le Pommier Vidal C[END_REF]. The concept of brain plasticity provides a fundamental [4] neurobiological insight into the processes of social and cultural construction of gender identity. Sex and gender are not separate variables, but interact in a process of "embodiment", a term that describes the reciprocal interactions between biological sex and the physical, emotional, social, and cultural environment (Fausto-Sterling 2012ab, [START_REF] Fine | Plasticity, plasticity, plasticity…and the rigid problem of sex[END_REF]. Gender influences biology, and biology affects gender.

These interactions result in a wide range of personalities, cognitive skills and social behaviors, which reveal both differences and similarities between women and men [START_REF] Hyde | Gender similarities and differences[END_REF]). This diversity is reflected in the brain and can be detected by neuroimaging studies [START_REF] Kaiser | On sex/gender related similarities and differences in fMRI language research[END_REF][START_REF] Bluhm | New research, old problems: methodological and ethical issues in fMRI research examining sex/gender differences in emotion processing[END_REF][START_REF] Mueller | Individual Variability in Functional Connectivity Architecture of the Human Brain[END_REF]. Several principles therefore arise in MRI studies on both men and women that need to be considered.

1) There is great diversity in brain anatomy and functioning, regardless of sex.

Meta-analyses comparing the brains of both sexes show that there is no strict dimorphism that differentiates male brains from female brains (MacCarthy 2011, Joël 2011[START_REF] Giedd | Magnetic resonance imaging of male/female differences in human adolescent brain anatomy[END_REF][START_REF] Ruigrok | A meta-analysis of sex differences in human brain structure[END_REF].

The brain volume of men is indeed greater (by about 10% on average) than that of women, even after considering the difference in body size [START_REF] Cosgrove | Evolving knowledge of sex differences in brain structure, function, and chemistry[END_REF].

Women also have on average slightly more gray matter, and men slightly more white matter (Hanggi 2014). These differences, however, are related to brain size, and not sex (Hanggi 2014[START_REF] Jancke | Brain size, sex, and the aging brain[END_REF]. If we compare the brains of men and women of the same volume (around 15-20% of cases in the population), we no longer see differences in gray and white matter ratios [START_REF] Luders | Why size matters: Differences in brain volume account for apparent sex differences in callosal anatomy[END_REF]. The few studies that have shown differences after taking the size factor into account are rare, and need to be replicated [START_REF] Luders | Why sex matters: brain size independent differences in gray matter distributions between men and women[END_REF][START_REF] Raznahana | Longitudinal four-dimensional mapping of subcortical anatomy in human development[END_REF].

On a functional level, meta-analyses also indicate significant diversity in brain activity (Wallentin 2009[START_REF] Bluhm | New research, old problems: methodological and ethical issues in fMRI research examining sex/gender differences in emotion processing[END_REF][START_REF] Mueller | Individual Variability in Functional Connectivity Architecture of the Human Brain[END_REF][START_REF] Miller | The new science of cognitive sex differences[END_REF]). An overview of the studies on the language areas of the brain that were published from 1995 to 2009, which together included 2,000 subjects, shows that interindividual variability is such that no statistical difference between the sexes can be detected [START_REF] Kaiser | On sex/gender related similarities and differences in fMRI language research[END_REF].

It is important to note that there is a certain degree of bias in the interpretation and media coverage of the results of some scientific studies [START_REF] Guo | A systematic review of the reporting of sample size calculations and corresponding data components in observational functional magnetic resonance imaging studies[END_REF], Ionnidis 2014[START_REF] Kriegeskorte | Everything you never wanted to know about circular analysis, but were afraid to ask[END_REF]. When comparing the brains of women and men in studies with a [5] large number of subjects, differences that are sometimes observed on a smaller scale go largely undetected. However, it is the studies that show differences that are cited the most often! When going through recent MRI studies on cognitive function, one finds that out of the approximately 16,000 articles published from 1992 to 2008, only 2.6% reported differences between the sexes [START_REF] Kaiser | On sex/gender related similarities and differences in fMRI language research[END_REF].

In conclusion, and contrary to popular belief, the brains of women and men show no distinct differences, at least to the degree that they can be easily identified.

Meta-analyses reveal that brain diversity is so rich that there is significant overlap (size effect) in the anatomy and function of the brains of both sexes. There is just as much variety in psychological traits, cognitive skills and social behaviors, all of which reflect both similarities and differences [START_REF] Petersen | Gender differences in sexual attitudes and behaviors: a review of meta-analytic results and large datasets[END_REF][START_REF] Miller | The new science of cognitive sex differences[END_REF][START_REF] Hyde | Gender similarities and differences[END_REF].

Recommendations 1:

Statistics and data analysis

Given the diversity, differences and overlap between the anatomical and functional traits in male and female brains, the following measures are recommended in statistical analysis:

-Use a sample that is large enough to avoid false positives and negatives.

-If the samples are small, as is frequent in MRI studies, the results need to be replicated before they are considered valid. Use non-parametric statistical tests.

-Estimate size effects and conduct meta-analyses.

Illustrations

MRI results for each sex often undergo separate statistical analyses that are illustrated with distinct images. If these images are different, their qualitative comparison is insufficient. It is important to instead make a quantitative statistical comparison in which the differences between the sexes are represented by a single image.

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Publications

Report the absence as well as the presence of differences between the sexes in studies.

This should make it possible to implement the consultation of databases, whose keywords currently only take the differences between the sexes into account.

2) Brain and cognitive characteristics are not fixed but evolve with time and according to the environment due to the brain's plasticity.

MRI research has amply demonstrated that learning and experiences alter both the structure (thickness of the cortex, amount of white matter, etc.) and functioning of the brain [START_REF] May | Experience-dependent structural plasticity in the adult human brain[END_REF][START_REF] Fine | Plasticity, plasticity, plasticity…and the rigid problem of sex[END_REF]. When an MRI scan shows differences between the sexes, it does not mean that these differences have been engraved in the brain since birth, or that they will persist. MRI scans only give a snapshot of the state of a person's brain at a given moment.

Differences between the sexes in cognitive abilities are not immutable. For example, spatial orientation test scores, which often reflect better performances from boys, become the same when the girls being tested are first trained to play video games, or do not fall victim to "stereotype threats" [START_REF] Spencer | Stereotype threat and women's math performance[END_REF][START_REF] Spelke | Sex differences in intrinsic aptitudes for mathematics and science ? A critical review[END_REF], Wraga 2006[START_REF] Feng | Playing an action video game reduces gender differences in spatial cognition[END_REF]. Epidemiological surveys show that differences in performance between the sexes in math and languages vary by country and socioeconomic status [START_REF] Guiso | Culture, gender, and maths[END_REF][START_REF] Hyde | Gender, culture, and mathematics performance[END_REF][START_REF] Nm | Cross-national patterns of gender differences in mathematics: a meta-analysis[END_REF].

In conclusion, the differences between the sexes in education, socialization and life experience are reflected in the functional structure of the brain and in behavior.

These gender differences are not fixed, and can be modified, neutralized or even reversed depending on personal experience and sociocultural, economic and political environment.

Recommendations 2:

Image interpretation

-Acknowledge the immediate nature of MRI images, and keep in mind the brain's capacity for plasticity when analyzing MRI scans.

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-Question the possible origins of the presence or absence of differences between the sexes.

Take variables other than biological sex into account when comparing the brains of women and men

-Collect bibliographical information other than sex, such as age, education, hobbies and interests (such as sports or games), occupation, ethnicity, family history, social status, and economic status.

-Incorporate these different variables when selecting subject groups, in order to form groups that could be more relevant than those which are simply classified by sex.

Writing articles

Use the terms sex/gender rather than just sex to acknowledge the complex relationships between the two.

General conclusion

Categorization by sex is a general practice that implies that biological sex is a significant factor when studying the neurobiological bases of cognitive function in women and men.

Neuroimaging studies often interpret brain-related differences between the sexes as the result of genetic and/or hormonal determinism (Jordan-Young 2010, Bluhm 2013).

When a region of the brain appears to be different between the sexes, it is often seen as reflecting a difference in cognitive skills or social behavioran interpretation which is often heavily influenced by gender stereotypes.

It is clear that despite current knowledge on brain plasticity, essentialist conceptions of the origins of gender differences persist in scientific publications.

Reflection on the ethical issues has to be undertaken in order to create the intellectual and methodological conditions needed to encourage researchers to integrate gender into neuroimaging research practices [START_REF] Illes | ELSI priorities for brain imaging[END_REF], Dussauge 2012[START_REF] Vidal | Le cerveau évolue-t-il au cours de la vie ? Paris, Le Pommier Vidal C[END_REF]. It is important to question the normal and the pathological through the lens of gender, and thus move past the simple dichotomy between the sexes. This approach will allow us to develop new models that articulate the biological and social mechanisms that may [8] explain the differences and inequalities between women and men in the field of health.

Taking gender into account in neuroscience also has a social impact when transmitting scientific research to a large public. Explaining that societal roles assigned to women and men are not determined by a biological law hardwired into their brains will help fight against conservative prejudices and sexist stereotypes.

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Wallentin M, 2009. Putative sex differences in verbal abilities and language cortex: a critical review. Brain Lang.108:175-83. Wraga M, Helt M, Jacobs E et al., 2006. "Neural basis of stereotype-induced shifts in women's mental rotation performance", SCAN, 2 : 12-19.

Recommendations for integrating sex and gender in research on cardiovascular diseases (Jennifer Merchant)

The link between sex, gender and cardiovascular diseases 1

Cardiovascular diseases are the leading cause of death for women in Europe.

While one in 26 European women dies of breast cancer, one in three dies of cardiovascular disease. Women develop cardiovascular disease on average ten years later in their lives than menthe most commonly cited reason is the notion that menopause can lead to hypertension, diabetes, hyperlipidemia, obesity and other metabolic disorders. This hypothesis reinforces stereotypical views among doctors and researchers regarding the differences between men and women. Yet there is no conclusive research evidence to support this hypothesis. In other words, we have been too quick to decide on the dominant role of hormones as a protective factor, followed by the lack thereof as a factor explaining cardiovascular diseases in women.

This observation invites us to reconsider research protocols. Indeed:

• Women are underrepresented in research on cardiovascular diseases, whether in clinical trials, intervention studies or biomedical research on female animals.

• Out of all of the research protocols, approximately 33.5% of participants are women.

• This underrepresentation is particularly noticeable in research on how to reduce cholesterol, the risk of ischemia and heart attacks.

1. http://www.fondation-recherche-cardio-vasculaire.org/

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• Because cardiovascular diseases are perceived as only affecting men, women tend less than men to consider the risk factors and participate in screening programs.

• Yet women suffering from diabetes have a greater risk of developing coronary heart disease or experiencing a stroke. Their prognosis is less encouraging than that of men following myocardial infarction and they are at greater risk of death from cardiovascular disease.

These considerations encourage both sex and gender to be taken into account in cardiovascular disease research. Doing so will enable researchers to formulate new questions, analyze symptoms differently, and as a consequence improve diagnosis and envisage new prevention and treatment strategies for the various cardiovascular diseases.

These measures have already been taken in other countries, notably by the National Institutes for Health in the USA and have consequently led to an increase in the representation of women in clinical trials, as well as increased knowledge about the influence of sex and gender on cardiovascular diseases. Another notable result of this initiative has been the launching of new public health campaigns that target women and men differently in an effort to provide more accurate information about risk factors and preventive measures.

Taking inspiration from the programs already underway not only in the USA, but in other countries as well (particularly in northern Europe), we make the following recommendations:

Recommendation 1: Consider the various cardiovascular diseases according to sex and gender for better adaptation of the diagnostic tools 2

It had long been believed that women suffered from the same cardiovascular diseases as men, namely coronary heart disease. However, recent research in the USA has found that ischemic heart disease is particularly prevalent among women [START_REF] Shaw | Women and Ischemic Heart Disease: Evolving Knowledge[END_REF]. Angiography, the most common technique used in the examination of patients complaining of chest pain, usually results in a diagnosis of coronary heart 2. https://genderedinnovations.stanford.edu/case-studies/heart.html#heart_ischemia_patho [13] disease in men but is not as effective at detecting the disease in women. Many women complaining of chest pain have "normal" angiograms, and are therefore left untreated.

Many of these women have a heart attack or a stroke shortly thereafter [START_REF] Robinson | Cardiovascular Risk in Women with Non-Specific Chest Pain (from the Women's Health Initiative Hormone Trials)[END_REF].

It is therefore important to use different tools and diagnostic techniques for women, such as coronary reactivity testing (Von Mering et al., 2004;[START_REF] Pepine | Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia: Results from the National Heart, Lung, and Blood Institute (NHLBI) Women's Ischemia Syndrome Evaluation (WISE) Study[END_REF], intravascular ultrasound [START_REF] Khuddus | An Intravascular Ultrasound Analysis in Women Experiencing Chest Pain in the Absence of Obstructive Coronary Artery Disease: A Substudy from the National Heart, Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE)[END_REF], cardiac MRI, cardiac spectroscopy [START_REF] Ishimori | Myocardial Ischemia in the Absence of Obstructive Coronary Artery Disease in Systemic Lupus Erythematosus[END_REF], myocardial scintigraphy, positron emission tomography (PET) [START_REF] Johnson | Positron Emission Tomography[END_REF], and stress echocardiography (Kaul, 2011).

Recommendation 2: Take sex and gender into account in the expression of symptoms

An international study of 26,755 patients with cardiovascular disease (only 29%

of whom were women) demonstrated that the most common symptom in men (94%)

and women (92%) is chest pain [START_REF] Dey | Sex-Related Differences in the Presentation, Treatment, and Outcomes among Patients with Acute Coronary Syndromes: The Global Registry of Acute Coronary Events[END_REF]. However, significant differences between the sexes are observed for more "atypical" symptoms [START_REF] Chen | Gender Differences in Symptoms Associated with Acute Myocardial Infarction: A Review of the Research. Heart and Lung[END_REF].

Women more frequently complain of intense fatigue, nausea and jaw painthree symptoms that are closely linked to cardiovascular diseases, but do not necessarily raise red flags for cardiologists.

Practitioners must be informed of these issues in order to improve diagnosis and determine the right treatment [START_REF] Zbierajewski-Eischeid | Myocardial Infarction in Women: Promoting Symptom Recognition, Early Diagnosis, and Risk Assessment[END_REF], and researchers need to focus more on explaining these differentiated expressions in the symptoms.

Recommendation 3: Challenge hypotheses regarding the role of hormones, particularly estrogen

As mentioned in the introduction, the decrease in estrogen levels has long been regarded as a causative factor for cardiovascular disease in women. As a result, hormone replacement therapy has often been recommended for female patients [START_REF] Khan | Nuclear Cardiology in Women[END_REF]. However, large-scale studies have shown the opposite, namely a correlation between hormone replacement therapy and an increased risk of infarction in women [START_REF] Wilson | Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50-The Framingham Study[END_REF][START_REF] Hulley | Randomized Trial of Estrogen plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women[END_REF]. Further research is required in order to precisely analyze the potential influence of hormones on cardiovascular disease in women.

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Recommendation 4: Take gender into account in order to better prevent and reduce the risk of developing cardiovascular disease

The risk factors for cardiovascular diseases are the same for men and women: age, hypertension, hyperlipidemia, diabetes, smoking, obesity, sedentary lifestyles, high-fat diets, and so on. However, the prevalence and impact of these factors differ according to sex [START_REF] Mosca | Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update: A Guideline from the American Heart Association[END_REF].

For example, smoking is historically more common among men than women (WHO, 2010). However, in certain countries such as Sweden and Iceland, women now smoke more than men (Shafey et al., 2009). Smoking rates among women are continuing to fall in the USA, Western Europe and other industrialized countries, but this is not the case in Central, Southern or Eastern Europe, nor in many emerging countries (Shafey et al., 2009). These geographical differences must be considered in research protocols. A recent study conducted on 3,587 people in five European countries has shown that smoking increases the risk of atherosclerosis in women as well as men. However, the adverse effects are twice as prevalent in women as in men [START_REF] Tremoli | The Association of Tobacco Smoke with Subclinical Atherosclerosis and Atherosclerosis Progression is Stronger in Women than in Men[END_REF].

These studies on smoking have shown that societal gender roles have an impact on the behavior of men and women who smoke or decide to start smoking.

Factors related to biological sex also contribute to the differences between men and women in the susceptibility to and expression of the symptoms related to cardiovascular diseases. In other words, anti-smoking programs must incorporate both sex and gender factors.

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General conclusion

For the last twenty years in North America, the introduction of the factors of While these initiatives are encouraging, there is still much work to be done, and Inserm researchers will have a key role to play here.

Integrating the factors of "sex" and "gender" in their cardiovascular disease research protocols can only enrich the knowledge of these diseases and benefit the health of both women and men.

Introduction

No other issues are said to affect women's health more than reproductive health, procreation, contraception, IVF, etc. … and their consequences. How can we reduce gender prejudice and bias in assisted reproduction, which many studies 3 have shown to impact health and contribute to the growing inequalities in access to research and healthcare? While the Inserm has produced many in-depth reports on "fertility disorders", the impact in terms of sex and gender on the inextricable link between sex and reproduction for womendespite the advent of the pillare barely touched on by these texts, as if the societal and gendered consequences of the research go beyond its scientific dimension and become minimized. But does such minimization of the social effects of research not help to reinforce gender bias in a research field in which the links between sex, reproduction and female/male infertility, generate inevitable ethical questions on gender relations 4,5 ?

It is therefore important to update how these gender relations biases are presented in the research hypotheses, even when the latter aim to be objective, in order to question the conditions and effects of this aim and its communication in the social sphere, and to take into account the gender-dimension of this research without challenging women's equality under the law to make individual decisions on their choices of procreation 6 .

Gender studies began to critically challenge reproductive research in the 1990s.

Such heterogeneous studies lead to dialog and debate that rarely permeate the scientific world but raise ethical issues regarding the reproductive rights of women and [20]

the quality of biomedical research.

They require researchers in human reproduction to confront the subjective aspect of reproductive rights, as set out in the Cairo Declaration 7 and since implemented in international regulations, insisting on the autonomy of women in controlling their sexual and reproductive lives, as well as the anthropological representations that they help to alter through the reproductive techniques themselves.

Techniques which, paradoxically, open up new possibilities for women but restrict their freedom of choice through regulations that make procreation a biopolitical issue that weakens their acquired reproductive rights: techniques where a critical dialogue between the human sciences and biotechnologies is established.

Gender studies generally reject the idea of scientific neutrality when it comes to research on women's bodies and question the lack of consideration given to the gender dimension of medical research participants in terms of the consequences of the risks and benefits of research.

While feminist studies agree on the fact that reproductive techniques increase

the procreation options open to women, they also question the proportion of risk assumed by women in the development of these techniques.

This concerns the medical procedures themselves, embryo transfers, and the invasive techniques involved: donation of gametes, cryopreservation, preimplantation genetic diagnosis. The risks of these techniques, which for women involve multiple pregnancies and their associated pathologies, had rarely been considered prior to their research in order to minimize risks and increase benefits for women.

While the issues raised by assisted reproductive technologies have been the subject of many national and international bioethics committee opinions, they have above all become a means of acclimatizing the public to these technologies without reaching a sharable consensus on what makes or does not make them legitimate.

Gender studies have refused to submit to a social signification of these technologies to the biological facts of reproduction and have produced an impressive body of critical literature on these technologies, all too often ignored by researchers in the field.

I will therefore concentrate here on the ethical and scientific reasons for taking seriously gender bias and the confusion between sex and gender in this debate, so as to improve the perception and quality of the research on present and future reproductive techniques which would include a gendered perspective of these techniques. We might ask ourselves why the numerous feminist studies on the subject have not seriously impacted the methodological a prioris of reproductive research. We might naively suggest that the hierarchy between the sexes has difficulty being challenged by disciplines, or that menwho are in the majorityhave difficulty negotiating their privileges around a social egalitarianism they consider to challenge the coherence of the neutrality of their epistemological model by introducing anthropological and social data that go beyond the realms of their expertise and seem too empirical to be verifiable.

To consider, for ethical reasons, that the integration of these two epistemological discourses implies an alternative and more egalitarian biopolitical model, driven by the research institutions and the researchers in a context in which the institutional hierarchy often confirms existing gender privileges, privileges which must be undone, which research ethics requires us to challenge. It is therefore about questioningin reproductive medicine and in generalthe myth of the axiological neutrality of the natural sciences.

For that we will need to challenge the resistance to the gender perspective in science and propose recommendations for the improvement of scientific excellence through the introduction of a gender perspective, hitherto perceived as incompatible with the hypothetico-deductive approach because, we are told: [23] constitutional factors among the causes of impaired reproductive health, but above all the behavioral aspect of delayed procreation for women and smoking. The servitude concerns the biological markers of male and female fertility. It is about "controlling fertility" and it is added in the introduction that social choices must be justified in order to harmonize the advances in knowledge in fundamental research, population research and surveillance. Nevertheless, the part devoted to societal challenges appears only in a few pages of the third section of the document which reports the evolution in knowledge on human reproduction, but only mentions the question of "individual aspirations", while noting that faced with a wide variety of demands, the legislator is led to make difficult choices and observes that faced with the restrictive regulation of assisted reproductive technologies, the reasons for which are not analyzed, increasing numbers of men and women go abroad to benefit from methods that are forbidden in France, without addressing the societal or gender issues, even the democratic dimension of the respect for "individual aspirations" beyond biological and gendered determinations 9 .

The domain of reproductive technologies is also paradoxically that in which gender biases have been displaced by the opening up of new reproductive possibilities, circumventing the biological determinations of individuals, to be better confirmed by genetic sex, bringing us back to an idea of the generalized plasticity of the living which minimizes the dimension of individual and social choice of the subjects of norms, which is not without raising fundamental ethical issues regarding the legitimacy of medical or political decisions that affect the private body.

The question being: how do the scientific and/or social norms that define human reproduction and filiation reconstitute and question the limits of subjects in what has become their reproductive choice? There again, the limit of legitimacy will depend on the political and institutional context of the subject, which questions the conditions of the universalization of scientific data. But also the normative capacity of States faced with reproductive tourism in a world of free movement of information and in a Europe of free movement of people.

Assisted reproductive technologies challenging the ability of biological determinism to infer social roles

9. Idem conclusion page 106.

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Assisted reproduction was indeed the first biomedical technique to challenge gender roles, while practically displacing the monopoly of the heterosexual model and opening up the possibility of homosexual reproduction using surrogates, even fantasies of an artificial uterus erasing all biological determinism 10 . Although these questions are regulated by law, the latter is always late when it comes to the normativity inherent to the practice of research and to its developments in healthcare.

Indeed, reproductive biotechnologies, which have displaced the embryo from its "natural" setting to the petri dish, have as a consequence modified the social representations of filiation and gender roles, and have had an unsuspected social impact, altering the anthropological representations of the gendered role of men and women since the dawn of humanity, there again confusing male and female, social roles of men and women.

The science of reproductive technologies has become an actor of social modifications and therefore cannot claim neutral epistemology on the definition of the supposed natural character of reproductive roles. It highlights the limit of the natural character and as a consequence the contingency of reproductive roles as inferring immutable social roles. Paradoxically, the refusal of procreation also became an option for women and not a failure of their social role predetermined by an androcentric society which had medicalized sterility. Motherhood could still be chosen despite biological sterility. Science therefore brought complexity to anthropology and opened up to the interpretation of these new possibilities. Reproductive medicine became empowering (giving additional capacities) or alienating for women, depending on the place it gave the right of people to express their subjective choice, to accept or refuse the application of certain research to their person.

The specificity of gender studies involves not submitting social signification to biological facts.

However, the purpose of assisted reproductive technologies is to compensate for the failure of natural human reproduction processes. French bioethics laws, for example, define assisted reproductive technologies (artificial insemination, IVF and embryo transfer) as having two purposes:

10. Atlan, Henri, L'utérus artificiel, Seuil, Paris, 2005.

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 to remedy medically diagnosed sterility in the man or woman or  to avoid transmitting a particularly severe disease to the child.

The social conditions of assisted reproductive technologies are more or less strict depending on the national culture and the representation of the family, and often exclusively concern married couples or couples which can supply proof of at least two years of living together.

We see that the social regulation of assisted reproductive technologies unconsciously reproduces the traditional social patterns which are here regulated by politics and medicine and withdrawn from the judgment of women by technical mediation.

It is therefore important to analyze the ethics of reproductive technologies, from a gendered, non-naturalist viewpoint, which defines the difference in sexual roles as social construction; this does not mean that the woman does not exist as a social reality, but precisely that she is determined by social structures that she should be able to help modify, but which often she can only confirm.

It would be useful to challenge the idea by which the technosciences are neutral and necessarily beneficent, when referring to this major biotechnological and biopolitical challenge which medicalized reproduction has become.

The critical view of assisted reproductive technologies by feminist sociologists

The epistemological and political problems related to this issue have been concealed and masked by the vague term of human reproduction, as if the issue of gender equality was already resolved. We wish to show that power issues between the sexes are fundamental around this technique whose protagonists are insidiously not the man and the woman but "the couple" and "the embryo", two new and particularly unclear legal entities 11 .

The questions asked by gender literature are: for which women are the assisted reproductive technologies intended? Why is the woman transformed into a "uterine supply system", serving the embryo and scientific research? 12 How does medical and 11. See here the French Bioethics Laws of 1994. 12. Duden, Barbara, Disembodying Women. Perspectives on Pregnancy and the Unborn, Harvard University Press, 1993.

[26] political expertise in procreation as quality production become a justified extension of the familial and private decision?

The debate is all the more complex in that it brings back into play the dichotomies between vitalism and materialism, public and private, corporatist rights of the mothers and the right of women to control their bodies, etc., and raises major power issues.

Faced with these phenomena, the need to rethink the bioethical concept of women's reproductive rights and responsibilities in the face of men re-emerges, but essentially feminist movements, too much in a minority to have political representativity, or women isolated in the face of the disappointments and suffering that these techniques often cause, even though they address a biologically determined and socially constructed desire to fulfill their womanhood through maternity. Because reproduction has become "assisted", the concepts of freedom and reproductive rights have been weakened and are perceived by some women as the price to pay for their sexual liberation. To this "personal tragedy" of infertility said to concern only five percent of women, contemporary biomedicine responded with a succession of IVF techniques. While their initially doubtful efficacy has continued to increase, they have helped to radically change our social perceptions of filiation, of the person, of the concept of birth and even the natural character of conceptionthe representations of which have gone from reproduction to production, even if common parlance refers to assisted reproduction. This concept of assisted reproduction is problematic from the gender viewpoint, because it hides from everyone that biotechnology in human reproduction takes the reductive and essentialist place hitherto held by the concept of natural reproduction, from the point that it comes an obligatory step and reimbursed by French state health insurance.

We can see, from the emergence of these new issues, that the "flip side" of this efficacy, from the viewpoint of our largely-patriarchal-remaining societies, is the intrusion or disruption of the symbolic representations in relation to the nature of reproduction 13 .

We read an underlying conflict between the social order of the biotechnologies 13. Chesler, Phyllis, Sacred Bond. The Legacy of 'Baby M' (publ. Crown, 1st ed. 1988) opposes a surrogate mother to her adoptive parents. The book reiterates the old belief that maternal filiation is more biological than paternal filiation, and this in a moment when legislators are trying to establish either biologically or genetically the role of the father (Vandelac 1990).

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and the natural order. It is all as if the social order was disrupting the natural order.

Scientific realism is no longer content with describing what is real. It modifies it, thereby becoming an anthropological player, which requires ethical reflection on the legitimacy of these modifications, which affect couples seeking medical help for infertility, but do not mention the fact that the treatment is much more invasive for the woman, even when it is the man who is infertile. The complex links between scientific possibilities and the need to re-evaluate our social choices, as to the limits of the field of expertise to give to these sciences, once sociocultural issues are involved, oblige the to assume a major biopolitical role: communicate and dialog in order to undo representations founded on partial knowledge or vectors of ideologies.

These issues, which seem remote from the research itself, have a major impact in terms of ethics or legitimacy of some studies, particularly on embryos and the place of the representations of the role played by women in technical decisions: implantation of a specific number of embryos, selection of the embryo under the microscope, etc.

which erases the dimension of chance. The responsibility caused by such embryo displacement has granted power and responsibility to research, which has often been criticized by women, and has given rise to the creation in Europe of national bioethics committees, meant to arbitrate these power struggles based on both scientific and ethical criteria, but again without the sex/gender perspective being incorporated in the majority of the European regulations. It gives women, particularly with the famous Perruche case in France, the impression of being dispossessed of the control over their bodies because the decision gave less space to sex-gendered representations than to "scientific" criteria.

Challenging the harmful effects for reproductive medicine of the hierarchization between the social and biological sciences

The concept of gender must be introduced into science reflectively in order to avoid supporting or reinforcing, through genetic jargon, social prejudices relating to reproductive roles and their biological determination.

It can be seen in the scientific literature that the terms sex and gender are often used interchangeably and still do not modify research practices to a sufficient extent.

It is important to promote the awareness of biomedical science researchers within the context of their respective fields, as requested by the European Commission [28] since 2010. The plasticity of the living already renders researchers particularly sensitive to these social and contextual dimensions, but tools of non-discrimination must be developed in order to transform this sensitivity into a capacity to resignify the impact of these techniques in relation to existing social norms and the hierarchization between men and women, which prevail over the topics and the priorities of research issues. Introducing the concept of gender into research must involve critical training on its relevance and on the knowledge of research regulations that the international bodies produce.

Does sexual division remain a relevant normative marker?

The status of the gender concept in the biological sciences was not the feat of the biological sciences themselves, even though they have helped challenge the social biases of gender through the reproductive possibilities that they have opened up. It was done by social sciences without always being able to establish a genuine dialog with biomedical research and assisted reproductive technologies. Nevertheless, the methodological decision to reduce sexual difference to masculine and feminine is a bias whose effects are both social and scientific. Among the scientists themselves, biological sex is inferred by simple observation, and the majority of scientific publications consider these categories as evident. The role of ethical reflection is precisely to question these unshakeable inferences by firmly showing the harmful effects they induce on the mental and physical health of those who do not recognize themselves in these a priori categories.

It is the ability to challenge the criterion of sexual difference in biomedical research which, out of prejudice, continues to attribute some diseases to women rather than men.

This gender perspective is a critical perspective, which challenges the biological difference of the sexes and the legitimacy of inferring normative knowledge on others from an observation. If this challenge is not effective in the upstream stages of research, new biotechnologies will only contribute to reproducing social biases in the name of a hypothetico-deductive approach.

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Recommendations for the inclusion of gender in assisted human reproduction  Train researchers in the issues of the social consequences of scientific research.

 Take seriously the polysemy of the biological sex concept from the gender viewpoint, and do not be afraid to embrace uncertainty.

 Face the challenge of the normativity criteria to be adopted for the incorporation of new reproductive technologies.

 Consider women rather than couples as decision-making agents in reproductive medicine.

It is therefore not just about promoting research policies in terms of gender equality, because research increases rather than eliminates differentiation.

By incorporating the complexity of the gender dimension in research, in the very name of research excellence, our aim must be to shed light on the gray areas and biases in research provoked by unconceived presuppositions upstream of the research protocol, which involves:

 assuming social equality between men and women in research institutions,  assuming biological differences between men and women without challenging the equality of opportunity and decision in terms of gendered reproduction,  avoiding invalid inferences by using critical thinking to update implicit gender bias in research practices 14 ,  paying upstream attention to gender bias in disease research and classification by raising researcher awareness of gendered variables,

 not presenting opposing methodologies between science and gender but promoting complementary epistemological models for the sciences that have a social effect.

  for neuroimaging research (Catherine Vidal) Principles and implications for the design, analysis and interpretation of experiments In neuroimaging research on brain functions and cognitive skills, studies that interrogate the impact of education and sociocultural environment on gender differences in men and women are still rare (Rippon 2014). Neuroscientists are still relatively unfamiliar with the concept of gender. Yet taking it into account can only enrich research on cognitive and behavioral disorders whose prevalence varies according to sex and environment (Dussauge 2012, Fausto-Sterling 2012 a-b, Fine 2014).

  gender and sex into research on cardiovascular disease has undeniably improved knowledge surrounding diagnosis and treatment. Prevention campaigns that take sex and gender into account have also helped to more accurately target at-risk populations and encourage them to adopt preventive behaviors.In 2005, the European Society of Cardiology (http://www.escardio.org/) launched the "Women at Heart" initiative, which aims to improve awareness and understanding of cardiovascular diseases in women, among both doctors and the general public. The European Medicines Agency has also made recommendations to include more women in clinical trials, and to collect data on gender in order to better assess the effectiveness of treatments for women and men(European Medicines Agency, 2006).The medical research community in France is gradually becoming aware of the importance of including the factors of sex and gender in research on cardiovascular diseases. The Foundation for Cardiovascular Research, for example, has recently launched the "At the Heart of Women" campaign, http://www.fondation-recherchecardio-vasculaire.org/coeur-de-femmes/la-recherche-pour-le-coeur-desfemmes/lancement-programmes-de-recherche-coeur-de-femmes/.

3.

  See Mikkola, Mary, Feminist Perspectives on Sex and Gender, Standford Encyclopedia of philosophy, May 2011. 4. Les troubles de la fertilité, état des connaissances et pistes pour la recherche, 2012. The report focuses on the biological causes of infertility and only addresses the social issues in the final pages, without mentioning the sex-differentiated issue of research consequences. 5. In the wake of the World Conference on Women held in Beijing in 1995, the French daily Le Monde pointed out that over forty Catholic and Muslim states had expressed reservations on the passages of the declaration recognizing for the first time the right of women to control and freely decide their sexuality. How does this right of women to control what happens to their bodies apply in the face of "fertility disorders", if decisions are made as a couple? 6. Novaes Bateman, Simone, Biomédecine et devenirde la personne, Collection Esprit, 1992.



  either neutrality towards gender would deny male/female biological determinism,  or positive discrimination skews the objective data from research on biological determinism through a belief in unalterable universals, or in an irrational relativism of the cultural values.Biotechnologies: redefining the reproduction playersRecent developments in assisted reproductive technologies have led women to question the purpose of the reproductive technologies in the redistribution of the roles of the procreation players.The field of reproductive research as laboratory for changing gender categories and power strugglesThe field of reproductive research is one of the most illustrative of this methodological bias and of the power struggles involved from a heterosexual research perspective, as the work of many sociologists and feminist biologists (Haraway, Fausto-Sterling) has shown.Indeed, men for a long time remained the principal players and women the subjects of research, without implementation of ethical rules of research, until the bioethics law in France in 2004. Reproductive technologies straddle multiple disciplines in the domain of therapeutic innovation, faced with women made vulnerable by sterility that deprives them of their traditional social role and for which they demand therapeutic solutions which did not require very clear informed consent protocols as they were the ones calling for those solutionsa situation which has evolved thanks to recent bioethics opinions and work. Feminist studies first criticized the seizing of power over women's bodies, in an area that was the only recognized social role of women. Science was going to make children with and for women. The situation in France, as the 2011 report by the French Biomedicine Agency shows 8 , is more nuanced. It states that sustained research efforts will be needed to improve infertility treatments, particularly assisted reproductive technologies, and highlights genetic or 8. Les troubles de la fertilité, état des connaissances et pistes pour la recherche. Rapport remis au parlement le 18 décembre 2012.

More generally

 In medical research, take into consideration both the differences between males and females and the social norms concerning men and women, which do not obey the same epistemological models.

 Fight the effects of sexism in the teaching of biomedical research.

 Associate social science researchers with innovative medical research.

 Take gender aspects into account in sex-specific medicine. They are not contrary to the equality of rights of access to research and healthcare. 15  Incorporate gender issues in the internal and external evaluations of research institutions.

 Implement at institutional level a strategy to promote gender equality and not positive discrimination, which would call into question people's real abilities.

 Continuously train researchers, by addressing the new technologies and their social impact, by involving human science researchers in the laboratories.

 Improve communication on biotechnological innovations, incorporating the gender perspective into the social consequences of research.

 Do not oppose social egalitarianism and gender-specific medicine.

General conclusion

The aim of these recommendations is to promote a culture that is more inclusive of gender issues, which can only improve the quality of and public receptivity to therapeutic innovations, rendering researchers more accountable for the social implications of their research in terms of the gender and sex aspects.

While assisted reproductive technologies have considerably modified the possibilities for women and men suffering from sterility, they have also modified our [31] anthropological perception of procreation and filiation. It is crucial that new biotechnological advances affecting procreation do not remain closed to research concerning conflicts of social perception of these technologies.

This also implies devising a more integrative and interdisciplinary epistemology and reducing opacity in decisions and in the choices of biomedical research subjects.

"GENDER AND HEALTH RESEARCH" GROUP 2014-2015 ACTIVITY REPORT

International Gender and Health Colloquium, held by the Emilie du Châtelet

Institute in partnership with the Inserm, June 8-9, 2015, Amphithéâtre Buffon, Paris

Diderot University

The objective of this multidisciplinary colloquium is to analyze how societal gender roles tend to influence how women and men (i) are exposed differently to health problems, (ii) perceive their health problems, (iii) use or do not use the healthcare system, and (iv) how healthcare professionals respond differently depending on the sex of their patients.

The colloquium looks at the links between gender and health in various For clinical research, a document summarizing the recommendations of this Memo will be sent to the project leaders for consideration regarding the links between sex and gender in the design, analysis and interpretation of experiments.

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"GENDER AND HEALTH RESEARCH" GROUP PROPOSED ACTIONS


2

Practical guidelines for the consideration of the link between sex and gender in medical research and health

CARDIOVASCULAR

In 2014, the Inserm Ethics Committee set up a "Gender and Health Research" group (http://www.inserm.fr/qu-est-ce-que-l-inserm/l-ethique-a-l-inserm/les-groupesde-reflexion-thematique-du-comite-d-ethique). As gender is often overlooked in biomedical research in France (unlike in Anglo-American and other European countries), one of the group's goals is to reflect on the ethical issues concerning the influence of social and cultural factors on the differences and inequalities between men and women when it comes to health and medical research practices.

It is important to encourage researchers to consider the differences between men and women -not just as a simple dichotomy between male and female, but as interaction between sex and gender (Fausto-Sterling 2000[START_REF] Springer | Beyond a catalogue of differences: A theoretical frame and good practice guidelines for researching sex/gender in human health[END_REF][START_REF] Springer | Beyond a catalogue of differences: A theoretical frame and good practice guidelines for researching sex/gender in human health[END_REF]Krieger 2003). Such an approach provides a framework for improved research practices, and consequently increases knowledge about the origins of differences between women and men in health.

Recommendations for integrating sex and gender in research on cardiovascular disease

The link between sex, gender and cardiovascular disease

In 2008, the World Health Organization reported that cardiovascular disease was the leading killer of women in Europe -while only one in 26 European women died of breast cancer, one in three died of cardiovascular disease (World Health Organization 2008). Five years later, the situation has not evolved. Cardiovascular disease is still the number one killer of women in the world, breast cancer coming in at tenth place as an explanation for women's deaths (World Health Organization 2013). Women suffering from diabetes have a greater risk of developing heart disease or experiencing a stroke. Following a heart attack, women's prognosis is less encouraging than that of men in the same situation, and they also present greater risk of dying from such the attack (Regitz-Zagrosek 2011; Taylor 2011).

Women develop heart disease on average ten years later in their lives than menthe most commonly cited reason is the notion that menopause can lead to hypertension, diabetes, hyperlipidemia, obesity and other metabolic disorders. This hypothesis reinforces stereotypical views among doctors and researchers regarding the differences between men and women. However, studies relying on this hormonal hypothesis were seriously questioned [START_REF] Wilson | Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50-The Framingham Study‖[END_REF]. Indeed, the protective role of feminine hormones present before menopause as preventing cardiovascular disease in women is no longer a matter of consensus (Hulley 1988;[START_REF] Khan | Nuclear Cardiology in Women‖[END_REF][START_REF] Springer | Beyond a catalogue of differences: A theoretical frame and good practice guidelines for researching sex/gender in human health[END_REF].

Numerous studies underline the fact that social representations linked to feminine and masculine gender roles have an impact on the attitude of patients as well as medical personnel. As a result, heart/coronary attacks are under-diagnosed among women. A woman who goes to see her doctor and expresses tightness and pain in her chest is more often than not prescribed anti-anxiety medication, whereas a man is almost immediately sent to a consult a cardiologist (Spring 2012;Klinge 2012;Krieger 2003).

Likewise, because cardiovascular disease is more often than not considered to be a man's disease, women are consequently underrepresented in research on cardiovascular disease, whether in clinical trials, intervention studies or biomedical research (Kim 2010;Gupta 2007;EMEA 2005EMEA , 2006)).

These observations invite us to reconsider the differences between men and women relative to cardiovascular disease, not as a result of sole biological differences, but as the product of the imbrication between sex and gender. Such an approach allows us to formulate new questions, to analyze symptoms under a new light, improve diagnoses, and also develop new strategies for the prevention and treatment for all kinds of cardiovascular diseases.

These new approaches have already been integrated into research organizations of several other countries, notably by the National Institutes for Health in the United States, and have consequently led to an increase in the representation of women in clinical trials, as well as increased knowledge about the influence of sex and gender on cardiovascular disease. Another notable result of this initiative has been the launching of new public health campaigns that target women and men differently in an effort to provide more accurate information about risk factors and preventive measures.

Taking inspiration from the programs already underway not only in the United States, but in other countries as well (particularly in northern Europe), we make the following recommendations:

Recommendation 1: Include as many women as men in clinical trial and research protocols.

Studies carried out internationally as well as in France point to only approximately 33.5% of women making up all participants in research protocols.

(http://genderedinnovations.stanford.edu/methods-sex-and-gender-analysis.html).

This under-representation is particularly noticeable in research on how to reduce cholesterol, the risk of ischemia and heart attacks.

Recommendation 2: Take different discourses expressed by women and men into account when evaluating symptoms so as to better establish diagnoses.

An international study of 26,755 patients with cardiovascular disease (only 29% of whom were women) demonstrated that the most common symptom in men (94%) and women (92%) is chest pain [START_REF] Dey | -Sex-Related Differences in the Presentation, Treatment, and Outcomes among Patients with Acute Coronary Syndromes: The Global Registry of Acute Coronary Events‖[END_REF]. However, significant differences between the sexes are observed for more -atypical‖ symptoms [START_REF] Chen | Gender Differences in Symptoms Associated with Acute Myocardial Infarction: A Review of the Research. Heart and Lung‖[END_REF]. Women in the study frequently complained of fatigue, nausea and jaw pain -three symptoms that are closely linked to cardiovascular disease, but do not necessarily raise red flags for cardiologists [START_REF] Zbierajewski-Eischeid | Myocardial Infarction in Women: Promoting Symptom Recognition, Early Diagnosis, and Risk Assessment‖[END_REF].

Recommendation 3: Adapt diagnostic tools to the specificities of cardiovascular pathologies experienced by women and men

It has long been believed that women suffer from the same cardiovascular diseases as men, namely coronary heart disease. However, recent research in the U.S. has found that ischemic heart disease is particularly prevalent among women [START_REF] Shaw | Women and Ischemic Heart Disease: Evolving Knowledge‖[END_REF]. Angiography, the most common technique used in the examination of patients complaining of chest pain, usually results in a diagnosis of coronary heart disease in men, but is not as effective at detecting the disease in women. Many women complaining of chest pain have "normal" angiograms, and are therefore left untreated. Many of these women have a heart attack or a stroke shortly thereafter [START_REF] Robinson | -Cardiovascular Risk in Women with Non-Specific Chest Pain (from the Women's Health Initiative Hormone Trials)‖[END_REF].

It is therefore important to use different tools and diagnostic techniques for women, such as coronary reactivity testing (Von Mering et.al., 2004;[START_REF] Pepine | Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia: Results from the National Heart, Lung, and Blood Institute (NHLBI) Women's Ischemia Syndrome Evaluation (WISE) Study‖[END_REF], intravascular ultrasound [START_REF] Khuddus | An Intravascular Ultrasound Analysis in Women Experiencing Chest Pain in the Absence of Obstructive Coronary Artery Disease: A Substudy from the National Heart, Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE)‖[END_REF], cardiac MRI, cardiac spectroscopy [START_REF] Ishimori | Myocardial Ischemia in the Absence of Obstructive Coronary Artery Disease in Systemic Lupus Erythematosus‖[END_REF], myocardial scintigraphy, positron emission tomography (PET) [START_REF] Johnson | Positron Emission Tomography‖[END_REF]stress echocardiography (Kaul, 2011).

6

Recommendation 4: Challenge assumptions and hypotheses regarding the role of estrogen in cardiovascular disease.

The decrease in estrogen rates has long been regarded as a causative factor for cardiovascular disease in women. As a result, hormone replacement therapy has often been recommended for female patients [START_REF] Khan | Nuclear Cardiology in Women‖[END_REF]. However, large-scale studies have shown the opposite, namely a correlation between hormone replacement therapy and an increased risk of infarction in women [START_REF] Wilson | Postmenopausal Estrogen Use, Cigarette Smoking, and Cardiovascular Morbidity in Women over 50-The Framingham Study‖[END_REF][START_REF] Hulley | -Randomized Trial of Estrogen plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women‖[END_REF]. At present, the current status of research on the specific role of hormones on heart disease in women before and after menopause has yet to be confirmed.

Recommendation 5: Take sex and gender into account in cardiovascular research in order to better prevent and reduce the risk of developing heart disease.

The risk factors for cardiovascular disease are largely the same for men and women: age, hypertension, hyperlipidemia, diabetes, smoking, obesity, sedentary lifestyles, high-fat diets, and so on. However, the prevalence and impact of these factors differ according to gender [START_REF] Mosca | Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update: A Guideline from the American Heart Association‖[END_REF].

For example: habitual smoking is historically more common among men than women (WHO, 2010). However, in certain countries such as Sweden and Iceland, women now smoke more on average than men (Shafey et al., 2009). Women smoke less than men in the United States, Western Europe and other industrialized countries, but this is not the case in Central, Southern or Eastern Europe, nor in many emerging countries (Shafey et al., 2009). A recent study conducted on 3,587 people in five European countries has shown that smoking increases the risk of atherosclerosis in women as well as men. However, the adverse effects are twice as prevalent in women as in men [START_REF] Tremoli | The Association of Tobacco Smoke with Subclinical Atherosclerosis and Atherosclerosis Progression is Stronger in Women than in Men‖[END_REF].

These studies on smoking have shown that that gender roles prevalent in specific geographic, economic, social, and cultural environments have a significant impact on the behavior of men and women who smoke, or decide to start smoking. In short, campaigns and programs that combat smoking should incorporate both sex and gender as factors to be taken into consideration.

Conclusion

For the last twenty years, the introduction of the factors of gender and sex into research on cardiovascular disease has undeniably improved knowledge surrounding diagnosis and treatment in North America. Prevention campaigns that take sex and gender into account have also helped to more accurately target at-risk populations and While these initiatives are encouraging, there is still much work to be done, and Inserm researchers will have a key role in the future of cardiovascular research.

Integrating the factors of sex and gender in research protocols in cardiovascular disease can only broaden and enrich the knowledge of these diseases, and benefit the health of both men and women.

Jennifer Merchant and Catherine Vidal

Members of the "Gender and Health Research" Group of the Inserm Ethics Committee

  the European Society of Cardiology (http://www.escardio.org/ ) launched the "Women at Heart" initiative, which aims to improve awareness and understanding of cardiovascular diseases in women among both doctors and the general public. The European Medicines Agency has also made recommendations to include more women in clinical trials, and to collect data on gender in order to better assess the effectiveness of treatments for women and men (European Medicines Agency, 2006). The medical research community in France is gradually becoming aware of the importance of including the factors of sex and gender in research on cardiovascular disease. The Foundation for Cardiovascular Research, for example, has recently launched the -At the Heart of Women‖ campaign (http://www.fondationrecherche-cardio-vasculaire.org/coeur-de-femmes/la-recherche-pour-le-coeur-desfemmes/lancement-programmes-de-recherche-coeur-de-femmes/), which aims to combat the under-representation of women in cardiovascular research.


Alexandre Bruckert

Yat Hong Lam

Marc Christie

Olivier Le Meur

DEEP LEARNING FOR INTER-OBSERVER CONGRUENCY PREDICTION

Keywords: visual dispersion, gaze patterns, prediction, deep features

According to the literature regarding visual saliency, observers may exhibit considerable variations in their gaze behaviors. These variations are influenced by aspects such as cultural background, age or prior experiences, but also by features in the observed images. The dispersion between the gaze of different observers looking at the same image is commonly referred as inter-observer congruency (IOC). Predicting this congruence can be of great interest when it comes to study the visual perception of an image. In this paper, we introduce a new method based on deep learning techniques to predict the IOC of an image. This is achieved by first extracting features from an image through a deep convolutional network. We then show that using such features to train a model with a shallow network regression technique significantly improves the precision of the prediction over existing approaches.

INTRODUCTION

The prediction of human gaze patterns and viewing behaviors has been a hot topic in the computer vision community these past years. Numerous models have been proposed, either for automatically identifying salient regions in an image or a video, or for studying the impact of different factors on gaze patterns. Usually, such factors are classified into two categories: stimulus-dependent (bottom-up) and observer-dependent (top-down). For instance, the age of the observer is a crucial top-down factor as shown by Le Meur et al. [START_REF] Meur | Visual attention saccadic models learn to emulate gaze patterns from childhood to adulthood[END_REF] since extreme discrepancies appear between the gaze patterns of children and adults. Cultural differences [START_REF] Chua | Cultural variation in eye movements during scene perception[END_REF][START_REF] Nisbett | and why[END_REF] could also be an important factor, even if discussed by Rayner et al. [START_REF] Rayner | Eye movements when looking at unusual-weird scenes: are there cultural differences?[END_REF]. On the contrary, bottom-up factors are only linked to the implicit properties of the stimuli, such as presence of faces in the image. Such features are so influential that, for example, Cerf et al. incorporated specific face detection techniques in their model [START_REF] Cerf | Predicting human gaze using low-level saliency combined with face detection[END_REF].

In this work, we focus on a phenomenon that contributes to the study of human gaze patterns and visual saliency, called interobserver congruency (IOC). IOC is a characterization of the dispersion of gazes between different users observing the same image and is measured using an IOC score (lower scores representing a higher dispersion). While IOC scores are easy to measure using gaze tracking, very few contributions address the problem of predicting the IOC score, despite its interest when it comes to explain in which conditions humans tend to have similar gaze behaviors or not.

Two main prior efforts have examined the influence of bottomup and top-down features on the IOC score prediction problem. In Le Meur et al. [START_REF] Meur | Prediction of the inter-observer visual congruency (iovc) and application to image ranking[END_REF], a regression-based learning approach is used to predict those scores from features such as color harmony measuring the dispersion in saturation within the image, a face detector described in Viola and Jones [START_REF] Viola | Rapid object detection using a boosted cascade of simple features[END_REF], the depth of field and the scene complexity. In Rahman and Bruce [START_REF] Rahman | Factors underlying interobserver agreement in gaze patterns : Predictive modelling and analysis[END_REF], a similar regression model is trained, using both simple diagnostic features and more complex bottom-up and top-down features. Among the diagnostic features, we can note the entropy over the image, the visual clutter as described in Rosenholtz et al. [START_REF] Rozenholtz | Measuring visual clutter[END_REF] and the JPEG image size, indicating the compression level. Bottom-up and top-down features from several popular saliency models are also used, such as the representation of the holistic scene envelope described in Oliva and Torralba [START_REF] Oliva | Modeling the shape of the scene: A holistic representation of the spatial envelope[END_REF], the histogram of oriented gradients (HoG) [START_REF] Felzenszwalb | Object detection with discriminatively trained part-based models[END_REF], but also deep topdown features extracted from the BVLC Reference CaffeNet architecture [START_REF] Jia | Caffe: Convolutional architecture for fast feature embedding[END_REF]. Finally, the features from 12 different saliency algorithms are combined using an histogram-based algorithm to create a feature set called Histogram of Predicted Salience (HoPS) features.

In this study, we present a new way to automatically predict IOC scores, solely based on deep bottom-up features, extracted by a pretrained convolutional neural network. The results of this work show that such a model can outperform other approaches that take into account observer-dependant features, and gives a reasonably good approximation of the IOC only based on the stimulus.

The paper is composed as follows. Section 2 introduces the inter-observer congruency score and the way it is measured. Section 3 describes the architecture of the proposed model as well as the training conditions and the databases that were used. Section 4 presents the performances, and confronts the model to previous work. Finally, in Section 5, we discuss the implications of our results and the benefit they may have on future work.

INTER-OBSERVER CONGRUENCY

Method for computing IOC from eye data

Inter-observer congruency, or the visual dispersion between observers, can be measured thanks to eye tracking techniques. An image is displayed onscreen while eye movements of an observer are recorded. If we assume that an image is seen by No observers, and that the scanpath for any i ∈ No is of length LN , a leave-oneout approach [START_REF] Torralba | Contextual guidance of eye movements and attention in realworld scenes: The role of global features in object search[END_REF] can be used to compute the IOC scores of the image. The first step consists in convolving the raw fixation maps of (No -1) observers with a 2-D Gaussian kernel. The σ for the Gaussian is set to one degree, which roughly estimates the fovea size. The convolution step provides a 2-D distribution map in which each pixel represents the probability for a fixation to be here. We then use two well known saliency measures, comparing each individual to the rest of the observers, to get the IOC scores, namely area under curve (AUC) and normalized scanpath saliency [START_REF] Peters | Components of bottom-up gaze allocation in natural images[END_REF] (NSS). Since the different approaches of AUC (Judd's approach [START_REF] Judd | A benchmark of computational models of saliency to predict human fixations[END_REF] and Borji's approach [START_REF] Borji | Analysis of scores, datasets, and models in visual saliency prediction[END_REF]) are highly correlated, we will only focus on one of 3766 978-1-5386-6249-6/19/$31.00 ©2019 IEEE ICIP 2019

them, AUC-Borji (AUCB).

In this paper, we compute the IOC scores for two well-known datasets, i.e. Judd/MIT dataset [START_REF] Judd | Learning to predict where humans look[END_REF] and CAT2000 dataset [START_REF] Borji | Cat2000: A large scale fixation dataset for boosting saliency research[END_REF]. The former dataset includes 1000 images with different resolutions and contents. The CAT2000 includes 2000 images, split into 20 different categories. One key difference between these datasets is the viewing duration, 3s for Judd/MIT and 5s for CAT 2000. Considering that the time given to the observers to look at the images is different, we set an arbitrary threshold to limit the number of fixations per scanpath. Short scanpaths (number of fixations below the threshold) are removed. In addition, any fixation points above that threshold are also discarded. We also define a fixed number of observers No to compute the IOC: if an image has less than No valid observers (i.e. with scanpath lengths long enough), this image will be left out. If an image has n > No observers, we randomly sample No observers among those and compute the IOC based on those No individuals. This sampling is done several times for the sake of robustness and relevance; the number of random samplings is a fixed parameter of the model. The IOC scores per observer are then averaged to give the final IOC.

Results on CAT2000 and Judd/MIT

Using the AUCB metric, the final IOC score is between 0 (i.e. very low congruency) and 1 (i.e. very high congruency). For the NSS, there is no upper bound, scores can span between 0 (i.e. very low congruency) and +∞ (i.e. very high congruency). Figure 1 illustrates images from CAT2000 database for which we observe a very low and very high inter-observer congruency. Figure 3 illustrates the IOC distributions computed by using AUCB and NSS metrics. The AUCB scores are usually within the range 0.75 -0.95. The NSS scores are usually within 1.5 -4.5. Since the Judd/MIT database only consits in natural images, the range of both AUCB and NSS scores is a bit shorter (typically between 0.85 -0.95). NSS scores also usually span within the range 2.5 -4.5.

Intuitively, there are many "simple" factors that can easily explain a low or a high IOC score. For instance, if an image has no salient regions, it is quite straightforward to assume that the IOC will be low, since no particular detail should catch the attention of a free-viewing observer. The opposite might also be true: an image with many salient regions could also produce a low IOC score if the viewing time is not long enough. We can observe that phenomenon when looking at the images of the dataset when ranked with their IOC score. On the other hand, high IOC scores can often be qualitatively explained by the presence of faces, written characters, or isolated objects, that tend to attract the gaze.

DEEP-LEARNING FOR IOC SCORE PREDICTION

In this paper we propose to rely on a learning approach to predict the inter-observer congruency score of an image. We exploit the IOC scores computed the CAT2000 and Judd/MIT databases to train a network in a two-staged approach: first (i) by designing an encoder based on VGG19 [START_REF] Simonyan | Very deep convolutional networks for large-scale image recognition[END_REF] to extract deep features, and second (ii) by designing a straightforward shallow network as a decoder to perform the regression.

A two-staged model architecture

The lack of images labeled with eye tracking data makes the creation of a reliable and robust model challenging. This is why we used transfer learning, using the pre-trained weights from a feature extractor architecture. Moreover, the shallow regression network seemed a good compromise between that lack of data, that precludes any kind of learning that uses too many parameters, and the capacities of a method that is more complex and efficient than simple linear regression.

The overall architecture is presented in Figure 2. The model first uses VGG19 network [START_REF] Simonyan | Very deep convolutional networks for large-scale image recognition[END_REF] for extracting a set of deep features. We chose that architecture for its excellent performances in the field of visual attention, especially through popular models such as DeepGazeII [START_REF] Kümmerer | Deepgaze ii: Reading fixations from deep features trained on object recognition[END_REF] and MLNET [START_REF] Cornia | A deep multi-level network for saliency prediction[END_REF]. VGG-based networks are well-known for their very good generalization properties, as well as their simplicity. The particularity of that structure is the use of multiple convolution layers with small kernel size (3 × 3). The layer stacking is then more discriminative due the multiple non-linear rectification layers. It also decreases the number of parameters, hence easing the training process. We used two different versions of that encoder, one for AUCB-based IOC score, and one for NSS-based NSS score. The first is the full VGG19 feature extractor, containing We then design a simple shallow network as a decoder to perform the regression task. After the input, a dropout layer is applied, followed by three convolution layers with [3 × 3] kernel sizes, reducing the number of features maps to 320, 64 and 1. Batch normalization is used to normalize the output, followed by a flattening layer, a second dropout and three fully connected layers, reducing the dimension from 1850 to 1024, 256 and 1. The final output is the predicted score of IOC. Best performances were achieved for AUCB by setting the dropout rate at 0.5, using sigmoid activation functions within the dense layers, and binary categorical entropy as a loss function. For NSS, the dropout rate is set as 0.2, with ReLU activation functions and mean squared error as a loss function.

Training database

To train our model and evaluate IOC prediction, we used the IOC scores (based on AUCB and NSS) computed over the Judd/MIT database [START_REF] Judd | Learning to predict where humans look[END_REF] and the CAT2000 database [START_REF] Borji | Cat2000: A large scale fixation dataset for boosting saliency research[END_REF], as described in Section 2.

The Judd/MIT database includes 1000 images with different resolutions, 500 of them being used for training, 200 for validation along the training process, and 300 have been held out to evaluate the performances. For the CAT2000 we use 1200 images for the training process, 400 for the validation and 400 for the test. This database is also split into 20 different categories of images, which allows to compare the precision of the prediction in each category.

Since the Judd/MIT database only contains 500 training images, we performed a first training merging the two databases together. We also performed data augmentation by flipping the images horizontally, making the assumption that such a transformation should not disturb the IOC score. The images are then rescaled into [400 × 300 × 3] images. We used the pre-trained ImageNet weights [START_REF] Russakovsky | Imagenet large scale visual recognition challenge[END_REF] for the encoder network and froze those layers during the training. A fine-tuning phase has also been performed, during which we froze the first convolution layer of the decoder network.

RESULTS

Comparison with standard approaches

We first tested simple regression models (SVM regression, simple random forests, simple multi-layers perceptrons, correlation between IOC and the entropy of predicted saliency maps) to ensure there was no easy way to deal with that problem, and that the relatively complex method in terms of parameters (around 6 million) was justified. We performed a quantitative analysis, using the testing holdouts of the two databases on which the network was trained. We predicted the IOC scores and computed the Pearson correlation coefficient between those predictions and the IOC ground truth. Results are shown in Table 1. Correlation coefficients for the 3 aforementioned methods is extremely low.

Performances of the proposed method

The distribution of prediction result of AUCB and NSS IOC scores are shown in Figure 3. For the AUCB prediction, the prediction mean is exactly the same as the ground truth mean, but its standard deviation is smaller. There is a tendency that the prediction value is closer to the mean, meaning that the prediction of outliers is more difficult. Similar effects can also be noticed with NSS score. When the global prediction mean is slightly smaller than that of the ground truth, the spreading of prediction NSS is significantly smaller than that of the ground truth. We also observe that when the ground truth AUCB distribution is almost symmetric along the mean value, the ground truth NSS is more right-skewed and has a long tail at high NSS values. It may explain the poorer performance in NSS prediction. This is most probably due to the regularization and dropout we used in the decoder network, in order to prevent overfitting issues. The range of the predictions, for both scores, are also smaller than the ground truth, which is due to the capacity of the model to generalize properties and to perform really well when averaged over a few images.

Overall, Table 1 indicates that the correlation coefficient between ground truth and prediction is 0.611 and 0.642 on Judd/MIT and CAT2000 databases, respectively. On Judd/MIT database, the proposed method significantly outperforms Le Meur [START_REF] Meur | Prediction of the inter-observer visual congruency (iovc) and application to image ranking[END_REF] and Bruce [START_REF] Rahman | Factors underlying interobserver agreement in gaze patterns : Predictive modelling and analysis[END_REF] methods.

We also applied our model on two other databases, namely the Memorability [START_REF] Mancas | Memorability of natural scenes: The role of attention[END_REF] and Bruce's database [START_REF] Bruce | Saliency, attention and visual search: an information theoretic approach[END_REF]. Compared to Bruce method [START_REF] Rahman | Factors underlying interobserver agreement in gaze patterns : Predictive modelling and analysis[END_REF], the proposed model is better on Memorability database while Bruce method provides the best results on Bruce database. Note that the proposed method has not been trained over neither Memorability nor Bruce database. Both results suggest that the proposed method has good generalizing properties.

To confirm these deductions, we performed a study of the IOC per image catagory based on the CAT2000 database. The mean ground truth IOC scores we computed consolidated our original intuitions about what kind of images should have a higher (or lower) IOC score. For example, the category getting the lowest IOC score is composed of satellite images, in which it is hard to distinguish specific objects. On the opposite, the highest IOC scores are performed by sketch drawings, that offer very specific locations to look at, a very high contrast between the drawing and the background, and display familiar objects. It also appears that the predicted mean IOC scores are really close to the ground truth (r = 0.953, p val << 10 -5 for AUCB, r = 0.845, p val << 10 -5 for NSS). IOC values are therefore partly correlated with the high level information of the scene (categories), and partly on the low level information in each individual image. When the effect of individual features is lowered due to the averaging, the categorical visual information becomes more important and leads to an improvement in correlation. This reflects that our model has a capacity to partially understand high-level features common in each category.

CONCLUSION

In this paper, we introduced a new model to predict an estimation of the visual congruence between observers. We showed that we can improve substantially the performances for such a task solely based on deep bottom-up features, provided that the right regression model is used. For that regression model, we proposed a shallow convolutional network, that performed better than previous models.

The information given by the IOC can also easily be used, at least as a sanity check to compare a predicted saliency map to its ground truth. IOC scores can also be of great use for image recommendation systems, as it gives an information on the possibility that an observer will focus on the same areas as another observers. It could also be very useful for outliers management in any visual attention problem: if a viewer exhibits very different gaze patterns that the others on images with high IOC, it could be easier to leave him out of the survey, or to note significant differences in top-down features. Finally, IOC can intuitively be linked to many other properties, such as the memorability, or the response time in task-dependant viewing. We plan to expand those questions to dynamic models, where IOC is of even greater interest, for advertisement or film mak-ing.

Fig. 1 .

 1 Fig. 1. Examples of pictures from the CAT2000 database sorted based on their IOC scores (top-left: highest congruency, bottomright: lowest congruency).

Fig. 2 .

 2 Fig. 2. Architecture of the proposed CNN. The upper part is the encoder based on VGG19, the lower part is the shallow decoder (for NSS prediction, we remove the two first max-pooling layers).

Fig. 3 .

 3 Fig. 3. Distribution of the IOC scores for (left) AUCB and (right) NSS over CAT2000 database.

Fig. 4 .

 4 Fig. 4. Mean AUCB-based IOC scores for each categories of CAT2000.

Table 1 .

 1 Pearson correlation coefficient between predicted IOC scores and ground truth IOC for several models and databases. 5 max-pooling layers. In that case, the output of the encoder is a tensor of size [37 × 50 × 1472]. For the NSS score, we observed better performances when removing two of the five max-pooling layers, leaving the output dimensions as [37 × 50 × 1280].

	Datasets	Judd	CAT	Memo. Bruce
	Methods	MIT	2000	[23]	[24]
	SVM	0.101	0.124	-	-
	Random Forest -0.162 -0.088	-	-
	Perceptron	0.073	0.139	-	-
	Le Meur [6]	0.340	-	-	-
	Bruce [8]	0.456	-	0.519	0.506
	Proposed	0.611	0.642	0.537	0.473