Keywords: Driving simulation, Virtual reality, CAVE, Scale 1:1 perception, Augmented Reality, Simulation sickness, Transport Delay

The separation between driving simulation and digital mockup design review is now fading though different uses will require different simulation configurations.

New application domains, such as automotive AR design, will bring combined features of VR and driving simulation technics, including CAVE like display system equipped driving simulators.

ABSTRACT

Driving simulation from the very beginning of the advent of VR technology uses the very same technology for visualization and similar technology for head movement tracking and high end 3D vision. They also share the same or similar difficulties in rendering movements of the observer in the virtual environments.

The visual-vestibular conflict, due to the discrepancies perceived by the human visual and vestibular systems, induce the so-called simulation sickness, when driving or displacing using a control device (ex. Joystick). Another cause for simulation sickness is the transport delay, the delay between the action and the corresponding rendering cues.

Another similarity between driving simulation and VR is need for correct scale 1:1 perception. Correct perception of speed and acceleration in driving simulation is crucial for automotive experiments for Advances Driver Aid System (ADAS) as vehicle behavior has to be simulated correctly and anywhere where the correct mental workload is an issue as real immersion and driver attention is depending on it. Correct perception of distances and object size is crucial using HMDs or CAVEs, especially as their use is frequently involving digital mockup validation for design, architecture or interior and exterior lighting.

INTRODUCTION

Driving simulation and Virtual Reality (VR) are closely connected from the very beginning. Their history starts for both in the 1960-s and very quickly they are using both computer generated imagery (CGI), are interactive with sensory feedback and provide physical and mental immersion for an efficient use [START_REF] Shermann | Understanding Virtual Reality[END_REF].

Driving simulation starts in the 1960s. Doron Electronics Inc., founded in 1970, acquires the driving simulation business from the Singer Company and becomes the first company to develop and produce complete driving simulation systems [START_REF] Allen | A short history of driving simulators[END_REF]. The early versions nevertheless do not use computer graphics imagery (CGI), only film based display systems. If the first real time CGI system from General Electric is ready in the early 1960s, it is displaying only a couple of dozen non-textured polygons [START_REF] Kemeny | Synthèse d'images fixes et animées[END_REF]. We have to wait until the 1970s to see the development and use of the first motion based driving simulator with CGI at VTI and the first full scale motion based driving simulator at Daimler in the late 1980s [START_REF] Drosdol | The Daimler-Benz driving simulator, a tool for vehicle development[END_REF], [START_REF] Nordmark | Driving simulators, Trends and Experiences[END_REF], [START_REF] Kemeny | Simulation and Perception of Movement[END_REF].

In the meantime, if the term of Virtual Reality was coined by Jaron Lanier only in 1987, the first Head Monted Display (HMD) for Virtual and Augmented Reality is built in 1968; even though it could display then only wired frame images [START_REF] Sutherland | A Head-mounted Three Dimensional Display[END_REF]. The first CAVE installations arrive in the early 1990s [START_REF] Cruz-Neira | The CAVE: Audio Visual Experience Automatic Virtual Environment[END_REF], [START_REF] Cruz-Neira | Surround-Screen Projection-based Virtual Reality: The Design and Implementation of the CAVE[END_REF]. In France, the 1 st CAVE is installed at Institut Image of Arts et Métiers ParisTech in Châlon-sur Saône in 2001. In the same time HMD based or head slaved display equipped driving simulator are installed at BMW, TNO, Renault and Volvo [START_REF] Kappé | Effects of Head-Slaved and Peripheral Displays on Lane-Keeping Performance and Spatial Orientation[END_REF], [START_REF] Kemeny | Simulation and Perception of Movement[END_REF], which show already the close relationship between the fields of driving simulators and VR. CARDS, a Comprehensive Automotive R&D Simulator, motion based and equipped with a large field of view (FOV) HMD, is developed in 1999 in the framework of a European Eureka project, in collaboration between Renault, the French national research organization CNRS, the British SEOS and the Swedish Clarus1 among others.

PERCEPTION OF MOVEMENT

If driving simulation and VR are using the same technics they share the same or similar difficulties in rendering movements of the observer in the virtual environments, at low speed in CAVEs and at higher speeds in driving simulators The worst case is when the observer/driver is turning while driving or moving using a control device (ex. Joystick) in a CAVE or in a static driving simulator. This is due to the visuo-vestibular conflict, due to the discrepancies perceived by the human visual and vestibular systems induce the so-called simulation sickness [START_REF] Kennedy | Use of a motion history questionnaire to predict simulator sickness[END_REF] as the observer/driver may see rotations not perceived by the inner ears.

Another cause is the transport delay, the delay between the action and the corresponding rendering cues.

This transport delay depends on the acquisition of observer/driver actions and movements (especially head movements), image frequency rate and motion rendering and may create strong perceptual discrepancies [START_REF] Berthoz | The Brain's Sense of Movement[END_REF]. When observing an image computed in function of head movements, small delays may induce nausea as the Vestibular Ocular Reflex (VOR), which is responsible of eye fixations, is very quick, about 20ms [START_REF] Kemeny | Recent developments in visuo-vestibular restitution of selfmotion in driving simulation[END_REF].

When driving, these effects may be smaller than for passengers or passive observers as the efferent copies of information given by steering wheel, pedals or other control devices help the driver to anticipate the movement [START_REF] Dagdelen | Analysis of the visual compensation in the Renault driving Simulator[END_REF].

To avoid simulation sickness transport delay should be limited to 50 ms in driving simulation [START_REF] Allen | Driving simulation, mechanization and application[END_REF], 20 ms using HMDs and CAVEs or head slaved or HMD based driving simulators because of the rapidity of the VOR reflex.

Other factors may play a role, as expectations based on previous experiences [START_REF] Reason | Motion Sickness[END_REF] or any other physiological parameters which influences postural stability. One way to deal with simulation sickness is to provide an acceptable face value of motion, for example by reducing sensory conflicts generating generic proprioceptive cues. For driving simulator experiments where rendering vehicle behavior is essential nevertheless high fidelity motion restitution is necessary and a scale 1 simulation of acceleration may be needed [START_REF] Zeeb | Daimler's New Full-Scale, High-dynamic Driving Simulator -A Technical Overview[END_REF].

PERCEPTION OF DISTANCE, SPEED AND ACCELERATION AT SCALE 1:1

Absolute validity of driver simulation is not always required as often, for human factors studies; only the comparison of the studied man-machine interface or traffic situation is needed, requiring only relative validity of the simulated driver-vehicle situations [START_REF] Kemeny | Driving simulation for virtual testing and perception studies[END_REF]. Correct perception of speed and acceleration in driving simulation is crucial for automotive experiments for Advances Driver Aid System (ADAS) experiments as vehicle behavior has to be simulated correctly and anywhere where the correct mental workload is an issue as real immersion and driver attention is depending on it [START_REF] Barthou | Driver trust and reliance on a navigation system: effect of graphical display[END_REF].

Speed perception is depending on the visual field of view, in part because of the role of peripheral field of view in motion perception by the human visual system and partly because of the corresponding generated immersion level and probably on other parameters, such as steering wheel force feedback and overall CGI quality [START_REF] Panerai | Speed and safety distance control in truck driving:comparison of simulation and real-world environment[END_REF]. The correct perception of accelerations requires the use of motion platform [START_REF] Siegler | Sensorimotor integration in a driving simulator: contributions of motion cueing in elementary driving tasks[END_REF], which makes driving in a CAVE difficult, especially with rear projection floor, allowing only limited payload.

Correct perception of distances and object size is also crucial using HMDs or CAVEs (Figure 2), especially as their use is frequently involving digital mockup validation for design, architecture or interior and exterior lighting. Early VR validation studies showed already differences in distance and scale 1:1 perception between VR and real life conditions [START_REF] Loomis | Visual perception of egocentric distance in real and virtual environments[END_REF].

One of the most important visual depth cues is motion parallax and its role was shown real, virtual environments [START_REF] Rogers | Motion parallax as an independent cue for depth perception[END_REF], [START_REF] Panerai | Contribution of extraretinal signals to the scaling of object distance during self motion[END_REF], [START_REF] Kemeny | Evaluating perception in driving simulation experiments[END_REF].

Nevertheless, the precise role of binocular convergence [START_REF] Paillé | Stereoscopic Stimuli are not used in Absolute Distance Evaluation to Proximal Objects in Multi-Cue Virtual Environment[END_REF], [START_REF] Kemeny | Perception of Size in Vehicle Architecture Studies[END_REF] and cognitive factors [START_REF] Glennerster | Humans ignore motion and stereo cues in favor of a fictional stable world[END_REF] are still to be further clarified both for scale 1:1 and distance perception.

APPLICATIONS

In the early years of driving simulation, most of the use-cases were concerning human factors [START_REF] Stein | Applications of Low-Cost Driving Simulation[END_REF] and driver training [START_REF] Flippo | Trust, the truck simulator for training[END_REF], though already ADAS simulation experiments were also carried out for preliminary engineering design [START_REF] Bernasch | The BMW driving simulator used for the development of a driver-biased Adaptive Cruise Control[END_REF]. Nevertheless an effective use for man-machine interface design was limited by the display system resolution, mostly limited to 2,5 to 3,0 arc min resolution [START_REF] Jamson | Driving Simulation Validity[END_REF] and even less, about 4,0 arc min in CAVEs [START_REF] Brooks | What's real about virtual reality?[END_REF], compared to the human eye approximately 1 arc min resolution [START_REF] Wheeler | High definition cinematography[END_REF].

These limitations in visual spatial resolution limited also the use CAVEs in the automotive area to mostly vehicle architecture (visibility), habitability and virtual mock-up assembly early design studies [START_REF] Voillequin | First steps of Haptics at PSA Peugeot Citroën, Special session of industrial applications of force feed-back[END_REF]. As in a CAVE motion is limited, applications are more oriented to interactions with the interior and exterior of a car. Limitations in visual and haptic resolution made until recently the HMDs as an acceptable alternative [START_REF] Kemeny | Perception of Size in Vehicle Architecture Studies[END_REF].

Today, the advents of high resolution 4K digital display technology allows near eye resolution stereoscopic 3D walls and integrate them in high performance CAVEs. High performance CAVEs now can be used for vehicle ergonomics, styling, interior lighting and perceived quality [START_REF] George | Nomad devices for interactions in immersive virtual environments[END_REF].

Figure 3. Renault's 70 M 3D pixels 5 -sided high performance CAVE™

One of the new application domains for both driving simulators and CAVEs, including CAVE like display system equipped driving simulators (Renault has recently invested in the upgrade of its motion based CARDS driving simulator with CAVE like display system with approximately 2 arc min resolution) is Augmented Reality (AR) vehicle equipment. Early design experimentations have already been carried out in the 1990s [START_REF] Kemeny | Cooperative Driving[END_REF], [START_REF] Servignat | The role of a driving simulator in an ergonomics evaluation procedure: the case of an on-board aid system[END_REF] for Head Up Display (HUD) systems. Extended HUD and AR systems now can be experimented in driving simulator and CAVE experiments.

Figure 4. Virtual view of Guyancourt, rendered with OpenSD2S

Convergence between driving simulation and VR technologies can also be observed in the recent evolution of driving simulation software (SCANeR © Studio, OpenSD2S) which integrate now virtual cockpit and stereoscopic view [START_REF] George | OpenSD2S: New features and perspectives for an Open-Source Driving Simulation software[END_REF] as well as of high end visualization software tools (DeltaGen from RTT Dassault Systems) which integrates a real driving module with IPG's Carmaker vehicle dynamics solution. Along with those applications high quality finger tracking technics shall also be integrated for complete virtual immersion both for driving simulation and virtual reality systems [START_REF] Gosselin | Design of a wearable haptic interface for precise finger interactions in large virtual environments[END_REF]. A number of CAVEs are already equipped with a removable driver stations for ergonomics or vehicle architecture applications in ecological driving situations (Figure 5.).

CONCLUSION

Driving simulation from the very beginning of the advent of VR technology uses the very same technology for visualization and more and more for tracking and high end 3D vision. The separation between driving simulation and digital mockup design review is fading even if different uses will require different simulation configurations. New application domains, such as automotive AR design, will bring combined features of VR and driving simulation technics.

From

Figure 1 .

 1 Figure 1. HMD equipped motion based simulator prototyping, CARDS © Renault

Figure 2 .

 2 Figure 2. Digital Mockup Design Review validity evaluation

Figure 5 .

 5 Figure 5. Renault's high performance CAVE™ with driver station

Clarus was founded by Dan Lejerskar and Stefan Hallin in 1977 in Goteborg, Sweden. Stefan Hallin was the CEO of Clarus, later CEO of Opticore. Dan Lejerskar was CEO of Prosolvia AB and founded EON Reality in Irvine, CA, based on Clarus EON ™ software, trademark of Prosolvia AB. Eon Reality announced on December 10,

EON Reality to establish subsidiary and open an edutainment and training hub in Laval, France. Stefan Hallin was previously head of VR group at Volvo and has built the first HMD based driving simulator in Sweden in the mid-1990s.


Yudi Nugraha Bahar
email: yudi.nugraha-bahar@ensam.eu

Christian Pere
email: christian.pere@ensam.eu

Jérémie Landrieu
email: jeremie.landrieu@ensam.eu

Christophe Nicolle
email: cnicolle@u-bourgogne.fr

A Thermal Simulation Tool for Building and Its Interoperability through the Building Information Modeling (BIM) Platform

Keywords: thermal simulation, BIM, interoperability, integration review

This paper describes potential challenges and opportunities for using thermal simulation tools to optimize building performance. After reviewing current trends in thermal simulation, it outlines major criteria for the evaluation of building thermal simulation tools based on specifications and capabilities in interoperability. Details are discussed including workflow of data exchange of multiple thermal analyses such as the BIM-based application. The present analysis focuses on selected thermal simulation tools that provide functionalities to exchange data with other tools in order to obtain a picture of its basic work principles and to identify selection criteria for generic thermal tools in BIM. Significances and barriers to integration design with BIM and building thermal simulation tools are also discussed.

Introduction

Thermal simulation tools are being used increasingly by all professions involved in the design of buildings. As building analysis software becomes more sophisticated, integrated, and easier to use, we are faced with the opportunity and the necessity to better our understanding of building performance in particular in terms of energy optimization.

Recognizing the implications of design decisions made by the different team members on the energy and environmental performance of the building engages all design team members in performing simulations. As a consequence, simulation tools have become recognized as design support tools within the Architecture-Engineering-Construction (AEC) industry [START_REF] Attia | Building Performance Simulation Tools: Selection Criteria and User Survey[END_REF].

From an AEC perspective, an advanced analysis of building thermal simulation in building modeling programs has become a critical part of high-performance buildings. The conceptual design phase of thermal modeling is used to provide the designer with first order of magnitude feedback about the impact of various building configurations on annual thermal performance [START_REF]Statsbygg and Senate, Information Delivery Manual (IDM) for BIM Based Energy Analysis as Part of the Concept Design BIM[END_REF].

Building thermal simulation is the dynamic analysis of the energy performance of buildings using computer modeling and simulation techniques. In this simulation, a calculation of building thermal loads and thermal consumption are involved in determining the thermal characteristics of the building and its building systems. Building thermal simulation is a powerful method for studying the thermal performance of buildings and to evaluate architectural design. Complex design problems can be investigated and their performance can be quantified and evaluated.

The thermal tool landscape for all building design professionals is diverse, ranging from research software to commercial products with thousands of users. They vary in their thermodynamic models, graphical user interfaces, purpose of use, life-cycle applicability, and ability to exchange data with other software applications. The fact that thermal simulation has become an integrated element of the design process has resulted in a diverse and growing user uptake, addressing the whole design team. On the other hand, due to the increasing importance of the decisions made early in the design process and their impact on energy performance and cost, several thermal simulation tools have been developed to perform early energy analysis independently.

With the development of building thermal tools incorporating local weather data and provision of local building materials, construction and codes, the number of tools users is growing enormously. Currently, there are more than 400 applications that can be applied to analyzing building energy and thermal simulation [START_REF]Building Energy Software Tools Directory[END_REF]. They are operated based on the manufacturers' instruction, spread all over the world and have their own standards. These various software applications need to be studied to determine which of them has performed a strong analysis of sustainable design as well as which provides a foundation for interoperability.

Today's emphasis on high-performance buildings makes it important to leverage BIM-based thermal analyses during design [START_REF] Welle | A Methodology for automated BIM-based multidisciplinary thermal simulation for use in optimization environments[END_REF]. BIM technology involves the creation and use of coordinated, consistent information about a building. It allows for better decision-making, documentation and accurate prediction of building performance. Direct links between BIM and non-BIM modeling tools are an important ramification of BIM technology, enabling the creation of deliverables that have an explicit relationship to each other, resulting in a better coordinated and seamless data exchange that saves time, resources, effort and assures quality based liability and reduces risk [START_REF] Attia | Building Performance Simulation Tools: Selection Criteria and User Survey[END_REF].

Reviewing and comparing tools in this paper will allow identification of the data exchange among the commonly used building thermal tools according to the selection criteria as regards their interoperability through the BIM platform. The following covers most of the tools widely known in thermal simulation, which have been selected based on their popularity within the AEC community.

Thermal Simulation Software and the BIM Platform

Overview of Building Thermal Simulation Tools

Building thermal simulation tools predict the thermal performance of a given building and the thermal comfort of its occupants. In general, they support the understanding of how a given building operates according to certain criteria and enable comparisons of different design alternatives [START_REF] Maile | Building Energy Performance Simulation Tools-A Life-Cycle and Interoperable Perspective[END_REF].

Evaluation of thermal comfort involves assessment of at least six factors: human activity levels, thermal resistance of clothing, air temperature, mean radiant temperature, air velocity and vapor pressure in ambient air [START_REF] Fanger | Thermal Comfort, Analysis and Applications in Environmental Engineering[END_REF].

Based on the evaluation in this study of various tools, some information required for thermal simulation includes as input data such as: building geometry, including the layout and configuration of the space (surfaces and volumes), grouping of rooms in thermally homogenous zones, building orientation, building construction, including the thermal properties of all construction elements, building usage including functional use, internal loads and schedules for lighting, occupants, and equipment, heating, ventilating, and air conditioning (HVAC) system type and operating characteristics, space conditioning requirements, utility rates, and weather data.

It is not easy to measure or to elaborate all of those values at a particular location in a building to create thermal comfort. Manual calculation of those values at every point within a building is almost impossible. One way to analyze thermal performance in buildings is by using thermal simulation programs that are capable of calculating all of those values accurately.

The accuracy of a thermal simulation result is determined by the input data. This input data mainly consists of the building geometry, internal loads, HVAC systems and components, weather data, operating strategies and schedules, and simulation specific parameters (Figure 1).

Results

Most thermal simulation programs consist of what is referred to as an engine, which enables detailed thermal simulations based on simple text-based input and output files. These engines contain mathematical and thermodynamic algorithms that are used to calculate the thermal performance according to the underlying model of the engine. The simulation engine uses an input file (or files) of a defined format that contains a representation of the input. Based on this input the engine performs a simulation and writes its output into one or more output files [START_REF] Maile | Building Energy Performance Simulation Tools-A Life-Cycle and Interoperable Perspective[END_REF]. These engines are mainly used to support the design process of a building by comparing energy consumption of different design alternatives.

Data come from internal and external parts of the building. The external loads, for example, are strongly influenced by weather and climate; collected and statistically assembled weather data are thus used in energy performance simulation. Weather data files are being created for design purposes in an increasing number of cities and regions around the world. These weather files do not reflect a specific year, but provide a statistical reference for the typical weather parameters of a specific location. During commissioning and operation, weather information can sometimes be measured directly at the building in question or at weather stations that are located close by. Internal loads such as loads from people, lights and equipment in a space depend greatly on the actual usage of the space and the behavior of its occupants. Figure 2 shows the grand picture of the thermal model production. The output results may include:

• Assessment of the space and building thermal performance for compliance with regulations and targets;

• Overall estimate of the energy used by the space and for the building and an overall estimate of the energy cost;

• Time-based simulation of the energy use of the building and time-based estimate of utility costs;

• Lifecycle estimate of the energy use and cost for the building.

Various thermal simulation tools are used to support almost all AEC design and management tasks, and the information entered into all of these tools describes the same physical project. However, this information is passed from one tool to the next by producing paper-based or electronic documents which can only be interpreted by people, who must re-enter relevant information into the next computer tool. This is because many thermal calculations and simulation software programs are part of the system of building energy performance and they generally receive geometry data from the design tool.

In addition, thermal simulation software sometimes does not present the overall results geometrically, but rather the forms of scale, charts or other notation codes. This format is sometimes not readable or hard to interpret by other software, which again creates more obstacles in the process of data exchange. This indicates that such tools are generally created as a multipurpose product or as a stand-alone tool and work independently. These kinds of applications store the building information in a native and proprietary format. In order to make this valuable information available to other project participants, these software applications must be able to understand the native formats of the other applications.

Interoperability through BIM Platform

Interoperability refers to the ability of two separate systems or software programs to communicate and exchange data with each other. The advantage that seamless data transfer offers is that this will remove redundancy and duplicate data generation, in analytical models and ensure the incorporation of sustainable features, at an early design stage [START_REF] Kumar | Interoperability between Building Information Models (BIM) and Energy Analysis Programs[END_REF]. Interoperability is one of the major themes of research and development in information technology for architecture, engineering, construction, and facilities management (AEC/FM) industries.

Interoperability-the possibility for information to flow from one computer application to the next throughout the lifecycle of a project-relies on the development and use of common information structures throughout the AEC/FM industry [START_REF] Froese | Future directions for IFC-based interoperability[END_REF]. Exchanging models and other data between different software platforms remains one of the industry's biggest challenges on the way to fully integrated and collaborative project teams.

A survey of building performance tools by Attia [START_REF] Attia | Building Performance Simulation Tools: Selection Criteria and User Survey[END_REF] describes the major difference between the needs and priorities of architects and engineers concerning the interoperability of the building model. Architects exchange models with 3D drawing packages and the exchange of models with CAD programs. On the other hand, engineers defined the ability to exchange models with MEP drawing packages and the ability to exchange models for multiple simulation domains.

In a typical construction project, the basic structure organization of the team includes client, project manager, architect, civil engineer, structural engineer, mechanical engineer and electrical engineer. It is now possible for them to work together within the model in an improved coordination and organization. This interaction depends on multi party tools to success. The method is called Integrated Design Process (IDP). The IDP's purpose is to utilize a collaborative team effort to prepare design and construction documents that result in an optimized project system solution [START_REF] Rossi | The Integrated Design Process on Paper and in Practice: A Case Study[END_REF][START_REF] Stamp | The Integrated Design Process and Integrated Project Delivery[END_REF]. As building codes are updated to take building performance into account, there is an increasing obligation on the part of designer to provide higher degrees of insight regarding building outcomes. The design team needs to define technology standards to encourage opportunities for increased project and data flexibility.

BIM has the real role in the IDP. BIM and web-based project management software has created a solid platform for an improved, more efficient means of collaboration between all the parties involved in project delivery.

BIM is a shared digital representation of the physical and functional characteristics of a facility founded on open standards for interoperability; a shared knowledge resource for information about a facility forming a reliable basis for decisions during its life-cycle from inception onward, a basic premise is the collaboration between different stakeholders at different phases of the life cycle of a facility to insert, extract, update or modify information in the process to support and reflect the roles of that stakeholder [START_REF] Buildingsmart | [END_REF].

BIM is a data-rich, object-based, intelligent digital representation of a facility which includes not only 3D geometric models (which, therefore, are capable of directly generating 2D and 3D drawings), but also specific information on a wide range of building elements and systems associated with a building (e.g., wall constructions, material properties, spaces and thermal zones, heating, ventilating, and air conditioning (HVAC) systems, geospatial information, space loads, etc.). This information can be used for other building analysis purposes [START_REF] Haymaker | An Integrated Conceptual Design Process for Energy, Thermal Comfort, and Daylighting[END_REF]. In most cases, only the mechanical engineer or modeling engineer completes energy simulations. To achieve a comprehensive thermal building, this organizational structure requires excellent communication between groups, particularly at the initial design stages. However, with the BIM concept, communication and data exchange among all parties can reach a high degree in particular, redundant building data can be significantly reduced by using BIM [START_REF] Narowski | Modeling of Conduction Transfer Functions for Typical Thermal Bridges Identified in BIM Data[END_REF].

The use of BIM as a central repository for the building project information has revolutionized information for project management. The AEC industry is constantly looking for new ways to improve collaboration and interoperability of BIM platforms through new technology and open-standards programs to be able to more readily share information among the various design and simulation platforms that are available on the market today.

A model-based approach to interoperability requires information structures that are standardized throughout the industry (Figure 3). Significant progress has been made in this common data exchange, particularly in multi-platform interoperability. Currently, the Industry Foundation Class (IFC) and Green Building XML (gbXML) are two prevalent informational infrastructures in the AEC industry. IFC and gbXML are both used for common data exchange between AEC applications such as CAD and building simulation tools [START_REF] Dong | A Comparative Study of the IFC and gbXML Informational Infrastructures for Data Exchange in Computational Design Support Environments[END_REF][START_REF] Dennis | Using BIM in HVAC design[END_REF]. Both IFC and XML create a common language to transfer BIM information between different BIM and building analyses applications while maintaining the meaning of different pieces of information in the transfer. This reduces the need to remodel the same building in each different application. It also adds transparency to the process [START_REF] Haymaker | An Integrated Conceptual Design Process for Energy, Thermal Comfort, and Daylighting[END_REF].

IFC represents a data schema for sharing construction and facility management data across various applications used in the AEC/FM industry domain. It is an object-oriented data schema based on class definitions representing the objects (such as building elements, spaces, properties, shapes, etc.) that are used by different software applications in the construction or facility management project. IFC has variant data file formats that facilitate exchange between applications, e.g., .ifc, which is the default IFC exchange format, .ifcXML, IFC data file using the XML document structure, and .ifcZIP, IFC data file using the PKzip 2.04 g compression algorithm [START_REF] Buildingsmart | [END_REF].

The AEC Industry has yielded the proprietary development of energy export and import capabilities in several major engineering modeling tools. A number of these involve the use of gbXML. With the development of integration modules inside major engineering analysis tools, gbXML has become the defacto industry standard schema [START_REF] Gbxml | Open Green Building XML[END_REF]. GbXML is based on the XML (Extensible Markup Language) deployed by Green Building Studio Inc. It has the ability to carry building environmental sensing information. It also has a global "language" format, with consistent syntax and can potentially represent any computational building model through translation using appropriate mapping engines.

In terms of geometry, the generic approach of IFC has the ability to represent any shape of building geometry, while gbXML only accept the rectangular shape. CAD-magazine has claimed that the IFC format is very powerful but rather few thermal simulation tools use it. They prefer the gbXML due to its capacity to provide a satisfactory answer [START_REF]CAD-magazine and btpinformatic.fr. De la conception numérique au PLM, Architecture: Les Défies des Nouvelles Réglementations Environnementales[END_REF].

IFC uses a "top-down" and relational approach, which yields a relatively complex data representation schema and a large data file size. Conversely, gbXML adopts a "bottom-up" approach, which is flexible, open source, and a relatively straight forward data schema. The "top-down" approach can trace back all the semantic changes when one value of the element in the schema is changed [START_REF] Dong | A Comparative Study of the IFC and gbXML Informational Infrastructures for Data Exchange in Computational Design Support Environments[END_REF].

The technology for exchanging information using IFC has now been established, but many areas require additional development before comprehensive interoperability solutions are reached. These areas include: extending the scope to include a broader range of project information, for more types of projects, and more types of information; developing the exchange mechanisms layer below the data standards and the formalized transactions layer above; developing the range of software applications that implement model-based interoperability; and re-examining project management practices based on new integration technologies [START_REF] Froese | Future directions for IFC-based interoperability[END_REF].

Thermal Simulation Tools and Their Interoperability

A multiplatform concept is a fundamental criterion for assessing thermal tools because it allows multidisciplinary storing of information with one virtual representation. The reliability of data exchange and the straightforward nature of the tool, as well as user-friendly interfaces are major aspects of the practical use of thermal tools. The success of interoperability is limited to the detailed design phase because it ensures access for the design team to building thermal model, only after the whole building design has been completed. The huge amount of input data, the availability of rich 3D geometry models, effective data exchange and software interfaces are crucial to enable faster and more reliable thermal performance simulation analysis.

With the increasing complexity of the geometry of buildings, the simulation tool requires an appropriate geometric model. For the comparison of simulated results with measured data, the simulation tool requires an integrated simulation. This means that it requires the feedback from the HVAC system response to the space or zone [START_REF] Maile | Building Energy Performance Simulation Tools-A Life-Cycle and Interoperable Perspective[END_REF]. Thermal zones are an agglomeration of one or more spaces with similar thermal characteristics such as orientation, size, HVAC system type, and internal loads.

The IFC provides the data concerning the semantics and syntax of construction elements; a comprehensive set covering tangibles and abstract entities such as windows, doors, walls, spaces, furnishing elements, etc. [START_REF] Cormier | Towards a BIM-Based Service Oriented Platform: Application to Building Energy Performance Simulation[END_REF]. Thermal characteristic is another kind of IFC product. It is included in a sub division in another concept of basic class for physical objects, along with spatial elements, physical elements, structural analysis items, and other concepts which are associated with materials, shape representations, and placement in space.

IFC and gbXML formats for thermal analysis can read as some distribution elements (HVAC, electricity, plumbing) which are organized according to the concept of ports, where elements may have specific connections for various services in the building, and be connected together to form a system. Since it is possible to write IFC and interfaces to HVAC design and simulation tools and cost estimation tools, it is possible to import building geometry data from design tools, which allows the exchange of thermal data (HVAC data), and performance specification, construction properties, and geometry.

Figure 4 illustrates the workflow that defines the area input of BIM in the thermal simulation process. The first step is to define the location of the building that provides a link to weather data. The second step will ideally provide information through importing data from a BIM. This information includes the needed 3D geometry information, construction and material definitions, and space types that are typically defined by the architect. A simplification of geometry might need to comply with the geometry definition of the relevant thermal performance simulation tool. Based on these geometry definitions, the user interface would be able to aggregate spaces into zones (as well as subdivide spaces into zones). A "thermal zone" which may cover one or more rooms, is an important basic structure for thermal simulation. In this process, the data will bind into an appropriate zone by the IFC or gbXML format, for example. In the next step, space loads (such as lighting loads) could be assigned to the specific appropriate space types that have been imported via the BIM link. However, this workflow might not immediately smooth management interoperability. The experiences of many BIM based projects show that interoperable thermal analysis software is not enough for the management of thermal performance during the building process, but also requires tools to manage different revisions of BIMs, to compare thermal performance of these revisions and to visualize this in an easy-to-understand way [START_REF] Laine | Benefits of BIM in the Thermal Performance Management[END_REF].

An advanced interoperability method was developed by Welle et al. [START_REF] Welle | A Methodology for automated BIM-based multidisciplinary thermal simulation for use in optimization environments[END_REF], with ThermalOpt. ThermalOpt is a methodology for automated BIM-based multidisciplinary thermal simulation that attempts to mitigate several technical barriers to BIM-based multidisciplinary thermal simulation encountered in practice today. In this method, the user can start the process by building a parametric BIM model and assigning analysis information using the BIM Application GUI (Digital Project) and the Analysis Application GUI (ThermalSim Plugin). When the user initializes the trade study, in this case an optimization, the BIM information is passed via IFC (DP Plugin) to a middleware (IFC2ThermalSim Plugin) for pre-processing, then to an energy simulation environment (EnergyPlus Wrapper) and a day lighting simulation environment (Radiance Wrapper) for analysis.

Figure 4.

An ideal workflow for energy performance in thermal simulation tools [START_REF] Maile | Building Energy Performance Simulation Tools-A Life-Cycle and Interoperable Perspective[END_REF].

ThermalOpt enables an automated methodology to pre-process, configure, execute, and post-process a BIM-based multidisciplinary thermal simulation process that may be used during early design. This method is capable of significantly reducing the time to pre-process, configure, execute, and post-process this design task while improving its consistency over conventional methods [START_REF] Welle | A Methodology for automated BIM-based multidisciplinary thermal simulation for use in optimization environments[END_REF].

Interoperability Review of the Most Applicable Building Thermal Simulation Tools in the AEC Community

There exist today a large number of simulation tools as BIM applications concerning thermal simulation in buildings. Crawley et al. [START_REF] Crawley | Contrasting the capabilities of building energy performance simulation programs[END_REF] have detailed the functionality and differences of 20 major building simulation tools. Attia [START_REF] Attia | Building Performance Simulation Tools: Selection Criteria and User Survey[END_REF] described eight building performance simulation tools according to selection criteria and user surveys. Dubois et al. [START_REF] Dubois | State-of-the-Art of Digital Tools Used by Architects for Solar Design[END_REF] reviewed the existing computer tools widely used by architects today, covering a total of 56 computer programs which were classified into three categories: CAAD (computer-aided architectural design) tools, Visualization tools, and simulation tools. Based on these reports, as well as on the analysis of recent trends in thermal tools, this report reviewed certain selected tools that are most applicable to the BIM application. The present review focuses on tools that can be used at multiple stages of the life-cycle and that provide functionalities to exchange data with other tools in open standard building information models, in this case IFC and gbXML.

Geometry Constructions and materials

Space types

Assignment of spaces to thermal zones

Location (Climate)

HVAC system and components

Space loads

Weather file

Simulation

BIM

Constructions and materials

Thus, the goals of the review are to draw a picture of the principles of data exchange in thermal simulation software and to compare the interoperability challenges and opportunities of using selected thermal tools and building performance simulation tools that integrate thermal analysis.

All data for the identification of the tools have been gathered and shortlisted in the chart below. The tools listed were selected as those most applicable by professional users in the AEC community (whether they focus on the BIM platform or not). These applications are DPV (Design Performance Viewer), Design Builder, Ecotect, EnergyPlus, eQUEST, EcoDesigner, ESP-r, Green Building Studio, Lesosai, IDA ICE, IES VE, TRACE700, TRNSYS and Riuska.

They have also been tested on their reliability according to the basic principal of thermal simulation and data exchange. The test is to illustrate interchanged between BIM design and thermal tools. The websites of each program were visited and a database with key information was selectively built and enriched by journal updates. In addition, scientific articles about the selected programs were consulted when necessary. As a thermal simulation tool is used within a design process that involves other software (e.g. CAD, spreadsheets, presentation, etc.) the assessment of the compatibility and interoperability of each tool focuses on typical software used in the industry (Table 1). This review indicates that there are many energy simulation tools that are used particularly for thermal calculation. In some cases, thermal tools are not stand-alone, but integrated into or as a part of design software. Among these thermal tools, the link with BIM applications is the most interesting possibility in terms of interoperability for energy simulations. These applications are DPV, Design Builder, Ecotect, EnergyPlus, eQUEST, EcoDesigner, Green Building Studio, IDA ICE, IES VE, and Riuska.

• The Design Performance Viewer (DPV) is an ongoing research project begun in 2007, conducted at the Institute of Technology in Architecture (ITA) at the Department of Architecture at the ETH Zurich [START_REF]Design Performance[END_REF]. The DPV enables instantaneous energy and CO 2 emission calculations and the graphical visualization of the resulting performance indices of a building design focused not only on form and geometry, but also viewed in an integrated way. Relevant energy data is calculated and visualized in real time. The user can immediately see how measures concerning building geometry, construction and technical systems affect energy and exergy consumption as well as costs. DPV is directly linked to the library of the CAD-BIM environment. To deliver immediate performance feedback, the DPV is integrated into the BIM-modeling environment (Autodesk Revit).

• DesignBuilder has been specifically developed around EnergyPlus [START_REF] Designbuilder | [END_REF], allowing input of all of the EnergyPlus fabric and glazing data. As an interface to EnergyPlus, it builds models for energy simulation using EnergyPlus. DesignBuilder allows compliance with energy certificates in UK, alternatives comparison and parametric analysis of different design parameters. It provides a wide range of environmental performance simulations in a 3D interface, also performing daylight analysis. Design Builder allows import of 3D architectural models created in Revit, ArchiCAD or MicroStation and other 3D CAD systems supporting .gbXML, and dxf data exchange.

• Ecotect was developed by Dr. Andrew Marsh and Square One Research Ltd. that was acquired by Autodesk. Ecotect analysis offers a wide range of simulation and building energy analysis functionalities to visualize and simulate a building's performance within the context of its environment [START_REF]Ecotect Analysis, Sustainable Building Design Software[END_REF]. The new Ecotect Analysis includes an expanded array of environmental analysis and simulation capabilities including shadows and reflections, shading design, solar analysis, photovoltaic array sizing and load matching, lighting design, right-to-light analysis for neighboring buildings, acoustic analysis, thermal analysis, and ventilation and airflow [START_REF]Thermal: Analysis Methods[END_REF]. Ecotect has added the support for IFC and gbXML schemas since the release of the newest version 5.6. Ecotect can perform more applications: daylight analysis, sound analysis and more visualization. It can import CAD-BIM models from most CAD software; Revit, AutoCad, ArchiCad and 3DsMax.

Ecotect can export to a wide range of other programs and CAD formats. Export is supported to Radiance (ray-traced rendering), POV-Ray and .wrl, .dxf (compatible with most CAD software), GBS, EnergyPlus and eQUEST. • eQUEST was developed by James J. Hirsch & Associates in collaboration with Lawrence Berkeley National Laboratory, with LBNL DOE-2 [START_REF] Hirsch | collaboration with Lawrence Berkeley National Laboratory[END_REF]. eQUEST is based on DOE-2 dynamic energy simulation software and calculates heating and cooling loads during a year based on a data-entry building description. eQUEST has the ability to import .dwg files. It is also possible to export analysis results in Excel (.xls) format. eQUEST can import building geometry via gbXML but it is not as generic as the IFC format.

• EcoDesigner is bound up with archiCAD. EcoDesigner integrates the VIP web engine directly into ArchiCAD's program core, but is configured to act as a design aid rather than a simulation tool. Although not as comprehensive as Ecotect, EcoDesigner provides ArchiCAD users with basic energy-and carbon-checking functions. EcoDesigner, EnergyPlus, Green Building Studio and Ecotect can link with ArchiCAD BIM.

• Green Building Studio (GBS) is a web-based energy analysis service supplied by Autodesk [START_REF]Autodesk-Autodesk Green Building Studio[END_REF].

GBS is an analysis tool, which performs whole building energy analysis but does not provide a 3D interface. • RIUSKA was developed by Granlund. The core of the software is the widely used DOE 2.1E simulation program [START_REF]RIUSKA-Energy Simulation Tool for the Entire Building Life Cycle[END_REF]. It calculates indoor temperatures, occupancy, lighting, equipment gains, and the heating and cooling of individual spaces, and can be used to compare and dimension HVAC systems as well as to calculate the energy consumption of whole buildings. Riuska allows the direct transfer and reuse of digital building geometry data from IFC-compliant architectural software (Autodesk Revit, ArchiCAD, Nemetschek`s Allplan and Visio). RIUSKA can also export main spatial thermal parameters to IFC to be used in other applications, such as building services system modeling or requirement management tools.

(Limitation: This test and review covers most of the tools widely known and used by the AEC community. However, a comprehensive review of all available tools world-wide is nearly impossible due to the amount of information that would need to be collected).

The review has indicated that there are many design or modeling tools commonly used today include some form of algorithm for the prediction of building energy simulations. These include the three CAD software programs widely used by the AEC community: Revit, Archicad, and Sketch-Up. Thus, to obtain thermal simulation results, the thermal analysis proceeds either by the thermal engine that has been integrated into them (in this case the mass model is automatically converted into the energy model) or by transferring it to another thermal engine that is interoperable with BIM models. Fortunately, many manufacturers and third-party vendors are beginning to provide BIM object libraries populated with many of the physical and analytical characteristics needed to perform HVAC analysis. This review has also indicated that when the model is used to perform analysis, either an integrated analytical modeling tool within the BIM software runs the analysis, or the information in the model is exported out of the physical model in a file format that the analytical modeling software accepts. Two of the most common formats are IFC and gbXML (Figure 5).

Revit (Architecture and MEP) is a tool supplied by Autodesk, purposely built for BIM. Green Building Studio and Ecotect are integrated with Revit, now known as Project Vasari. Revit links with DPV (Design Performance Viewer), Design Builder, EnergyPlus, eQUEST, ESP-r, Lesosai, TRNSYS, IDA ICE, IES VE, TRACE700 and Riuska. makes it easy to create and edit building geometry in EnergyPlus input files. It allows the launching of EnergyPlus simulations and visualization of the results without leaving SketchUp. This plugin performs energy analysis on a SketchUp design by adding attributes to the geometry and then connecting it to Green Building Studio's web service, or other analysis applications that import .gbXML. With the plugin, SketchUp is able to both import and export .gbXML files.

Conclusions

Interoperability through the BIM platform offers one solution to the problem of integration. It reduces the time needed to develop a building and also assures that when the building is put into operation it will meet the design intent. IFCs and gbXMLs seems to be very promising standards that facilitate data interoperability, particularly for building thermal performance tools.

The IFC adopts a standard data model approach to providing interoperability. A different solution to providing integration is that of integrated systems, which can be defined as multipurpose tools that combine many different views (both data and functionality). In addition, gbXML is a schema developed to facilitate a common interoperability model integrating a myriad of design and development tools used in the building industry. GbXML is currently integrated into a range of CAD software and engineering tools.

The gbXML format provides functionality to exchange simplified building geometry and some limited HVAC information, but needs to be extended to allow data exchange of complete HVAC definitions and schedules. The IFC model intentionally contains more thorough definitions across all disciplines and life-cycle phases. However, for a reliable data exchange these definitions need to be implemented in software applications and thoroughly tested. In particular, the HVAC domain in the IFC model still needs such an implemented definition to provide the foundation for exchange related to HVAC data.

Interoperability between BIM-based design and energy simulation tools can improve the workflow between design deliverables and analysis applications. The challenge that is facing the BIM is to assure utmost interoperability by fluidizing model representation, allowing low and high resolution building models that correspond to all design phases and allow a design team based model. Several technical barriers that BIM-based thermal simulation tools continue to face today are: long analytical model preparation times, missing or invalid data in architectural models and inconsistent conversion of architectural models to thermal models.

Automated transactions between the tools, however, require that the information be improved, so as not to be fragmented in the passage between architectural data and thermal engineering data and to guarantee the tool's workflow. These improvements must be evaluated through a series of interoperability test to ensure consistency between all participants using AEC software.

Interoperability between BIM and energy analysis programs is a developing area and the potential of BIM in terms of energy analysis has not been completely optimized as yet. Until now, BIM software has been especially oriented toward architecture, with such developments as Autodesk Revit, Bentley Architecture, Graphisoft/Bentley ArchiCAD, and Vectorworks have focused primarily on modeling and refining building geometry. For example, to perform an energy analysis especially a more comprehensive, detailed and specialized thermal analysis, users have sometimes relied on stand-alone thermal software that creates its own geometry.

Although the functionality of the popular building thermal tools has progressed significantly in the past few years, much of the potential of their interoperability through BIM remains largely untapped. Further work is needed to determine if the appropriate design information for use in thermal analyses can be captured within a building information model, in particular their highest priority interoperability enhancements for the purposes of sustainable building design.

Figure 1 .

 1 Figure 1. General input data of thermal simulation engines [5].

Figure 2 .

 2 Figure 2. Workflow to produce a thermal simulation model.

Figure 3 .

 3 Interoperability and Architecture-Engineering-Construction (AEC) Practice[START_REF] Sullivan | Current BIM Interoperability Methods; Autodesk Business Development[END_REF].

Figure 5 .

 5 Figure 5. Summary of data exchange between modeling tools and thermal simulation tools. The linkages include those as interface, add-on or plug-in. The data exchange is conducted in various formats, primarily by IFC and gbXML.

Table 1 .

 1 Interoperability of the thermal tools investigated.

	Tool	Application	Input data	Output data	BIM based geometry import
	DPV (Design Performance Viewer)	Environmental design, thermal design and analysis, heating and cooling loads, energy cost, Exergy/CO 2 , life cycle assessment, scheduling.	CAD-BIM, revit	-	The building model is directly built in the CAD-BIM environment.
	DesignBuilder	Environmental design, 3D Model (3D Design), thermal design and analysis, heating and cooling loads, natural and artificial lighting, Internal air, mean radiant and operative temperatures, humidity, CO 2 emissions, solar shading, heat transmission, solar shading, scheduling.		CAD: AutoCAD, Microstation, SketchUp using 3-D dxf, .epw, .csv, .tmy, .tmy2	Provides interoperability with BIM models through its .gbXML import capability.
				Metafiles,
	Ecotect	Environmental design, 3D Model (3D Design), thermal design and analysis, heating and cooling loads, Validation; Solar control, overshadowing, prevailing, winds & air Flow, natural and artificial lighting, life cycle assessment, life cycle statistical acoustic analysis. costing, scheduling, geometric and	.dwg, .ifc,gbXML, .obj, 3DS, .xml, ASCII, etc.	Bitmaps or animations. Mod files, ESP-r, ASCII RADIANCE, POV Ray, VRML, AutoCAD dxf, EnergyPlus,	Imports CAD-BIM models from most CAD software
				XML, etc.
		Energy performance, simulation, energy
		use analysis, conceptual design
		performance analysis, 3D Model (3D
	eQUEST	Design), thermal design and analysis, heating and cooling loads, Solar control,	gbXML, .dwg, dxf	dxf, gbXML, .xls	Support gbXML format
		overshadowing, Lighting system, life
		cycle assessment, life cycle costing,
		Scheduling.

Table 1 .

 1 Cont.

	Tool	Application	Input data	Output data	BIM based geometry import
		Energy Simulation, thermal design and
		analysis, Heating and cooling loads,
	EnergyPlus	Validation; Solar control, Overshadowing, Natural and artificial	ifc, gbXML, text	ASCII	.ifc compatible. (BIM Application)
		lighting, Life cycle assessment, Life
		cycle costing, Scheduling.
		Energy balance evaluation, CO 2 ,			Provides another
	EcoDesigner	overshadowing, heating, cooling, lighting, water use, Life cycle costing, Scheduling, prime energy usage	gbXML	gbXML, .pdf	dimension in the BIM environment for the architect in
		(gas, energy, electricity etc.)			shaping his design
		Environmental Design, 3D Design,
		thermal design and analysis, heating and
		cooling loads, Solar control, lighting,
	ESP-r	natural ventilation, combined heat and electrical power generation and	XML	XML, csv, VRML	no
		photovoltaic facades, acoustic analysis,
		life cycle and environmental impacts
		assessments.
	Green Building Studio	Environmental Design, thermal analysis, annual energy consumption (electric and gas), Carbon emissions, day lighting, water usage and cost, Life cycle costing, natural ventilation.	gbXML-enabled BIM or 3D-CAD	gbXML, VRML	Supports gbXML format and has easy interoperability with BIM Application
	Lesosai	thermal design and analysis, Heating and cooling loads, Solar control, CO 2 , natural and artificial lighting, life cycle assessment, life cycle costing, Scheduling.	gbXML, .nbdm, .skp	.xls, .xml, .pdf, .bld, .txt files	Supports gbXML format and has easy interoperability with BIM Application
		Environmental design, 3D Model (3D
		Design), thermal design and analysis,	.ifc, .dxf,
	IDA ICE	heating and cooling, Solar and shading, surface transmissions, air leakage, cold	.dwf, .3ds, .cgm, .cmx,		.ifc compatible. (BIM Application)
		bridges and furniture, lighting, Air CO 2	.dgn
		and moisture levels, Energy costing.
	IES VE	Thermal design and analysis, heating and cooling loads, CO 2 , Validation; Solar, Shading, Lighting, Airflow, Life cycle costing, Scheduling, fire evacuation.	gbXML, .dxf, .dwg	.ve	Supports gbXML format and has easy interoperability with BIM Application
	TRACE 700	Environmental design, 3D Model (3D Design), thermal design and analysis, heating and cooling, life cycle costing, plants system.	gbXML	.pdf, .rtf, .txt, .doc, .xls	Supports gbXML format and has easy interoperability with BIM Application

Table 1 .

 1 Cont.

	Tool	Application	Input data	Output data	BIM based geometry import
		Environmental design, 3D Model (3D
		Design), thermal design and analysis,		ASCII
	TRNSYS	heating and cooling loads, Solar control, overshadowing, prevailing winds & air	.skp, ASCII, .xml	(Simulation Studio Tool :	no
		Flow, electrical, photovoltaic, hydrogen		HTML, C++)
		systems, Life cycle costing.
		Environmental design, 3D Model,
		thermal design and analysis, heating
	Riuska	and cooling loads, validation; Solar control, overshadowing, lighting,	.ifc	.ifc	.ifc compatible. (BIM Application)
		life cycle assessment, life cycle
		costing, scheduling.

•

  EnergyPlus is an energy analysis and thermal load simulation program. EnergyPlus is a new-generation building energy simulation program based on DOE-2 and BLAST, with numerous added capabilities. Released in April 2001, the program was developed jointly by Lawrence Berkeley National Laboratory, the University of Illinois, the U.S. Army Construction Engineering Research Laboratory, GARD Analytics, Inc., Oklahoma State University and others, with support from the U.S. Department of Energy, Office of Building Technology, State and Community Programs [27]. EnergyPlus has data exchange via IFC, gbXML, and dxf. All CAD programs linked to EnergyPlus through a plugin or export function (ArchiCAD, Google/Trimble SketchUp, MicroStation, Revit, Vectorworks) allow active solar system calculation. EnergyPlus and Green Building Studio can operate or allow performing of thermal simulations from Google/Trimble SketchUp (.skp) and Excel (.xls), the non-BIM application.

  The model has to be created by another software program which can export to the .gbXML format. GBS does not support the .ifc format but provides easy interoperability with BIM tools and other software; it offers a great interoperability with Autodesk Revit, ArchiCad, Ecotect, eQuest, and EnergyPlus. Various file formats are supported, such as .gbXML, VRML, and some weather files. • VE (Virtual Environment) was developed by IES (Integrated Environmental Solutions) in Scotland [32]. It is an integrated system that operates all of its building simulations from a central building model. The software allows the assessment of performance and providing feedback on a building energy consumption and carbon dioxide emission. IES VE supports gbXML and dxf and it can import files from Revit, ArchiCad and as a plug-in of Google SketchUp. Vectorworks BIM software is interoperable with IES VE and Autodesk Ecotect Analysis.

Acknowledgments

This work would not have been possible without the support of many people. The authors wish to express their gratitude to Gunzo Team of ENSAM ParisTech Cluny, for their help, as well as providing the laboratory and necessary information regarding the research.


Germain Lemasson
email: germain.lemasson@univ-ubs.fr

Philippe Lucidarme
email: philippe.lucidarme@univ-angers.fr

Sylvie Pesty
email: sylvie.pesty@imag.fr

Dominique Duhaut
email: dominique.duhaut@univ-ubs.fr

Augmented collar for assistance dog

In this paper we present briefly our reflexion on how to communicate with a dog using embedded devices. We also present the prototype collar we made in order to improve the communication between an assistance dog and his disabled master.

Author Keywords


Marianne Canonico
email: marianne.canonico@inserm.fr

Agnès Fournier

Laure Carcaillon

Valérie Olié

Geneviève Plu-Bureau

Emmanuel Oger

Sylvie Mesrine

Marie-Christine Boutron-Ruault

Françoise Clavel-Chapelon

Pierre-Yves Scarabin

Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

ATVB R2

3/25

Condensed abstract

We assessed the association between hormone therapy and venous thromboembolism among postmenopausal women. Oral but not transdermal estrogens were associated with an increased thrombotic risk. There was no significant association of venous thromboembolism with progesterone, pregnanes and nortestosterone. However, norpregnanes were associated with an increased thrombotic risk.

ATVB R2

4/25

Despite recent data showing that overall health risks may exceed benefits from postmenopausal hormone therapy (HT) [START_REF] Rossouw | Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial[END_REF][START_REF] Anderson | Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial[END_REF] , many women remain eligible for this treatment in order to correct menopausal symptoms [START_REF] Haas | Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results[END_REF]4 . However, harmful effects of HT may include breast cancer and venous thromboembolism [START_REF] Rossouw | Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial[END_REF][START_REF] Cushman | Estrogen plus progestin and risk of venous thrombosis[END_REF][START_REF] Curb | Venous thrombosis and conjugated equine estrogen in women without a uterus[END_REF] . Recent guidelines recommend that women be prescribed the lowest effective dose of HT for the shortest possible duration [START_REF] Pines | IMS updated recommendations on postmenopausal hormone therapy[END_REF][START_REF] Utian | Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society[END_REF] . Since the risk of venous thromboembolism is highest during the first year of treatment [START_REF] Canonico | Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis[END_REF][START_REF] Miller | Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force[END_REF] , pulmonary embolism, which already represented one-third of the potentially fatal events attributable to long-term HT [START_REF] Beral | Evidence from randomised trials on the longterm effects of hormone replacement therapy[END_REF] , has become one of the major side effects of short-term treatments. Reducing thrombotic risk may therefore have important clinical implications in the management of postmenopausal symptoms. Recent observational data have suggested that transdermal estrogens might be safe with respect to thrombotic risk [START_REF] Scarabin | Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk[END_REF][START_REF] Canonico | Hormone therapy and ATVB R2 20/25 venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study[END_REF] but the impact of estrogens by route of administration is not fully established. In addition, data on the role of concomitant progestogens are scarce [START_REF] Canonico | Hormone therapy and ATVB R2 20/25 venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study[END_REF] . Therefore, we investigated the impact of estrogens by route of administration as well as the influence of concomitant progestogens on the risk of idiopathic venous thrombosis in a large cohort of French women.

ATVB R2

5/25

Methods

E3N Study

The E3N (Etude Epidémiologique de femmes de l'Education Nationale) Study is a prospective cohort study initiated in 1990 among 98,995 women born between 1925 and 1950 and insured by a healthcare plan covering mostly teachers. Participants who gave written informed consent completed biennial self-administered questionnaires (sent between 1990 and July 2005) which included items about anthropometric measurements, medical history, menopausal status and a variety of lifestyle habits (e.g. contraceptive use, HT use, alcohol consumption, smoking). Details of the E3N design have been described elsewhere [START_REF] Fournier | Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort[END_REF][START_REF] Fournier | Use of different postmenopausal hormone therapies and risk of histology-and hormone receptor-defined invasive breast cancer[END_REF] .

Ascertainment of venous thromboembolism cases

Non-fatal venous thromboembolism events were initially self-reported by women in the questionnaires. Participants who declared to have had either a thrombosis or a pulmonary embolism were then asked to complete a specific questionnaire and to send medical documentation related to the thrombotic event. In addition, a questionnaire including information on potential predisposing factors for thrombosis and characteristics of the event was sent to the medical doctors reported by the women. In order to be validated, clinical events had to be diagnosed using an imaging procedure. Pulmonary embolism was defined as the presence of either a positive pulmonary angiography or a positive helicoidal computed tomography or a high-probability ventilation/perfusion lung scan. Deep venous thrombosis had to be diagnosed by use of compression ultrasonography or venography. Events were centrally validated by a medical committee blinded to HT use. Cases of fatal ATVB R2 6/25 pulmonary embolism were identified from death certificates from the National Service on Causes of Deaths (Inserm) using International Classification of Diseases (ICD) 9

(codes 4151 and 4539) and ICD-10 (codes I26.0 and I26.9). In the present analysis, the main clinical outcome was a first documented incident episode of pulmonary embolism or lower-extremity deep vein thrombosis having occurred without any of the following predisposing factors, i.e. cancer, surgery, immobilization or trauma.

Among the 98,995 women included in the E3N Study, 2,142 episodes of venous thromboembolism were self-reported during the overall follow-up. Among those, 1,696 non-fatal thrombotic events were further validated and 446 were not considered as venous thromboembolism episode because they were not thrombotic events (n=149) or no information could be obtained (n=297). Superficial vein thrombosis (n=216), upper-extremity thrombosis (n=23), central retinal vein obstruction (n=2), and recurrent events (n=80) were also treated as non events which resulted in a total of 1,375 incident cases of non-fatal deep vein thrombosis or pulmonary embolism. In addition, 68 cases of fatal pulmonary embolism were identified by death certificates. Overall, 1,443 incident thrombotic cases (including 68 deaths) were eligible for inclusion in the present study.

Study sample and follow-up

The present investigation was limited to postmenopausal women. Information on menopausal status was updated at each follow-up questionnaire. Women were considered postmenopausal if they had had 12 consecutive months without menstrual periods (unless due to hysterectomy), had undergone bilateral oophorectomy, had ever used HT, or self-reported that they were postmenopausal. From the full cohort, 12,471 women including 219 cases were excluded because they were not menopausal or had had a thrombotic event before the start of follow-up. Of the remaining 86,524 women, 5,822 were excluded from the analyses due to personal history of cancer other than basal cell carcinoma (n=213 cases including 30 fatal events) or a non-idiopathic thrombotic event (n=329) or an event without information on predisposing factors (n=65 including 38 fatal pulmonary embolisms).

In addition, 68 women with a validated thrombotic event were censored at the date of cancer diagnosis because of a validated cancer predating the thrombotic event.

The final analysis was therefore performed on 80,308 postmenopausal women without personal history of thrombotic events or cancer before the start of follow-up.

The study population included 549 incident events of first documented idiopathic venous thromboembolism (134 pulmonary embolisms and 415 deep vein thromboses).

E3N ATVB R2

8/25

Classification of HT

The 1992 questionnaire inquired about lifetime use of HT. It was accompanied by a booklet and photos of available estrogens and progestogens mailed to all participants. For each treatment episode, women were asked to report information on brand name, age at first use and duration of treatment. Information on HT was updated from each of the subsequent questionnaires.

Women were classified as current users if they had used HT at any time during the 3 months prior to the date of completion of the questionnaire, otherwise they were considered as past users or never users. Current users of HT were classified according to estrogens by route of administration and to the type of concomitant progestogen. Route of estrogen administration included oral, transdermal (patch or gel). Other treatments included tibolone, vaginal treatments, injectable treatments, HT without any information regarding the route of estrogen administration, and estrogens combined with androgens. Most current users of oral and transdermal estrogens received 17-estradiol. Progestogens were categorized according to the progestogen North American Menopause Society (NAMS) classification [START_REF]Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society[END_REF]

Statistical analysis

HT exposure was taken into account as a time-dependent variable. In order to preserve the prospective nature of the study, exposure status declared at the completion of each questionnaire was maintained during the entire interval until completion of the following questionnaire (or until the end of follow-up). Since data on exposure were available from the 1992 questionnaire onward, exposure between 1990 and 1992 was considered as "unknown" for all women. Cox proportional hazards models with age as the time-scale were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for venous thromboembolism associated with HT. The HRs were adjusted for body-mass index (as a continuous variable), parity (total number of stillborn and live births as a continuous variable) education level (six ordered categories as continuous variable) and time-period (before or after 2003 in order to take into account the changes in HT use after the publication of the Women's Health Initiative trial results). These potential confounders were chosen because they have been related to thrombotic risk (e.g., body-mass index and parity [START_REF] Simon | Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism[END_REF] ) or because they have been linked to HT exposure and might have an impact on thrombotic risk (e.g., education level and time-period). Women with missing data for a covariate were excluded from analyses including that covariate.

E3N ATVB R2

11/25

Results

Table 1 shows the general characteristics of the study population. Mean age at the beginning of follow-up was 54.0 years and women were followed for an average of 10.1 years. At the beginning of follow-up, mean body-mass index was 22.6 kg/m² and nearly 18% of the women were overweight or obese.

Table 2 shows the HRs of venous thromboembolism by type of HT. Women who had never taken any HT were used as the reference group (n=181 cases). Past users of HT had similar thrombotic risk as never users (adjusted HR=1.1; 95% CI: 0.8-1.5).

There was no significant interaction between the route of estrogen administration (either oral or transdermal) and concomitant progestogens (either micronized progesterone, pregnane derivatives, norpregnane derivatives or nortestosterone derivatives) (p for interaction=0.62). After adjustment for potential confounders, oral but not transdermal estrogen use was associated with an increased risk of thrombosis (HR=1.7; 95% CI: 1.1-2.8 and HR=1.1; 95% CI: 0.8-1.8, respectively). In addition, among users, the hazard ratio was significantly increased in oral estrogen users as compared to transdermal estrogen users (HR=1.5; 95% CI: 1.1-2.0).

Regarding the impact of concomitant progestogens, the test for homogeneity among pharmacological subgroups was statistically significant (p<0.01). However, no significant heterogeneity was found between molecules within the groups of pregnane and norpregnane derivatives (p=0.07 and p=0.17, respectively). There was no significant association of venous thrombosis with micronized progesterone and pregnane derivatives (HR=0.9; 95% CI: 0.6-1.5 and HR=1.3; 95% CI: 0.9-2.0, respectively). In addition, nortestosterone derivatives were not significantly associated with thrombotic risk (HR=1.3; 95% CI: 0.7-2.4). By contrast, norpregnane

E3N ATVB R2

12/25 derivatives were associated with an increased thrombotic risk (HR=1.8; 95% CI: 1.2-

2.7).

Stratified analyses by type of diagnosis showed no striking differences in thrombotic risk associated with HT use between deep vein thrombosis and pulmonary embolism (data not shown).

In the principal analysis, 65 of the validated cases were excluded because no information on predisposing factors was available. These cases included fatal pulmonary embolisms identified from death certificates which did not contain such information (n=38). Thus, additional analyses were performed with pooled idiopathic cases and cases without any information on predisposing factors (n=614). The inclusion of these cases did not substantially modify the results. Indeed, the hazard ratios of venous thromboembolism for oral and transdermal estrogens were respectively 1.6 (95% CI 1.0-2.4) and 1.1 (95% CI 0.8-1.6). Using this same study sample, an additional analysis restricted to non-fatal events (n=576) led to similar results (data not shown).

ATVB R2

13/25

Discussion

These findings suggest that the route of estrogen administration and the type of concomitant progestogen are both important determinants of thrombotic risk among postmenopausal women who use HT. Transdermal estrogens may be safe when they are administrated alone or along with micronized progesterone but not with norpregnane derivatives. By contrast, oral estrogens are associated with an increased thrombotic risk irrespective of the presence of concomitant progestogens.

Our results regarding oral estrogen therapy are in agreement with those from both observational studies and clinical trials which have shown that oral estrogens were thrombogenic [START_REF] Canonico | Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis[END_REF][START_REF] Gomes | Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review[END_REF] . Thus far, only four studies have investigated the impact of transdermal estrogens on the risk of venous thrombosis [START_REF] Scarabin | Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk[END_REF][START_REF] Daly | Risk of venous thromboembolism in users of hormone replacement therapy[END_REF][START_REF] Perez Gutthann | Hormone replacement therapy and risk of venous thromboembolism: population based case-control study[END_REF][START_REF] Douketis | Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study[END_REF] . A combined analysis of these studies yielded an overall odds ratio close to one in transdermal estrogen users compared to non-users [START_REF] Canonico | Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis[END_REF] . Our results showing no increased thrombotic risk among women who use transdermal estrogens alone are consistent with this previous report.

While some previous studies have focused on the estrogens by route of administration, few data are available regarding the impact of concomitant progestogens by pharmacological classes on the risk of venous thromboembolism.

On one hand, some observational studies [START_REF] Daly | Risk of venous thromboembolism in users of hormone replacement therapy[END_REF][START_REF] Perez Gutthann | Hormone replacement therapy and risk of venous thromboembolism: population based case-control study[END_REF][START_REF] Douketis | Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study[END_REF][START_REF] Jick | Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens[END_REF][START_REF] Smith | Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis[END_REF] and one clinical trial [START_REF] Vickers | Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women[END_REF] have compared the risk of venous thromboembolism between users of estrogens alone and users of estrogens combined with progestogens. Overall, these results showed that oral estrogens combined with progestogens could be more thrombogenic than oral estrogens alone [START_REF] Canonico | Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis[END_REF] . In addition, a comparison of both Women's Health Initiative trials also suggested that the risk of thrombosis was higher among users of opposed E3N ATVB R2 14/25 estrogens than among users of estrogens alone [START_REF] Rossouw | Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial[END_REF][START_REF] Anderson | Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial[END_REF][START_REF] Cushman | Estrogen plus progestin and risk of venous thrombosis[END_REF][START_REF] Curb | Venous thrombosis and conjugated equine estrogen in women without a uterus[END_REF] . On the other hand, the ESTHER case-control study recently investigated the impact of concomitant progestogens by pharmacological classes [START_REF] Canonico | Hormone therapy and ATVB R2 20/25 venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study[END_REF] . In this study, micronized progesterone and pregnane derivatives were not significantly associated with an increased risk of venous thromboembolism, while norpregnane derivatives were thrombogenic compared to non-use. The present findings regarding micronized progesterone and norpregnane derivatives are consistent with these previous results. Finally, to our knowledge, the E3N study is the first to assess thrombotic risk in relation to nortestosterone derivatives used in HT and only few data are available on the effect of nortestosterones used alone. Although not statistically significant, the increased thrombotic risk associated with combined use of nortestosterones and estrogens in the E3N study can be paralleled with the elevated thrombotic risk observed in premenopausal women who received nortestosterone derivatives alone [START_REF] Poulter | Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications[END_REF] . However, the limited number of cases exposed to nortestosterone derivatives in our study did not allow assessing the effect estimates with sufficient statistical power.

The potential mechanisms underlying the increase in thrombotic risk among users of specific treatments include a prothrombotic state, a decrease in blood flow and/or an alteration of the vessel wall [START_REF] Virchow | Phlogose und Thrombose in Gefäßsystem[END_REF][START_REF] Cano | The mechanisms of thrombotic risk induced by hormone replacement therapy[END_REF] . Since 1997, several studies have shown that oral but not transdermal estrogens activate blood coagulation and induce an activated protein C resistance, providing a biological evidence to support the difference in thrombotic risk by route of estrogen administration [START_REF] Scarabin | Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial[END_REF][START_REF] Koh | Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women[END_REF][START_REF] Teede | Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis[END_REF][START_REF] Lowe | Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein--a cross-sectional population survey[END_REF][START_REF] Oger | Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial[END_REF][START_REF] Post | Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women[END_REF] . In some of the studies, oral and transdermal estrogens were both combined with micronized progesterone. These haemostatic data, together with the results of both the ESTHER [START_REF] Canonico | Hormone therapy and ATVB R2 20/25 venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study[END_REF] and the E3N studies, support the potential safety of transdermal estrogens combined with E3N ATVB R2 15/25 micronized progesterone. Data on the effect of progestogens on haemostasis are scarce and results remain inconsistent. One study has shown that a pregnane derivative had little to no effect on haemostasis [START_REF] Alhenc-Gelas | Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives[END_REF] . Moreover, several trials have failed to show any changes in levels of haemostatic parameters between progestogen subgroups [START_REF] Conard | Cardiovascular risk factors and combined estrogen-progestin replacement therapy: a placebo-controlled study with nomegestrol acetate and estradiol[END_REF][START_REF] Van Baal | Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo-controlled 12-week study[END_REF][START_REF] Post | Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized, placebo-controlled, 12-week study in early postmenopausal women[END_REF][START_REF] Collins | Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP Pilot Study[END_REF] . Nevertheless, recent data suggested that trimegestone, a norpregnane derivative, had a stronger effect on fibrinolysis inhibition as compared to dydrogesterone [START_REF] Norris | Inhibitors and activation markers of the haemostatic system during hormone therapy: a ATVB R2 22/25 comparative study of oral estradiol (2 mg)/ dydrogesterone and estradiol (2 mg)/ trimegestone[END_REF] . Thus, whether or not progestogens have differential effects on haemostasis requires further investigation.

The increase in thrombotic risk among postmenopausal women using some progestins could also be mediated by changes in venous structure and function [START_REF] Cano | The mechanisms of thrombotic risk induced by hormone replacement therapy[END_REF] .

The occurrence of venous stasis, especially observed during pregnancy and the luteal phase, could be modulated by steroid sex hormones via progesterone receptors which are present in the venous wall [START_REF] Perrot-Applanat | Progesterone receptor expression in human saphenous veins[END_REF] . Therefore, an increase in progestational activity of progestins, especially norpregnanes, compared to micronized progesterone might further alter blood flow and increase thrombotic risk.

One potential limitation of the E3N prospective cohort study is that, as an observational study, it is subject to bias. Several types of bias have already been discussed 14, 15 . In the present analysis, potential limitations include how selected the population was, why women were prescribed a specific treatment, misclassification regarding diagnosis and/or exposure and potential confounders in the statistical analysis. First, women recruited in the E3N study were mostly teachers and could represent a health-conscious population which might be at lesser risk than the general population. However, it is unlikely that this non-differential selection of healthy subjects could affect the comparison between users and non-users of HT.

E3N ATVB R2

16/25

Second, an indication bias might have occurred due to differential prescription of concomitant progestogens according to the estrogenic status of women using HT.

Norpregnane derivatives are potent progestogens with anti-estrogenic activity.

Women with moderate to severe hyperestrogenic symptoms, such as breast tenderness or endometrial diseases, may be more likely to be prescribed these types of progestogen [START_REF] Fraser | The effects of the addition of nomegestrol acetate to post-menopausal oestrogen therapy[END_REF][START_REF] Sitruk-Ware | Progestogens in hormonal replacement therapy: new molecules, risks, and benefits[END_REF] . Since there is evidence that lifetime estrogen exposure is positively related to venous thromboembolism in postmenopausal women [START_REF] Simon | Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism[END_REF] , this prescription bias could partly explain the increase in thrombotic risk among women using such anti-estrogenic progestogens.

Another limitation of our cohort study is that HT use was self-reported and nondifferential misclassifications regarding exposure might have occurred during followup. The effect of such errors is to decrease the strength of the observed associations towards the null. This limitation could explain the lower relative risks observed in our study compared to previous findings [START_REF] Canonico | Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis[END_REF] . We also cannot rule out a potential nondetected relationship between some treatments which appear safe and thrombotic risk. Another possible dilution of risk estimates may result from our definition of exposure. We used hormonal exposure declared at the beginning of each follow-up interval for the entire interval until the following subsequent questionnaire. This strategy allowed preserving the prospective nature of the study and avoiding differential recall bias between cases and non-cases. However, such exposure classification might lead to an incomplete capture of exposed cases, especially for those who started their treatment just after the date of questionnaire completion.

Further, potential confounders including elevated levels of thrombotic risk factors could explain our findings related to the effects of estrogens by route of administration and concomitant progestogens. Although some thrombotic risk factors,

17/25 such as prothrombotic mutations or family history of venous thromboembolism, were not measured in this study, adjustment for other predisposing factors for thrombosis, such as body-mass index or parity, did not appreciably change the results. The unavailable information on estrogens doses was also a limitation of our study. While increasing doses of estrogens may increase the coagulation activation [START_REF] Eilertsen | Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation[END_REF] , observational studies have suggested no significant difference in thrombotic risk by estrogen dose [START_REF] Scarabin | Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk[END_REF][START_REF] Daly | Risk of venous thromboembolism in users of hormone replacement therapy[END_REF][START_REF] Perez Gutthann | Hormone replacement therapy and risk of venous thromboembolism: population based case-control study[END_REF][START_REF] Jick | Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens[END_REF][START_REF] Smith | Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis[END_REF] . However, studies with high level of evidence comparing estrogen doses effect on thrombotic risk are still lacking.

Finally, our analysis was restricted to idiopathic venous thromboembolism because inclusion of cases with predisposing factors might have attenuated the associations between hormone use and thrombotic risk. In addition, it is likely that the presence of predisposing factors for venous thromboembolism could modify hormone exposure. Therefore, analysis restricted to idiopathic cases provides more accurate estimates of thrombotic risk. Nonetheless, this selection criterion did not allow extrapolating our results to secondary events.

The E3N cohort study also has several strengths including its prospective, population-based design as well as its large number of participants. In addition, follow-up questionnaires sent biennially starting from 1990 allow for the frequent update of information on menopausal status and HT use. In the present ancillary study, a further strength is the large number of well documented incident cases of venous thromboembolism.

Our findings regarding the impact of estrogens by route of administration and concomitant progestogens on thrombotic risk may have important clinical implications. Since pulmonary embolism has become a major determinant of the E3N ATVB R2 18/25 benefit/risk ratio of short-term oral estrogen therapy, reducing the risk of venous thromboembolism could substantially improve the benefit/risk profile of HT.

Therefore, short-term use of transdermal estrogens alone or combined with progesterone could be a good option in the management of postmenopausal symptoms. However, further data are needed and the present results should be confirmed with randomized controlled trials.

Follow-up started

  on the return date of the first questionnaire where women declared to be menopausal. Participants contributed person-years of follow-up until the date of death for fatal cases and, for other subjects, until the date of a venous thromboembolism event, the date of cancer diagnosis (other than basal cell skin cancer), the date of the last completed questionnaire or July 2005, whichever occurred first.

  Data were analyzed by classifying women according to HT use. The main effects of past use, current use of estrogens by route of administration (either oral, transdermal or other) and current use of concomitant progestogens (either micronized progesterone, pregnanes, norpregnanes or nortestosterones) were estimated in the same model with never use of HT as the reference group. Homogeneity of estimated HRs was tested among different pharmacological classes of concomitant progestogen and between molecules within the groups of pregnane and norpregnane E3N ATVB R2 10/25 derivatives. Interactions between the effects of estrogens and concomitant progestogens were tested by using a multiplicative HR model. Stratified analyses were conducted by type of diagnosis (deep vein thrombosis or pulmonary embolism) and mortality. Statistical analyses were performed using SAS statistical software (version 9.1, SAS Institute Inc, Cary, NC, 2004).

Acknowledgment section

Fundings: Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la recherché Médicale, Institut Gustave Roussy, 3M Company.

Acknowledgments:

We thank Aline Dugravot and Violaine Héraut for the technical assistance. The authors are also grateful to all participants for providing the data and to practitioners for providing the pathology reports.

ATVB R2

23/25

Conflict of interest disclosure: none

Authors' contributions