C H Pham

• F Adzima

• J Coër

• P Y Manach

P Y Manach

Anti-Buckling Device for Ultra-Thin Metallic Sheets Under Large and Reversed Shear Strain Paths

Keywords: Simple shear test, Ultra-thin sheet, Stainless steel, Cu alloy, Buckling, Bauschinger effect

The kinematic contribution to the hardening of ultra-thin metallic sheets characterized by monotonic and reversed simple shear tests is of high interest in the sheet metal forming industry, because of its influence on the accurate prediction of springback. However, ultra-thin sheets are very sensitive to buckling when submitted to shear stress because of the large gauge width to thickness ratio, the stress perturbations induced by the clamping and the alignment of sample, which thus limit the attainable strain levels using conventional simple shear devices. In this paper, a new simple shear test dedicated to ultra-thin metallic sheets is proposed through the development of a specific support. A transparent glass part enables the application of a normal tightening force to prevent the out-of-plane buckling of the sheets whilst also allowing full field strain measurements to be taken. Firstly, the capabilities of the device are shown by comparing the mechanical behavior in a simple shear test on an austenitic stainless steel with and without the support. A good reproducibility of the flow curves is observed with the support and large shear strains are reached without buckling. Secondly, the influence of friction due to the contact between the sample and the support is checked by finite elements simulations and shown to be negligible compared to the shearing force. Finally, monotonic and reversed shear tests on a pure copper sheet with a thickness of 0.1 mm

Introduction

The forming of very small metallic parts by plastic deformation is playing an increasingly key-role in manufacturing [START_REF] Vollertsen | State of the art in micro forming[END_REF]. Due to the trend of miniaturization in high technology fields like micro-electronics, ultra-thin metallic sheets are widely used [START_REF] Weiss | Characterization of mechanical and thermal properties of thin cu foils and wires[END_REF][START_REF] Engel | Microforming -from basic research to its realization[END_REF], particularly Cu alloys due to its good electrical and thermal conductivity and malleability [START_REF] Tsai | Size-effects in micro-metal sheet forming of unalloyed copper and brass[END_REF][START_REF] Gau | Springback behavior of brass in micro sheet forming[END_REF]. The fabrication processes of small parts [START_REF] Kals | Miniaturization in sheet metal working[END_REF], i.e. those having dimensions between 2 and 20 mm [START_REF] Costache | Prediction and prevention of material cracking in the case of micro or milli drawn parts made from aluminium foils[END_REF], with ultra-thin sheets, lead to low production cost and low energy consumption compared to those of larger parts [START_REF] Peng | Investigation of micro/meso sheet soft punch stamping process -simulation and experiments[END_REF][START_REF] Fu | A review on the state-of-the-art microforming technologies[END_REF]. The latest development in forming processes have demonstrated that progressive die micro-stamping may be used to plastically deform ultra-thin sheets [START_REF] Qin | Develoment of a new machine system for the forming of micro-sheet products[END_REF]. In successive stages, the metal strip is punched and bent successively to obtain the finished part. The band enters the tool that then closes: firstly, the strip is clamped between the blank-holder and the die and in a second step, the punches cut or fold the material. The tool opens, the band moves a step forward through the tape guide and the cycle continues until the workpiece reaches its final shape. Between each step of the forming process, the material is subjected to the opening and closing of the tools that generates a release of the stresses that produces springback and a succession of loading-unloading or even reloading. In such cases, the numerical simulation of the forming process of ultra-thin metallic components may require a fine modeling of the constitutive behavior. This is particularly important in progressive die micro-stamping processes [START_REF] Razali | A review on micro-manufacturing, micro-forming and their key issues[END_REF], regardless of the retained constitutive approach that could use phenomenological, mean field or crystal plasticity models.

As is common in many industrial fields, the simulation of micro-forming processes is currently based on the mechanical properties measured in tensile tests but the actual results are still far from those of the experimental results [START_REF] Vollertsen | State of the art in micro forming[END_REF][START_REF] Fu | Experimental and simulation studies of micro blanking and deep drawing compound process using copper sheet[END_REF]. From manufacturers, the thickness of the material is what determines whether it is called ultra-thin sheet, thin sheet, or even plate, and ultra-thin sheets have usually a thickness ranging from 13 μm up to 200 μm. But this division depends also on the ratio N = t/d between the thickness t and the average grain size d. When this ratio decreases down to 10 or lower, which is the case of both materials considered in this study, the mechanical behavior is strongly affected. Therefore, there are specificities of ultra-thin sheets that are revealed when the material thickness decreases and prevents the use of previous knowledge acquired from traditional methods and thicknesses. First of all, the material behavior is strongly influenced by the so-called size effect [START_REF] Michel | Size effects on the constitutive behavior for brass in sheet metal forming[END_REF][START_REF] Vollertsen | Size effects in manufacturing of metallic components[END_REF]: the yield stress decreases following the increase of the proportion of surface grain with respect to the total number of grains. The anisotropy is modified and the strain in the thickness becomes predominant [START_REF] Kals | Miniaturization in sheet metal working[END_REF]. The decrease in ductility is even more dramatic, falling almost to zero for very low thicknesses, with a change of necking and rupture modes [START_REF] Dodd | Ductile fracture and ductility[END_REF]. The relative contribution of friction increases significantly (up to a factor 20) when the size of the parts decreases [START_REF] Tiesler | Microforming size effects in friction and their influence on extrusion processes[END_REF]. Friction is a microstructural effect arising from the micro geometry, especially the surface roughness. As observed by numerous authors, the friction coefficient increases with decreasing size, resulting in an increased influence of the friction on the measured flow stress. Finally, a large dispersion of the mechanical properties is systematically noted, the overall behavior becoming more dependent on the individual behavior of each grain compared to polycrystalline materials. However, from a macroscopical point of view, the mechanical behavior of metallic sheets is usually modeled within a large deformation framework and using elasticplastic models. During stamping and springback processes of ultra-thin sheets, the material is affected by various deformation modes such as stretching, shearing, bending, and unbending [START_REF] Peng | Investigation of micro/meso sheet soft punch stamping process -simulation and experiments[END_REF]. If the material exhibits a significant Bauschinger effect, mixed hardening models should be considered to represent its mechanical behavior [START_REF] Ragai | Anisotropy and springback in draw-bending of stainless steel 410: experimental and numerical study[END_REF]. For all these reasons, to increase the accuracy of the numerical predictions and in particular for springback, a database of the mechanical properties of ultra-thin metallic material should include not only tensile stress-strain curves but also reverse loading sequences.

Several methods have been developed to test materials along reverse loading paths. In-plane compression can be performed using standard samples together with side constraints or loads to avoid buckling in the thickness direction [START_REF] Kuwabara | Tension-compression asymmetry of phosphor bronze for electric parts and its effect on bending behaviour[END_REF][START_REF] Libura | Antibuckling system for flat specimens investigations under cyclic tension-compression[END_REF][START_REF] Boger | Continuous, large strain, tension/compression testing of sheet material[END_REF][START_REF] Cao | Experimental and numerical investigation of combined isotropickinematic hardening behaviour of sheet metals[END_REF][START_REF] Knoerr | Cyclic tension compression testing of AHSS flat specimens with digital image correlation system[END_REF]. However these methods are unable to generate large strains because of buckling outside of the supported region, particularly when dealing with ultra-thin sheets. Reverse torsion [START_REF] Chen | Bauschinger effect and multiaxial yield behavior of stress-reversed mild steel[END_REF] or a combination of torsion and tension [START_REF] Brown | Inelastic deformation of an aluminum alloy under combined stress at elevated temperature[END_REF] has also been used successfully to reach high strains. But the sample preparation requires the sheet to be welded into a thin-walled tube, and such operations can change the microstructure of the sheet, thus altering its macroscopic properties. Another disadvantage of torsion testing is that stress and strain are not uniform throughout the cross section of the sample, requiring the strain gradient in the radial direction to be taken into account [START_REF] Wu | Simulation of the behaviour of fcc polycrystals during reversed torsion[END_REF].

Planar simple shear tests become a common practice in the characterization of metallic material in sheet form [START_REF] Manach | Elastoviscohysteresis constitutive law in convected coordinate frames: application to finite deformation shear tests[END_REF][START_REF] Bouvier | Simple shear tests: experimental techniques and characterization of the plastic anisotropy of rolled sheets at large strains[END_REF][START_REF] Thuillier | Comparison of the workhardening of metallic sheets using tensile and shear strain paths[END_REF]. Unfortunately, the large gauge-width to thickness ratio of classical devices, the width of which is necessary to reach a sufficient accuracy in the strain measurement, and the non-homogeneity of shear deformation in ultra-thin sheet leads to unwanted side-effects such as the development of out-of-plane buckling of the sheet [START_REF] Boni | Microscopic in situ observation of the plastic deformation of polybutene-1 films under simple shear[END_REF]. According to the knowledge of the authors, in shear tests, unlike in tension tests, no specific tools or devices have been developed to prevent this phenomenon. In this paper, a new simple shear test dedicated to ultra-thin metallic sheets is proposed through the development of a specific support. A transparent glass part enables a normal tightening force to be applied to prevent the out-of-plane buckling of the sheets while also allowing full field strain measurements to be taken. Firstly, the principle of the planar simple test is recalled, and next the parameters that lead to the occurrence of buckling in shear. Then, the capabilities of the device are demonstrated by comparing the mechanical behavior in a simple shear test on an austenitic stainless steel, with and without the support. The influence of friction due to the contact between the sample and the support is checked by finite elements simulations and finally, monotonic and reversed shear tests on a pure copper sheet of 0.1 mm thick are performed up to rupture without buckling to demonstrate the potential of the proposed device.

Planar Shear Test

The device, presented in detail in [START_REF] Manach | Elastoviscohysteresis constitutive law in convected coordinate frames: application to finite deformation shear tests[END_REF][START_REF] Thuillier | Comparison of the workhardening of metallic sheets using tensile and shear strain paths[END_REF] is directly connected to a tensile test machine. Samples are rectangular with a length of L = 30 mm and a width of l = 15 mm. The samples are set in the shear device and clamped at both sides, such that a planar load distribution is applied along the grip length (see Fig. 1). The grips are screwed with a Fig. 1 On the left-hand side, schematic drawing of a shear test sample, before and after shearing. On the right-hand side, representation of the stress distribution σ n along the clamped edges, highlighting the tension (t) and compression (c) state corners as well as the area of strain measurement torque wrench and after several trials, a suitable torque is applied to minimize the sliding between the specimen and the grips. One grip moves upwards while the other remains fixed, inducing a simple shear deformation in the gauge width h between the movable and the fixed grips. To impose the condition h constant for a simple shear deformation, the moving grip cannot move laterally (along the horizontal axis). The rolling direction is aligned with the shear direction. The simple shear tests have been carried out at room temperature at a constant strain rate γ = 10 -3 s -1 .

The shear strain measurement is made using a noncontacting 3D optical system (Aramis 5M, GOM, Germany). Two video cameras (8-bit gray levels, 2050 × 2448 pixels images at 15 Hz maximum) record the motion of a random pattern spray painted on the sample surface, by means of digital image correlation (DIC) technique. The complete gauge area of the sample is observable by the cameras: the number of non-overlapped subsets defined on this zone, which corresponds to the size of the virtual grid used in DIC is 4-5 wide and 100 long. The subset size is 11 × 11 pixels square leading to a scaling value in the range of 15-18 pixels/mm. The measurement is performed with a step size of 8 pixels which corresponds to an overlap of 70 %. The shear strain field measured by DIC is fairly homogeneous on the specimen, but inevitable edge effects are observed near the free edges of the specimen, due to the stress distribution on the borders (see Fig. 1). So, the shear strain γ is calculated as the average of the shear strain field in the homogeneous zone (named average area in Fig. 1), i.e. by removing the values near the free edges. The average area is depicted in Fig. 1 and the length a = 16 mm. The accuracy of this measurement is of the order of 10 -4 [START_REF] Pham | Mechanical properties involved in the micro-forming of ultra-thin stainless steel sheets[END_REF].

The kinematics of the simple shear test can be described by the transformation gradient F:

F = I + F 12 1 ⊗ 2 (1)
Using this kinematics, the planar shear component of the Cauchy stress tensor can be deduced from the measurement with the load cell of the tensile test machine of the actual force F such as τ = F /Lt, where t is the thickness of the sample, I is the second order identity tensor, 1 is parallel to the shear direction and 2 perpendicular to 1 in the sheet plane. The test is controlled by the evolution of F 12 with time. Due to the edge effects, the Cauchy stress tensor also involves tensile components. In the frame (1, 2, 3), where 3 is the normal direction, it can be written:

σ = ⎛ ⎝ σ 11 τ 0 τ σ 22 0 0 0 0 ⎞ ⎠ (2)
The components σ 11 and σ 22 (whose distribution is denoted by σ n in Fig. 1) are not equal to zero due to the imposed conditions that L and h are constants, which generates lateral compression forces that can reach high values near the free ends of the sample. But these stresses can be disregarded by using a large length-over-width ratio L/ h [START_REF] Bouvier | Simple shear tests: experimental techniques and characterization of the plastic anisotropy of rolled sheets at large strains[END_REF]. It should be emphasized that in shear, the displacement necessary to reach a large deformation is rather limited compared to tension-compression. For example, by using a shear width of 3 mm, a displacement of 1.5 mm generates a shear strain of 0.5, while in tension using a classical gauge length of 12.5 mm, a displacement of 2.5 mm is required to obtained a strain of 0.2.

Origin of Buckling

Unlike the problem of normal buckling, the shear buckling of plates is mathematically described by differential equations having a term with an odd order of derivatives with respect to each of the planar spatial coordinates. Therefore, their governing equations cannot be solved exactly, except in the case of an infinite length of one side of the rectangular plate [START_REF] Southwell | On the stability under shearing forces of a flat elastic strip[END_REF]. In our samples, the length is systematically large compared to the width and the thickness. Using the Young's modulus and Poisson's coefficient denoted by E and ν respectively, the Euler shear buckling stress is obtained by the following relation:

τ E = π 2 E 12(1 -ν 2 ) t h 2 k s (3)
The value of k s = 8.98 depends on the L and h of the long and short sides of the shear zone through α = L/ h the sample aspect ratio. Its value has been determined by [START_REF] Southwell | On the stability under shearing forces of a flat elastic strip[END_REF] for the theoretical buckling stress in shear of a clamped rectangular plate of an infinitely long strip. So, the critical buckling stress τ E for which buckling occurs is conversely proportional to the square of the buckling length, which depends on the width of the sheared area and on the clamping, and is proportional to the square of the thickness of the specimen [START_REF] Bouvier | Simple shear tests: experimental techniques and characterization of the plastic anisotropy of rolled sheets at large strains[END_REF][START_REF] Boni | Microscopic in situ observation of the plastic deformation of polybutene-1 films under simple shear[END_REF]. Since the thickness is essentially determined for a rolled sheet, and considering the material properties of the sample, the condition of avoiding buckling is essentially to limit the width h of the specimen. Unfortunately, with our device [START_REF] Thuillier | Comparison of the workhardening of metallic sheets using tensile and shear strain paths[END_REF], the width of the shear zone cannot be decreased to less than 1.4 mm since the shear zone becomes too narrow to access the shear strain by DIC. For ultra-thin copper sheets considered in this study (t = 0.1 mm), the critical buckling stress is lower than the yield stress (τ y = 141 MPa) regardless of the width h > 1.4 mm. Then, it was not possible to perform any planar shear tests on this material with such a thickness. So, as classically performed in tensioncompression [START_REF] Libura | Antibuckling system for flat specimens investigations under cyclic tension-compression[END_REF], the main idea was to develop a specific device in order to apply a slight normal force to prevent buckling.

Recently, several solutions have been developed using a hydraulic actuator operating on the specimen inserted between the supporting blocks [START_REF] Kuwabara | Tension-compression asymmetry of phosphor bronze for electric parts and its effect on bending behaviour[END_REF][START_REF] Boger | Continuous, large strain, tension/compression testing of sheet material[END_REF]. Another solution has been proposed for the side-supporting fixture which is to implement sliding blocks with angular chamfers [START_REF] Cao | Experimental and numerical investigation of combined isotropickinematic hardening behaviour of sheet metals[END_REF], while in [START_REF] Knoerr | Cyclic tension compression testing of AHSS flat specimens with digital image correlation system[END_REF] a clamping force was applied to the springs to support the tested samples. Since in all these solutions the side force and the friction coefficient needs to be known, the friction force can be approximately calculated on the basis of Coulomb law assuming a constant coefficient. However, such hypotheses have to be treated cautiously because of the large increase of the surface roughness of the sample, that leads to a non-constant friction coefficient [START_REF] Tiesler | Microforming size effects in friction and their influence on extrusion processes[END_REF].

Anti-Buckling Device

To generate a lateral force in the thickness direction to prevent buckling, a support is composed of two plates applied in contact with both sides of the shear zone. On one side, the plate is transparent in order to enable the measurement of the shear strain by digital image correlation. The support is composed of 8 parts as presented in Fig. 2. The rear plate (1) made of aluminum with the dimensions 60 × 2.8 × 4.0 mm 3 (length, width, thickness respectively). The front plate (2) made of glass, with the dimensions 40 × 2.8 × 4.0 mm 3 (length, width, thickness respectively). Glass with the lowest refractive index was selected in order to prevent errors in the measurement of strain. The specimen is set between these two plates. M2 screws [START_REF] Peng | Investigation of micro/meso sheet soft punch stamping process -simulation and experiments[END_REF] and nuts [START_REF] Costache | Prediction and prevention of material cracking in the case of micro or milli drawn parts made from aluminium foils[END_REF] are used to clamp both plates via the clamping plates (3) and plastic rods [START_REF] Kals | Miniaturization in sheet metal working[END_REF]. The shims (2) have a thickness equal to the sum of those of the glass plate and the sample, while the plastic rods (6) prevent the tightening force from breaking the glass plate. In order to limit the friction between the aluminum plate and the sample, Castrol LMX grease was used for lubrication. The tightening force is controlled by a torque wrench and set by the trial-and-error method to the value 1.25 Nm. The positioning of the support in the shearing device [START_REF] Manach | Elastoviscohysteresis constitutive law in convected coordinate frames: application to finite deformation shear tests[END_REF][START_REF] Thuillier | Comparison of the workhardening of metallic sheets using tensile and shear strain paths[END_REF] is presented in Fig. 2 and corresponds exactly to the distance between both grips of the machine.

In order to validate the support, the first step consists of comparing the results obtained with and without the support. To do so, a reference material was chosen to calibrate the device, whose mechanical properties and thickness resides within the range where the variation of h leads to either buckling or not. This enables the determination of the influence of the use of the device on stress-strain curves and if large strains are achievable. A stainless steel sheet AISI 304 of 0.15 mm thick was selected for this test, which average grain size measured by EBSD is 19 μm, leading to a ratio N = t/d = 8 characteristic of an ultra-thin sheet. Due to the mechanical properties of this material presented in Table 1, the sample exhibited buckling in shear for a width h greater than 1.4 mm as can be observed in Fig. 3). Using the support, it can be observed in Fig. 3 that the shear width can be set to 3 mm and from Fig. 4 that the shear strain γ could reach 0.5 without any occurrence of buckling.

Figure 4 presents the flow curves obtained for monotonous shear tests with and without the support. For tests without the support, h varies from 2.2 mm down to 1.4 mm, for which the samples do not present any buckling effect for a strain up to γ = 0.7. However, the results are scattered with an uncertainty of ±20 MPa, corresponding to 10 % of the shear stress for γ = 0.5. This dispersion increases when the thickness of the sheet or the yield strength decreases [START_REF] Chen | Post-buckling shear strength of thin steel plates[END_REF]. In addition, the quality of the strain measurement is poor due to the narrowness of the shear zone leading to reduced size of the gauge area observable by the DIC system. When using the support, shear tests can be performed successfully up to a width h = 3 mm and until γ = 0.5, no buckling effect is observed on the sample (Fig. 4). Conversely, a very good reproducibility is obtained for the tests performed with a narrower shear zone. In addition, by comparing these results with the results obtained for h = 1.4 mm without the support, a good correlation between these tests was observed, but the accuracy of the strain measurement was higher using the support.

Then, the comparison between the shear tests of the AISI 304 ultra-thin stainless sheet, with and without the support, shows some capabilities of the device as well as its benefits for ultra-thin sheet shear testing. Note that the influence of the refractive index of the glass part has been checked to be negligible on the measurement of the shear strain.

Results and Discussion

Following the previous results, the support was then used to perform shear tests on ultra-thin pure copper sheets (99.9 % Cu) with a thickness of 0.10 mm. An average grain size of 10 μm has been measured by EBSD, leading to N = 10 characteristic of an ultra-thin sheet. In fact, the achievement of shear tests for this material and such a thickness is impossible because of the onset of buckling for early shear strains, even for a width h less than 1.0 mm. The mechanical properties of this material are given in Table 2 and E = 137 GPa and ν = 0.34. Figure 5 presents the virgin samples, and those obtained after shearing without and with the support for h = 3 mm. The samples, of initial dimensions 30 × 15 mm 2 , are cut directly into the sheet in the rolling direction. One of the two surfaces of the sample is painted with a layer of black and white speckle for measuring the shear strain using the DIC system (Aramis) (Fig. 5). The other side is lubricated with Castrol LMX grease in order to reduce friction with the aluminum support. Figure 5 shows that without the support, the sample demonstrates an extensive buckling all over the gauge area for h = 3 mm. Conversely, with the support, the shear strain could reach γ = 0.25 without any occurrence of buckling.

Figure 6 presents the flow curves obtained for monotonous shear tests with the support. Due to its purity, the hardening of this material is particularly weak (see n coefficient in Table 2) and the flow curves are close to a prefect plastic material. This hardening is conducive to the development of geometric instabilities and thus the onset of buckling, even for small shear strains. It is observed that the three tests present a good reproducibility, within the range of discrepancy that is generally recorded in shear tests [START_REF] Thuillier | Comparison of the workhardening of metallic sheets using tensile and shear strain paths[END_REF]. The capabilities of the support are then confirmed and the following sections present the results to evaluate the influence of the proposed device on the test results. The homogeneity of the shear strain in the gauge area and the influence of the tightening force of the support are studied. The black and white speckle is for the shear strain measurement with the DIC system. Buckling effects occur only in the left case 2

Homogeneity of the Strain

The shear strain γ = 2ε xy corresponding to the nondiagonal component of the planar transformation gradient is measured with the DIC system over the entire gauge area, and is then calculated as an average value over a rectangular zone on the sample surface presented Fig. 7. To investigate the homogeneity of strain over the gauge area, the shear strain evolution is analyzed along three sections. The distance between two successive sections is 0.5 mm. Figure 7 shows the strain distribution determined after testing sheets of Cu 0.1 mm thick to several average shear strain values γ = 0.078, 0.136, 0.196. It can be seen that there is a zone of nearly constant shear strain in the center region of the gauge area while towards the ends the shear strain becomes non-uniform. According to [START_REF] Weiss | On the Bauschinger effect in dual phase steel at high levels of strain[END_REF], the difference of calculating the average of the shear strain over the full length of the gauge area or over a reduced area is negligible. This leads to a strain tensor that is close to the radial path in the principal strain space and material anisotropy may therefore only have a minor effect on the material response in forward and reverse shear.

Influence of the Tightening Force

To carry out the tests with the support, the aluminum and glass plates are tightened together during the tests. The clamping force between the two plates is limited by the contra-plate (2) and the plastic rods [START_REF] Kals | Miniaturization in sheet metal working[END_REF] and is controlled by the screws (8) (see Fig. 2). Even if experimentally the contact between the sample and the aluminum plate has been lubricated in order to limit friction, the influence of the clamping force of the support has to be checked. However, a direct measurement of this force is hard to achieve and it is not possible to determine whether it evolves during testing. So the numerical prediction of the tightening force is an effective way to determine its evolution.

The gauge area of the sample is modeled by a rectangular plate of 30 mm long and 3 mm wide. Solid elements with linear interpolation and reduced integration of Abaqus Explicit (C3D8R) are used. The sheet is meshed with three layers in the thickness and the element size is 0.1×0.1 mm 2 in the sheet plane. To reproduce the buckling effect, a small defect is generated before shearing the sample. The left side of the sample presented in Fig. 8 is clamped, while the right side moves slightly (0.005 mm) in the z direction. Then this side is moved in the y direction in order to shear the sample in the plane, but also out-of-plane due to the a small amount of z displacement. The width of the specimen is kept constant during the numerical simulation. Using these boundary conditions, the sample buckles after a small amount of deformation γ = 0.07 as it can be observed in Fig. 8.

In order to represent the action of the support, two rigid plates are added to the numerical model, on both free surfaces of the sample. These two plates 2.8 mm wide are meshed by rigid elements R3D4. A tightening force is applied to the plates during the simulation. As the contact between the sample and the support is lubricated, the conditions of contact-friction between the blank and the support are defined as a common practice in sheet metal forming processes, by the penalty method associated with the Coulomb friction law, with a weak friction coefficient of 0.05. The same boundary conditions as the previous simulation, including the out-of-plane movement, are applied to the sample. In this configuration, no buckling effects are observed up to large shear strain (γ = 0.3). Two different values of the clamping force are applied on the support, i.e. F c = 45N and 90N. These values have been estimated analytically according to the resistance of the plastic rods (parts 6 in Fig. 2). They correspond respectively to a compression stress of 16 MPa and 32 MPa in the plastic rods, chosen from the range of variation found in the literature of the yield stress of the polymer. The reaction forces in the y direction for nodes outside the shearing boundary conditions, are extracted and plotted as a function of the displacement of the lateral side of the sample in Fig. 9. Obviously, the results show that the greater the clamping force, the greater the reaction forces in the y direction, but in both cases (45N and 90N), it remains weak compared to the shearing force (less than 1 %) that are superimposed.

Reversed Shear Tests

The previous results have confirmed the capabilities of the proposed support in the achievement of shear tests on ultrathin metallic sheets. As a final example of the potential of the device, reversed shear tests are performed. Many authors have pointed out the importance of considering the Bauschinger effect in numerical simulations of sheet metal forming, by using a mixed isotropic-kinematic hardening law instead of purely isotropic hardening, e.g. [START_REF] Gau | Springback behavior of brass in micro sheet forming[END_REF][START_REF] Geng | Role of plastic anisotropy and its evolution on springback[END_REF]. The Bauschinger effect corresponds to early re-yielding under reversed loading with a rounded yield point, followed by a transient stage before the onset of stable work-hardening. Particularly in the case of ultra-thin metallic sheets, the taking into account of mixed hardening is a key-point to master the springback effect [START_REF] Eggertsen | On the modelling of the bending-unbending behaviour for accurate springback predictions[END_REF]. Some commercial Finite Element Analysis (FEA) softwares already enables the direct incorporation of tension-compression test data for advanced model development but buckling and frictional effects limit the test to weak reverse strain levels.The planar simple shear test provide an alternative solution since it gives complementary informations to determine yield functions and reversed tests can be performed to identify the kinematic hardening contribution.

Reversed shear tests were performed to highlight the Bauschinger effect of the pure copper material in order to evaluate its kinematic work-hardening. These tests, presented in Fig. 10, are composed of a loading up to several values of γ (0.02, 0.05, 0.1) followed by a loading in the opposite direction until rupture. In order to highlight differences between the first and the second strain path, the curves are also plotted in a positive quadrant (in dashed lines), i.e. the shear strain is the cumulated shear strain along both paths while the shear stress is its absolute value. For comparison, the results obtained in a monotonic shear test under the same experimental conditions are superimposed on the figure (black curve). Figure 10 clearly highlights that the Bauschinger effect (a lower absolute yield stress at reversed loading) occurs for all pre-strain levels. Furthermore, for the largest pre-strain, a transient effect appears during reloading that is characterized by a stagnation of the hardening rate. This transient effect is not observed for lower pre-strains and in all cases, the curves converge to the equivalent monotonic curve which means that this material does not present permanent softening. This stagnation of the hardening rate during reloading is mainly associated with two physical mechanisms. Firstly, after strain reversal, the motion of the dislocations is facilitated by the dislocation substructure developed during the loading. Secondly, during reloading, the material exhibits intense dislocation annihilation leading to a dissolution of the preexisting substructure. In all cases, this transient behavior disappears when the density of the newly activated dislocations is high enough to permit resumption of work-hardening. This result is in good agreement with [START_REF] Proudhon | The role of internal stresses on the plastic deformation of the Al-Mg-Si-Cu alloy AA6111[END_REF], who observed the same pre-strain dependence on an aluminum alloy subjected to tension-compression tests, but for much lower pre-strains.

Conclusion

A new simple shear test dedicated to ultra-thin metallic sheets has been proposed through the development of a specific support. The transparent glass part allows a normal tightening force to prevent the out-of-plane buckling of the sheets while also allowing full field strain measurements of the specimen using the Digital Image Correlation (DIC) method. The main results are:

-The capabilities of the device were confirmed by comparing the data obtained in a simple shear test on an austenitic stainless steel (AISI 304) with a thickness of 0.15 mm with and without the support. A good reproducibility of the flow curves is observed with the support and shear strains up to γ = 0.5 are reached without buckling. -The influence of friction due to the contact between the sample and the support was checked by finite elements simulations. The friction force was shown to be weak compared to the shear force, so its influence can be ignored during the test. -Monotonic simple shear tests on a pure copper sheet with a thickness of 0.10 mm were performed up to rupture without buckling using this device, these were not conceivable without the support. For the first time on such a material, shear strains up to γ = 0.25 were reached. -Reversed shear tests were performed for several values of the pre-strain without buckling, that exhibit both the Bauschinger effect and transient effect characterized by a stagnation of the hardening rate during reloading for higher pre-strains that could not have been investigated previously in tension-compression tests.

Such a test is a good alternative to complex devices that have been developed recently in tension-compression to characterize kinematic hardening contributions of constitutive laws.

Fig. 2

 2 Fig. 2 Shear test support for ultra-thin sheets. Left-hand side: description of the device: (1) aluminum plate, (2) front plate, (3) clamping plate, (4) transparent glass plate, (5) sample, (6) plastic rod, (7) nuts, (8) screws. Right-hand side: positioning of the support into the shear device (the left grip is removed for clarity reasons)

Fig. 3

 3 Fig. 3 Planar simple shear test on AISI 304 stainless steel sheet. From left to right: width h = 2.2 mm without support, h = 1.4 mm without support and h = 3 mm with support.The black and white speckle is for the shear strain measurement with the DIC system. Buckling effects occur only in the left case

Fig. 4

 4 Fig.[START_REF] Tsai | Size-effects in micro-metal sheet forming of unalloyed copper and brass[END_REF] Comparison of shear stress-strain curves obtained with or without support (hx.x indicates the width used for the tests without support)

15 30Fig. 5

 155 Fig. 5 Planar simple shear samples of Cu sheets with a thickness of 0.1 mm. From left to right: dimensions of the virgin sample, shear test without support and with the support for a width h = 3 mm. Buckling effects occur in the middle case (out-of-plane waves), as long as the support is not used

Fig. 6

 6 Fig.[START_REF] Kals | Miniaturization in sheet metal working[END_REF] Reproducibility of the simple shear tests on the pure copper sheet with a thickness of 0.1 mm

Fig. 7 Fig. 8 Fig. 9

 789 Fig. 7 Analysis of the homogeneity of the shear strain distribution along several sections parallel to the shear direction, for different values of the global shear strain. γ is calculated in the region where the distribution is homogeneous. The curve above the color legend shows the whole distribution of the shear strain in the image for γ = 0.136

Fig. 10

 10 Fig. 10 Flow curves for reversed shear tests up to several values of the prestrain (γ = 0.02, 0.05, 0.1) superposed with a monotonic shear test on the Cu sheet 0.1 mm thick. Dashed lines correspond to the reversed curves of the shear tests plotted in cumulated shear strain

Table 1

 1

	Measured mechanical properties of the studied AISI 304
	stainless steel
	YS (MPa)	UTS (MPa)	r	n
	320	704	0.899	0.6

Table 2

 2 Measured mechanical properties of the pure copper material

	E (GPa)	YS (MPa)	UTS (MPa)	ν	r	n
	137	245	285	0.34	0.674	0.31

Acknowledgments

The French Agence Nationale de la Recherche (ANR) is gratefully acknowledged for funding this work under the project ANR-12-RMNP-0009-02 as well as Delta Composants for providing the materials. The authors would like to thank A. Jégat for his collaboration and S. Thuillier for the useful discussions.


MD MSc Guillaume Bouzillé
email: guillaume.bouzille@univ-rennes1.fr

PharmD Marie-Noëlle Osmont
email: marie-noelle.osmont@chu-rennes.fr

PharmD Louise Triquet
email: louise.triquet@chu-rennes.fr

PhD Natalia Grabar
email: natalia.grabar@univ-lille3.fr

MD Cécile Rochefort-Morel

MD Emmanuel Chazard
email: emmanuel.chazard@univ-lille2.fr

PhD Elisabeth Polard
email: elisabeth.polard@chu-rennes.fr

MD PhD Marc Cuggia
email: marc.cuggia@univ-rennes1.fr

Drug safety and big clinical data: detection of drug-induced anaphylactic shock events Running head: Detecting anaphylaxis from big clinical data

Keywords: Adverse Drug Reaction Reporting Systems, Drug-Related Side Effects and Adverse Reactions, Electronic Health Records, Information Storage and Retrieval 1

Rationale, aims and objectives: The spontaneous reporting system currently used in pharmacovigilance is not sufficiently exhaustive to detect all adverse drug reactions (ADRs).

With the widespread use of electronic health records (EHRs), biomedical data collected during the clinical care process can be reused and analyzed to better detect ADRs. The aim of this study was to assess whether querying a Clinical Data Warehouse (CDW) could increase the detection of drug-induced anaphylaxis.

Methods: All known cases of drug-induced anaphylaxis that occurred or required hospitalization at Rennes Academic Hospital in 2011 (n=19) were retrieved from the French pharmacovigilance database, which contains all reported ADR events. Then, from the Rennes Academic Hospital CDW, a training set (all patients hospitalized in 2011) and a test set (all patients hospitalized in 2012) were extracted. The training set was used to define an optimized query, by building a set of keywords (based on the known cases) and exclusion criteria to search structured and unstructured data within the CDW in order to identify at least all known cases of drug-induced anaphylaxis for 2011. Then, the real performance of the optimized query was tested in the test set.

Results: Using the optimized query, 59 cases of drug-induced anaphylaxis were identified among the 253 patient records extracted from the test set as possible anaphylaxis cases.

Specifically, the optimal query identified 41 drug-induced anaphylaxis cases that were not detected by searching the French pharmacovigilance database, but missed seven cases detected only by spontaneous reporting.

Discussion: We proposed an information retrieval-based method for detecting drug-induced anaphylaxis, by querying structured and unstructured data in a CDW. CDW queries are less specific than spontaneous reporting and DRG queries, although their sensitivity is much higher. CDW queries can facilitate monitoring by pharmacovigilance experts. Our method could be easily incorporated in the routine practice.

Introduction

Pharmacovigilance is an essential component of drug safety. The main goals of pharmacovigilance are the post-marketing drug surveillance and reducing the risk of adverse drug reactions (ADR) associated with drug use. The French pharmacovigilance system is based on a network of 31 regional pharmacovigilance centers. Spontaneous reporting (i.e., the unrequested notification of ADR events) by healthcare professionals or consumers to pharmacovigilance centers is the cornerstone of this surveillance system. Moreover, pharmaco-epidemiological studies assess the benefit/risk ratio when a drug is prescribed in "real life" to a large population of patients. Safety data are then analyzed by the competent authorities at different levels (national, European, global) that can then call attention to pharmacovigilance signals. Validated signals allow the authorities to develop regulatory measures to better control drug-related risks.

Spontaneous reporting has the advantage of covering a large number of patients (ideally, the entire population) and a wide range of drugs. It is a cost-effective method for monitoring drug safety [START_REF] Hazell | Under-Reporting of Adverse Drug Reactions[END_REF] , but has some limitations, mainly the under-reporting of ADR events, particularly those occurring in hospitals or leading to hospitalization. Indeed, it is estimated that more than 90% of ADR events are currently not reported to the authorities [START_REF] Hazell | Under-Reporting of Adverse Drug Reactions[END_REF] .

Several studies have assessed whether medico-economic databases could be used to improve ADR detection [START_REF] Jorup-Rönström | Could Swedish 'Yellow Cards' Be Substituted by E-Coded Summaries?[END_REF][START_REF] Wodtke | Use of medical record codes to identify adverse drug reactions[END_REF][START_REF] Cox | Adverse drug reactions in patients admitted to hospital identified by discharge ICD-10 codes and by spontaneous reports[END_REF] . These authors detected more ADRs using the billing codes of the international classification of diseases, 10 th edition (ICD-10), compared to the number of ADRs identified via spontaneous reporting for the same period. Moreover, they observed little or no overlap between the numbers of ADR events detected using the two methods.

Similarly, the French Medical Information System Program (PMSI) database generates Diagnosis-related Groups (DRGs) that contain administrative and medical data, including diagnoses that are classified according to the ICD-10 codes. By querying this database using selected ICD-10 billing codes, it is possible to identify serious ADR events. This system is now routinely used by the Regional Pharmacovigilance Center of Rennes [START_REF] Osmont | Use of the PMSI for the detection of adverse drug reactions[END_REF] to detect serious ADRs, such as generalized rash, anaphylaxis, nephropathy, liver damage, polyneuropathy, neuroleptic malignant syndrome and interstitial lung disease (see Appendix 1 for a list of ICD-10 billing codes used by the Regional Pharmacovigilance Center of Rennes). All hospital stays involving a hospitalization summary that includes at least one of the selected ICD-10 billing codes are investigated to validate whether the extracted ADR is relevant to pharmacovigilance.

Big data analysis also could contribute to improving the relevance of the detected signals. In France, this could be done with the support of institutions that run large databases and/or manage several health professionals' databases, such as the French National Agency for Medicines and Health Products Safety (ANSM), the French National Health Insurance Agency (CNAM), the French Public Regional Health Agencies (ARS), the Hospital Information Technology Agency (ATIH), or the French national inter-scheme information system of health insurance (SNIIRAM, Système national d'information inter-régimes de l'Assurance maladie), which combines the French healthcare reimbursement system and PMSI databases. Nevertheless, they should be considered as extra sources of information rather than as replacements for spontaneous notifications that remain the most effective tool to date [START_REF] Vial | French pharmacovigilance: Missions, organization and perspectives[END_REF] . As these methods are not exhaustive, the use of other data sources and methods becomes necessary to effectively identify ADR events in hospitals [START_REF] Asfari | Drug-related anaphylactic shocks: under-reporting and PMSI[END_REF] . Due to the widespread use of electronic health records (EHRs), biomedical data collected during the clinical care process could be reused and analyzed to improve ADR detection [START_REF] Coloma | Electronic healthcare databases for active drug safety surveillance: is there enough leverage?[END_REF][START_REF] Trifirò | From Big Data to Smart Data for Pharmacovigilance: The Role of Healthcare Databases and Other Emerging Sources[END_REF][START_REF] Black | Pharmacovigilance in children: detecting adverse drug reactions in routine electronic healthcare records. A systematic review[END_REF] . Technologies, such as Clinical Data Warehouses (CDW), have these abilities. They are currently deployed in many hospitals, thus making possible the efficient exploitation of clinical data [START_REF] Lowe | STRIDE -An Integrated Standards-Based Translational Research Informatics Platform[END_REF][START_REF] Cuggia | Roogle: an information retrieval engine for clinical data warehouse[END_REF][START_REF] Murphy | Serving the enterprise and beyond with informatics for integrating biology and the bedside (i2b2)[END_REF] . We believe that such technologies can also be used to address some of the issues currently encountered in pharmacovigilance.

We are interested in improving the detection of anaphylactic shock events. We previously carried out a study to evaluate the performance of a data-gathering method using a CDW for cases of anaphylactic shocks (IgE-mediated) that specifically occurred during anesthesia at the Academic Hospital of Rennes (CHU-RENNES) [START_REF] Osmont | Peranesthesic Anaphylactic Shocks: Contribution of a Clinical Data Warehouse[END_REF] . In that study, anaphylactic shock during anesthesia proved to be an easily identifiable clinical entity. However, we think that the identification of anaphylactic shock events due to other causes also could be improved by using the same kind of information retrieval method. Therefore, the objective of the current study was to assess whether clinical data from narrative EHRs can help pharmacovigilance centers to detect drug-induced anaphylaxis. More specifically, we propose an optimal method, based on a CDW, to detect drug-induced anaphylaxis events.

Material and methods

Data sources and studied population

At the CHU-RENNES, we developed our own CDW solution, called eHOP (formerly Roogle) [START_REF] Delamarre | Semantic integration of medication data into the EHOP Clinical Data Warehouse[END_REF][START_REF] Cuggia | Roogle: an information retrieval engine for clinical data warehouse[END_REF] . Briefly, this CDW integrates all types of documents produced by the hospital information system and connected with healthcare:

• structured data using reference terminologies (e.g., ICD-10 diagnoses from DRGs, local terminology codes for laboratory tests, Association for the Development of Informatics in Cytology and Pathology codes for pathology diagnoses, Anatomical Therapeutic Chemical terminology corresponding to drug prescriptions and administration);

• unstructured data, such as clinical narrative notes, surgical protocols, X-rays or pathology reports.

Hence, a unique attribute of eHOP is that it allows users to search for information from both structured and unstructured data. Additionally, two different ways of querying data can be combined. Users can build queries based on reference terminologies (e.g., ICD-10), or simply submit keywords to retrieve both structured (e.g., terminology labels) or unstructured documents that contain these terms or keywords. Users can then access documents via a dedicated interface that incorporates functionalities to allow navigating through the entire patient EHR. eHOP is routinely used at the CHU-RENNES to support clinical research in feasibility studies, or for screening patients for eligibility criteria.

The eHOP CDW currently provides the possibility to search among 25 million unstructured data and 170 million structured elements. Some unstructured data, such as laboratory results or diagnoses, are also recorded in a structured form thanks to the corresponding terminological codes. All these data are collected from EHRs and cover more than 1.2 million patients.

For this study, we defined two datasets from eHOP: i) a training set that contained information on patients who stayed at the hospital between January 1 and December 31, 2011; and ii) a test set that contained data on patients who stayed at the hospital between January 1 and December 31, 2012.

The inclusion period of one year for the two sets was extended by three months to ensure that the data obtained would be complete. This was done to take into account possible delays in the production of documents for patients with a suspected anaphylaxis event who, at the end of the studied period, had allergy-related consultations. All documents related to these patients and produced during the studied period (including the three additional months) were used as part of the information retrieval process.

Definition of anaphylaxis

This study focused on patients who had drug-induced anaphylaxis. Anaphylaxis is an acute, potentially life-threatening hypersensitivity reaction that involves the release of mediators from mast cells, basophils and recruited inflammatory cells. Anaphylaxis is defined by a number of signs and symptoms, alone or in combination, that occur within minutes, or up to a few hours after exposure to a causative agent [START_REF] Montañez | Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis[END_REF] . Concerning the underlying mechanisms, the anaphylactic reaction can be IgE-mediated or non-IgE-mediated. Based on the reaction severity, anaphylaxis can be classified in four levels: [START_REF] Delamarre | Semantic integration of medication data into the EHOP Clinical Data Warehouse[END_REF] • level I: presence of cutaneous signs;

• level II: presence of measurable, but not life-threatening symptoms, including cutaneous effects, arterial hypotension, cough or ventilation difficulties;

• level III: presence of life-threatening symptoms (e.g., cardiovascular collapse, tachycardia or bradycardia, arrhythmias, severe bronchospasms);

• level IV: circulatory failure, cardiac and/or respiratory arrest.

All anaphylaxis episodes that occurred at CHU-RENNES or led to hospitalization or required allergy investigations at the hospital were considered relevant for our study. As in France, there are 31 regional pharmacovigilance centers, we included only the anaphylaxis cases that occurred in the geographic area covered by the Regional Pharmacovigilance Center of Rennes.

Moreover, a given patient was included in the study and considered as having had a new anaphylaxis episode each time that she/he was hospitalized or required allergy investigations at the hospital for drug-induced anaphylaxis during the study period.

Extraction of the known drug-related anaphylaxis cases

The known cases of drug-related anaphylaxis (reference drug-related anaphylaxis cases throughout the text) that occurred within or required care at CHU-RENNES during the training period (2011) were retrieved from the French pharmacovigilance database, which contains all reported ADRs, spontaneously reported and identified using DRGs (based on two ICD-10 billing codes: T88.2 and T88.6) (see Figure 1 for the study design). The Medical Dictionary for Regulatory Activities (MedDRA®) term "Anaphylactic responses" and the high-level term belonging to the System Organ Classes "Immune system disorders" were used to query the database. Criteria on the active substance responsible for the anaphylaxis were not included in the query.

The same procedure was used to extract the drug-related anaphylaxis cases from the French pharmacovigilance database for 2012 for the comparison with the results obtained with the test set (2012).

Identification of keywords related to the reference drug-related anaphylaxis cases

Two different methods were used to identify potentially relevant keywords: a) Experts from the Regional Pharmacovigilance Center of Rennes reviewed the discharge summaries of the reference drug-related anaphylaxis cases extracted from the French pharmacovigilance database, in order to identify terms used by clinicians in connection with such episodes. b) Analysis of the keywords used in the previous study to detect cases of anaphylactic shock occurring during anesthesia [START_REF] Osmont | Peranesthesic Anaphylactic Shocks: Contribution of a Clinical Data Warehouse[END_REF] . These keywords were "anaphylaxis" and "anesthesia". Only the cases in which "anaphylaxis" OR "anaphylactic" OR "anaphylactoid" was not mentioned in the discharge summaries could not be identified in this study. Moreover, these previous results suggested that keywords connected with symptoms of anaphylaxis were not sufficiently specific.

Definition of the optimized query

To define the optimized query, the set of keywords identified in 2.4 were used to query structured and particularly unstructured data to find, at least, the reference drug-related anaphylaxis cases in the training set (2011) from the eHOP CDW. Moreover, the performance of each keyword was independently tested in terms of retrieval of the reference drug-related anaphylaxis cases, by using the following standard evaluation measures:

-Precision: fraction of drug-related anaphylaxis cases among all retrieved patients -Recall: fraction of retrieved drug-related anaphylaxis cases among all anaphylaxis cases

-Synthetic F-measure: 2 • 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 • 𝑝𝑝𝑝𝑝𝑝𝑝𝑟𝑟𝑟𝑟𝑟𝑟 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 + 𝑝𝑝𝑝𝑝𝑝𝑝𝑟𝑟𝑟𝑟𝑟𝑟
A given keyword was considered to be relevant if its recall was at least 0.5. The recall measure was prioritized because it is essential for pharmacovigilance experts not to miss any relevant case. The optimized query was built by combining the retained keywords (recall ≥ 0.5) with the help of the inclusive disjunction ("OR"), so that the query would retrieve all documents matching at least one of the relevant keywords.

Evaluation of the optimized query in the test set

The real performance (precision, recall and F-measure) of the optimized query and of each keyword forming this query (i.e., all keywords with a recall ≥0.5 in the training set) was assessed in the test set.

Two pharmacovigilance experts from the Regional Pharmacovigilance Center of Rennes reviewed all potential cases returned by the query in an independent and blind validation process to confirm that they were real drug-related anaphylaxis cases. Any disagreements between experts required a consensus session before reaching the final decisions on the patient's status and relative to the definition of anaphylactic shock (and to the inclusion criteria) mentioned above. Validated cases from the test set were then compared with the drug-related anaphylaxis cases (spontaneous and DRG-based reporting) identified in the French pharmacovigilance database for 2012. Duplicated cases present in different data sources were identified using administrative data (initials, date of birth, etc.), the characteristics of the side effects, suspected drugs and date of occurrence. This step was necessary because a given patient could present with several episodes of anaphylaxis during the study period.

Final tuning of the query

During the final step, exclusion criteria were added to the optimized query, consisting of keywords connected with the causes of anaphylaxis, identified by experts, in patients who had not suffered drug-induced anaphylaxis. This pruning phase was validated by testing the optimized, pruned query using the training set to check whether all reference drug-induced anaphylaxis cases were still detected.

The study design is summarized in Figure 1.

Ethics statement and funding sources

This study was approved by the Ethics Committee of the academic hospital of Rennes and performed in accordance with the Declaration of Helsinki guidelines.

The funding source, the French National Agency for Medicines and Health Products Safety (ANSM), had no role in the study.

Results

Extraction of reference drug-induced anaphylaxis cases from the French pharmacovigilance database

In total, 30 anaphylaxis cases were identified in the French pharmacovigilance database for the area covered by the Regional Pharmacovigilance Center of Rennes for the year 2011.

Among them, 19 cases were selected as confirmed cases that occurred or required care at the CHU-RENNES. For the remaining 11 cases, 9 did not occur at the CHU-RENNES, one had a final diagnosis of mastocytosis and one included an anaphylactoid reaction.

Keyword identification and evaluation in the training set

On the basis of the review of the 19 reference drug-related anaphylaxis cases by the experts at the Regional Pharmacovigilance Center of Rennes and the previous study on anaphylaxis during anesthesia, the following keywords were selected: ̵ Anaphylaxis query: words prefixed by "anaphy." ̵ Tryptase query: "level" AND "tryptase" OR "increase" AND "tryptase," with a maximum of two words between them.

̵ Allergo-anesthesia query: words prefixed by "allergo-anesth."

̵ Allergen-specific IgE query: "allergen-specific IgE."

The two experts identified 59 cases of drug-induced anaphylaxis among the 253 patients retrieved from the test set using the optimized query: 38 cases of drug-induced anaphylaxis that occurred or required care at the CHU-RENNES, and 21 cases that required allergy investigations at the hospital (Table 3). The detailed results on each keyword performance can be found in Table 4.

Specifically, among the 253 patients, one expert identified 60 and the other one 56 cases of drug-related anaphylaxis. Ten disagreements between experts were resolved during consensus sessions. These disagreements included three cases that were validated by one of the experts, although the date of occurrence of the shock was not included in the study period; one case that was wrongly excluded because the date of occurrence was inaccurate, but within the study period; three cases that were included by one expert, although the name of the drug was not reported (only its pharmacological class); and three other cases that were not identified by one of the two experts when reading the records.

Comparison of data sources for the identification of anaphylaxis cases

Analysis of the in French pharmacovigilance database for the year 2012 highlighted the presence of 17 drug-induced anaphylaxis cases at the CHU-RENNES and 10 cases that required care at the hospital (Table 3). Comparison of the data concerning the drug-induced anaphylaxis cases identified in the test set (eHOP) and in the French pharmacovigilance database showed that among the 41 cases that occurred at the hospital (test set + French pharmacovigilance database cases, see Table 3), 17 were already recorded in the French pharmacovigilance database (10 cases identified from DRGs and 7 spontaneously reported by physicians). Only two cases were shared by these two last data sources. Among these 17 cases, only three cases, which were spontaneously reported by physicians, were not found by querying the test set. One had a missing discharge summary, one was described as an "allergic reaction", and the last one was only described using symptoms related to anaphylaxis. Twenty six cases were only found by querying the test set from eHOP.

Among the 25 cases that required allergy investigations at the hospital (Table 3), 10 were spontaneously reported by physicians. Four of these spontaneously reported cases were not detected via eHOP. These four cases occurred in the area covered by the Regional Pharmacovigilance Center of Rennes, but allergy investigations were not conducted at the CHU-RENNES during the studied period. Fifteen cases were detected only in the test set.

Final tuning

Besides drug-induced anaphylaxis, the main causes of anaphylaxis identified by experts were food and insect stings. Therefore, the following keywords were added to the optimized query as exclusion criteria: "flour," "rye," "wheat," "venom," "wasp," "hymenopteran," "stings," "bee," "bumble bee" and "insect". The other source of false positive cases was the mention of "shock" or "collapse" in the documents describing the patients' medical history.

Consequently, another exclusion criterion was added to exclude patients for whom only the keywords "shock" or "collapse" appeared in their medical history (see Appendix Finally, based on the dates on the retrieved documents, it was calculated that the median number of potential cases per week was three (IQR: [2-5]), with a median number of validated drug-induce anaphylaxis cases of one every two weeks (IQR: [0-3]).

Discussion

Comparison of data sources for the identification of anaphylaxis cases

Our study demonstrates the added value of using information technologies, such as CDWs to improve the current practice, specifically in terms of identifying ADRs. The methods currently used, such as spontaneous reporting and DRG queries, do not detect all relevant ADRs and thus lead to underestimating drug safety issues. As suggested by some authors, it is extremely valuable to use additional data sources that allow better ADR detection and contribute to improving drug safety for patients [START_REF] Asfari | Drug-related anaphylactic shocks: under-reporting and PMSI[END_REF] .

We do not intend to offer a method that exhaustively detects every case of drug-induced anaphylaxis. Producing reliable estimates for missing cases is undoubtedly a complex and time-consuming task because it would require reviewing all hospital visits during a given period to confirm both the occurrence of the anaphylaxis episode and the causal link with the administration of a drug. Yet, we do believe that spontaneous reporting, DRG queries and CDW (eHOP in our study) queries are complementary and can be integrated into a global strategy for the systematic detection of ADRs.

Evaluation of the query on the test set

If we compare the performance of three ADR detection methods on the test set, all cases spontaneously reported by physicians were valid drug-related anaphylaxis cases. In addition, DRG reporting allowed the validation of 10 of the 11 (90.9%) potential cases of anaphylactic shock (ICD-10 billing codes T88.2 and T88.6). In contrast, only 59 cases were validated among the 200 anaphylaxis cases (29.5%) identified in the test set (from eHOP) using the improved query with exclusion criteria (38 cases that occurred or required care at the CHU-RENNES [19%], and 21 cases that required allergy investigations at the hospital [10.5%]).

The eHOP query is less specific than spontaneous reporting and DRG queries, although its sensitivity is far higher, thus allowing the detection of a larger number of relevant cases (41 of the 59 cases identified via the eHOP query were new). Concerning the drug-related anaphylaxis cases that occurred or required care at the CHU-RENNES, the proposed eHOP query detected all the cases identified through the DRG query, four of the seven spontaneously reported cases, and 26 not previously known cases. The eHOP query also detected several cases that did not occur at the CHU-RENNES, but that only required allergy investigations (including outpatients). This kind of case cannot be identified via DRG queries because DRGs are only produced for inpatients. In addition, our method retrieved patients mainly from outpatient discharge summaries or laboratory results that are inaccessible to the DRG query.

Comparison of the keyword recall values in the training (2011) and test (2012) sets showed that the keywords "anaphylaxis" and "allergen-specific IgE" allowed the detection of more relevant cases. Conversely, "allergo-anesthesia" and "tryptase" displayed a lower recall value in the test set than in the training set. This could lead to false positive results when using these two keywords, which can be explained by the fact that consultations for anesthesia-related allergy problems and tryptase tests are only performed after the identification and investigation of drug-induced anaphylaxis (i.e., the type of cases that were identified in the training set). Thus, these keywords are not as pertinent for the identification of unknown cases that have not been spontaneously declared or identified via DRG. These observations highlight the complementarity of these three methods to improve the use of the available data sources for ADR detection.

Added value of the eHOP CDW

One of the strengths of the eHOP technology is the possibility to query both unstructured and structured data. For instance, 56.9% of all retrieved documents were unstructured: discharge summaries from inpatients, outpatients or emergency departments (Table 2). Structured data (DRG codes and laboratory results) constituted only 33.6% of all retrieved documents, and most information found in EHRs is recorded as free text. More specifically, the search terms "tryptase" and "allergen-specific IgE" may improve the thoroughness of anaphylaxis detection. Most institutions currently use the standard i2b2 platform as their CDW technology, although its main purpose is the integration of structured data. Therefore, when only structured data are obtainable (or full-text information retrieval systems are not available), querying tryptase laboratory tests or allergen-specific IgE assays from i2b2, or even directly from laboratory information systems, can help to improve the detection of druginduced anaphylaxis cases.

We consider that it is crucial to have the appropriate tools to adequately leverage the richness of the different data sources. Therefore, the eHOP CDW is currently deployed in the six main academic hospitals of western France. This could lead to the implementation of our query method by other pharmacovigilance centers, thus allowing the assessment of its potential and also an easier ADR detection at a larger scale.

Another advantage of eHOP over other CDW technologies is its easier access to EHR data that could facilitate the investigation process by pharmacovigilance experts. We found that if the eHOP query was used in routine practice by pharmacovigilance experts, the average number of potential cases to be investigated would be three per week (IQR: [2-5]). This method would result in one valid case detected every two weeks (IQR: [0-3]). This additional workload would be viable and could be handled by pharmacovigilance experts as part of their practice. In addition, eHOP provides a user interface for navigating through EHRs, thus making the investigation process even easier.

Perspectives

Several options can be further explored to improve the proposed method. For instance, natural language processing (NLP) could increase the detection accuracy, as the presence of the keyword "anaphylaxis" in the patients' medical history yielded several false positive cases.

Most importantly, the available amount of health data and their heterogeneity require using machine learning and text mining approaches. Our study demonstrates that simple information retrieval methods are very efficient when the concepts to be retrieved can be described with relatively specific keywords. This is particularly true in pharmacovigilance, where there is still space for significantly improving ADR detection rate and accuracy. Our method could be applied to other ADR type. However, many diseases have complex characteristics and several etiologies, besides ADRs. In such cases, machine learning approaches could help to detect hidden or latent characteristics that are specific to complex ADRs.

Conclusion

Pharmacovigilance is crucial for the efficient long-term management of drug safety. This requires the development of suitable tools. Here, we described an information retrieval-based method for the detection of drug-induced anaphylaxis, based on querying both structured and unstructured data from a CDW. Besides the 25 cases already known from spontaneous and DRG reporting for 2012, with this method we could identify 41 additional cases. Our method can be easily implemented in the routine practice and could be proposed to other regional pharmacovigilance centers to better identify well-defined ADRs. Additional improvements may be necessary for the detection of more complex ADRs, possibly by using NLP processing, as well as machine learning and text mining methods.

Figures legends

  3, containing the complete Oracle text SQL query). The new optimized query that included also the exclusion criteria retrieved 200 potential cases from the test set (2012), compared to the 253 cases obtained by using the first version of the optimized query. This reduced group still contained all 59 drug-related anaphylaxis cases, thus resulting in a final precision of 0.29. The same process using the training set (2011) still retrieved the 19 reference drug-related anaphylaxis cases among 202 potential cases, compared with 270 cases retrieved by the original query.

Figure 1 .

 1 Figure 1. Study design to build the optimized query used to identify drug-related anaphylaxis cases

Table 1 .

 1 Query results using the training set (2011)

	Tables
	Id Query	No. of retrieved	No. of returned	Precision Recall F-measure
			cases out of 19	patients out of
				178,676
	1	anaphylaxis	17	226	0.08 0.89	0.15
	2	allergo-anesthesia	13	44	0.30 0.68	0.42
	3	tryptase	10	38	0.26 0.53	0.22
	4	allergen-specific IgE	10	87	0.11 0.53	0.18
	5	prick-testing	7	28	0.25 0.37	0.30
	6	intradermal allergy	6	100	0.06 0.32	0.10
		testing
	7	histamine	4	9	0.44 0.21	0.28
	8	contraindication	4	6	0.67 0.21	0.32
	9	immunoallergic	2	13	0.15 0.11	0.13
	10 RAST-inhibition	1	2	0.50 0.05	0.09
		Optimized query (1 OR 2 OR 3 OR 4)	19	270	0.07 1.00	0.13

Table 2 .

 2 Summary of the types of retrieved documents (test set, 2012)

		Overall	Outpatient	Inpatient	DRGs		Discharge	Laboratory	Other
				discharge	discharge			summary	results
				summary	summary			from
										emergency
										department
	Query N	% No.	% No.	% No.	% No.	% No.	% No.	%
		o
		.
	anaph	3	100 149 43.4	73 21.3	42 12.3	25 7.3	11	3.2	42 12.5
	ylaxis	4
		3
	allerg	3	100	36 94.8	1	2.6	0	0	0	0	0	0	1 2.6
	o-	8
	anesth
	esia
	tryptas	6	100	19 29.2	2	3.1	0	0	0	0	42 64.6	2 3.1
	e	5

Table 3 .

 3 Comparison of data sources for the identification of drug-induced anaphylaxis cases

	(2012)
	Source	Number of cases	Number of cases that	Total number
		that occurred at	required allergy	of cases
		CHU-RENNES	investigation at
			CHU-RENNES
	eHOP CDW (test set)
	total	38	21	59
	only detected in eHOP	26	15	41
	not detected in eHOP	3	4	7
	DRGs
	total	10	n/a	10
	only detected with DRGs	0	n/a	0
	not detected with DRGs	31	n/a	31
	Spontaneous reports
	total	7	10	17
	only detected by spontaneous reports	3	4	7
	not detected by spontaneous reports	34	15	59
	Total*	41	25	66
	*Total number of individual cases of drug-related anaphylaxis identified using the three
	sources.

Table 4 .

 4 Optimized query evaluation using the test set (2012) Optimized query with exclusion criteria: complete Oracle text SQL query (shock or collapse) and (anaphy% OR NEAR((level, tryptase), 2, TRUE) OR NEAR((increase%, tryptase), 2, FALSE) OR allergo-anesth% OR allergen-specific IgE%) not (flour or rye or wheat or venom% or wasp% or hymenopter% or sting% or bee% or bumble bee% or insect% or near((medical history%, shock% or collapse), 50, true))

	Id	Query	No. of retrieved	No. of returned	Precision	Recall F-measure
			cases out of 59	patients out of
				182,127
	1	anaphylaxis	44	190	0.23	0.74	0.15
	2	allergo-anesthesia	11	35	0.31	0.19	0.42
	3	tryptase	22	56	0.39	0.37	0.22
	4	allergen-specific IgE	42	114	0.37	0.71	0.18
		Optimized query (1 OR 2 OR 3 OR 4)	59	253	0.23	1	0.13
	Figures
	Figure 1

Acknowledgements

We would like to thank the French National Agency for Medicines and Health Products Safety (ANSM), for funding this work inside the Breizh project (Evaluation of under-

̵ Prick testing query: "prick-test."

̵ Intradermal allergy testing query: "intradermal" OR "intra-dermal." ̵ Histamine query: words "histamine" AND "increased" with a maximum of two words between them.

̵ Contraindication query: "strictly contraindicated." ̵ Immunoallergic query: words prefixed by "immunoaller." ̵ RAST inhibition query: "RAST inhibition."

The next step was to evaluate the capacity of different queries in which the term "shock" or "collapse" was combined with one of these keywords (all Oracle Text SQL queries are in Appendix 2) to retrieve the reference drug-induced anaphylaxis cases from the training set (n=178,676 patients with at least one hospital visit in 2011). Among the tested queries, "anaphylaxis" showed the highest recall, because it retrieved 17 of the 19 reference druginduced anaphylaxis (0.89). It was also the keyword with the lowest precision (0.08) (Table 1). The queries "allergo-anesthesia," "tryptase," and "allergen-specific IgE" retrieved at least half of the reference cases (i.e., with a recall higher than 0.5).

On the basis of these results, an optimized query that included all individual queries with recall ≥ 0.5 was built by using the inclusive disjunction ("OR"), so that any fulfilled condition was sufficient to retrieve a relevant case. This optimized query had a recall value of 1 and a precision value of 0.07 (all 19 reference cases among the 270 patients retrieved by the query) (Table 1).

Optimized query performance in the test set

The test set included 182,127 patients with at least one hospital visit in 2012. The optimized query identified 253 patients and 452 matching documents: 159 outpatient discharge summaries (35% of all documents), 110 biology results (24%), 73 inpatient discharge summaries (16%), 42 DRGs (9%), 25 discharge summaries from the emergency department (6%) and miscellaneous narrative documents (10%). The "anaphylaxis" and "allergoanesthesia" queries (which correspond to signs and symptoms) mainly matched outpatient discharge summaries, whereas the "tryptase" and "allergen-specific IgE" queries (which correspond to biological results) matched laboratory results (Table 2).

Expert evaluation

reporting of adverse drug reactions in public hospitals in Brittany: the contribution of PMSI and a biomedical data warehouse) (grant no. AAP-2014-014).

Appendices