1. Maria Grazia Pia, INFN Genova for Microdosimetry for Microdosimetry CECAM Workshop Lyon, 3-6 December 2007 DNA Maria Grazia Pia INFN Genova S. Chauvie (Cuneo Hospital and INFN), S. Incerti and Ph. Moretto (CENBG) Partly funded by

2. Maria Grazia Pia, INFN Genova Courtesy Borexino Courtesy H. Araujo and A. Howard, IC London ZEPLIN III Courtesy CMS Collaboration Courtesy ATLAS Collaboration Courtesy K. Amako et al., KEK Courtesy GATE Collaboration Courtesy R. Nartallo et al.,ESA Widely used also in  Space science and astrophysics  Medical physics, nuclear medicine  Radiation protection  Accelerator physics  Humanitarian projects, security  etc. Technology transfer to industry, hospitals… Born from the requirements of large scale HEP experiments Most cited “Nuclear Science and Technology” publication! S. Agostinelli et al. GEANT4 - a simulation toolkit NIM A 506 (2003) 250-303 GEANT4 - a simulation toolkit

3. Maria Grazia Pia, INFN Genova LHC ATLAS LHCb Complex physics Complex detectors 20 years software life-span

4. Maria Grazia Pia, INFN Genova Dosimetry Space science Radiotherapy Effects on components Multi-disciplinary application environment Wide spectrum of physics coverage, variety of physics models Precise, quantitatively validated physics Accurate description of geometry and materials Courtesy of ESA Courtesy of CERN RADMON team

5. Maria Grazia Pia, INFN Genova Dosimetry in Medical Applications Courtesy of L. Beaulieu et al., Laval Brachytherapy Radiation Protection Courtesy of J. Perl, SLAC Hadrontherapy Courtesy of P. Cirrone et al., INFN LNS Courtesy of F. Foppiano et al,. IST and INFN Genova Radiotherapy with external beams, IMRT Courtesy of F. Foppiano et al., IST and INFN Genova

6. Maria Grazia Pia, INFN Genova Exotic Geant4 applications… FAO/IAEA International Conference on Area-Wide Control of Insect Pests Area-Wide Control of Insect Pests: Integrating the Sterile Insect and Related Nuclear and Other Techniques Vienna, May 9-13, 2005 K. Manai, K. Farah, A.Trabelsi, F. Gharbi and O. Kadri (Tunisia) Dose Distribution and Dose Uniformity in Pupae Treated by the Tunisian Gamma Irradiator Using the GEANT4 Toolkit

7. Maria Grazia Pia, INFN Genova Precise dose calculation Geant4 Low Energy Electromagnetic Physics package Electrons and photons (250/100 eV < E < 100 GeV) Models based on the Livermore libraries (EEDL, EPDL, EADL) Models à la Penelope Hadrons and ions Free electron gas + Parameterisations (ICRU49, Ziegler) + Bethe-Bloch Nuclear stopping power, Barkas effect, chemical formula, effective charge etc. Atomic relaxation Fluorescence, Auger electron emission, PIXE Fe lines GaAs lines Atomic relaxation Fluorescence Auger effect shell effects ions

8. Maria Grazia Pia, INFN Genova Fundamental concepts Functionality: physics, geometry etc. Software technology Open source distribution Toolkit Transparency International Collaboration

9. Maria Grazia Pia, INFN Genova Physics From the Minutes of LCB (LHCC Computing Board) meeting on 21 October, 1997: “It was noted that experiments have requirements for independent, alternative physics models. understand physics validation In Geant4 these models, differently from the concept of packages, allow the user to understand how the results are produced, and hence improve the physics validation. Geant4 is developed with a modular architecture and is the ideal framework where existing components are integrated and new models continue to be developed.”

10. Maria Grazia Pia, INFN Genova Domain decomposition hierarchical structure of sub- domains Geant4 architecture Uni-directional flow of dependencies Interface to external products w/o dependencies Software Engineering plays a fundamental role in Geant4 User Requirements formally collected systematically updated PSS-05 standard Software Process spiral iterative approach regular assessments and improvements (SPI process) monitored following the ISO 15504 model Quality Assurance commercial tools code inspections automatic checks of coding guidelines testing procedures at unit and integration level dedicated testing team Object Oriented methods OOAD use of CASE tools openness to extension and evolution contribute to the transparency of physics interface to external software without dependencies Use of Standards de jure and de facto

11. Maria Grazia Pia, INFN Genova Toolkit components A set of compatible components specialised each component is specialised for a specific functionality refined each component can be refined independently to a great detail integrated components can be integrated at any degree of complexity alternative it is easy to provide (and use) alternative components customised the user application can be customised as needed extensionevolution Openness to extension and evolution new implementations can be added w/o changing the existing code maintenance Robustness and ease of maintenance protocols dependencies protocols and well defined dependencies minimize coupling OO technology Strategic vision

12. Maria Grazia Pia, INFN Genova http://www.ge.infn.it/geant4/dna

13. Biological models in Geant4 Relevance for space: astronaut and aircrew radiation hazards Project originally motivated and partly funded by

14. Maria Grazia Pia, INFN Genova Simulation of nano-scale effects of radiation at the DNA level Various scientific domains involved medical, biology, genetics, physics, software engineering Multiple approaches can be implemented with Geant4 RBE parameterisation, detailed biochemical processes, etc. First phase: 2000-2001 Collection of user requirements & first prototypes Second phase: started in 2004 Software development & open source release DNA “Sister” activity to Geant4 Low-Energy Electromagnetic Physics Follows the same rigorous software standards INFN (Genova) - IN2P3 ( CENBG) Partly sponsored by ESA New collaborators welcome!

15. Maria Grazia Pia, INFN Genova Multiple domains in the same software environment Macroscopic level calculation of dose already feasible with Geant4 develop useful associated tools Cellular level cell modelling processes for cell survival, damage etc. DNA level DNA modelling physics processes at the eV scale bio-chemical processes processes for DNA damage, repair etc. Complexity of software, physics and biology addressed with an iterative and incremental software process Parallel development at all the three levels (domain decomposition)

16. Maria Grazia Pia, INFN Genova What’s new? Many “track structure” Monte Carlo codes previously developed A lot of modelling expertise embedded in these codes one Each code implements one modelling approach (developed by its authors) Stand-alone “Stand-alone” codes, with limited application scope Legacy software technology (FORTRAN, procedural programming) Not publicly distributed Geant4-DNA “Track structure” simulation in a general-purpose Monte Carlo system Toolkit approach: many interchangeable models Advanced software technology software process Rigorous software process Open source Open source, freely available, supported by an international organization Foster a collaborative spirit in the scientific community Benefit of the feedback of a wider user community

17. Maria Grazia Pia, INFN Genova 1 st development cycle: Geant4 physics extensions Complex domain Physics: collaboration with theorists Technology: innovative design technique introduced in Geant4 (1 st time in Monte Carlo) Experimental complexity as well Scarce experimental data Collaboration with experimentalists for model validation Geant4 physics validation at low energies is difficult! Physics down to the eV scale

18. Maria Grazia Pia, INFN Genova Geant4-DNA physics processes Models in liquid water More realistic than water vapour Theoretically more challenging Hardly any experimental data New measurements needed Status 1st  -release Geant4 8.1 Full release on 14 December 2007 Further extensions in progress Models for water vapour Models for other materials than water ParticleProcesses e-e- Elastic scattering Excitation Ionisation p Charge decrease Excitation Ionisation H Charge increase Ionisation He++ Charge decrease Excitation Ionisation He+ Charge decrease Charge increase Excitation Ionisation He Charge increase Excitation Ionisation Specialised processes for low energy interactions with water

19. Maria Grazia Pia, INFN Genova (Current) Physics Models epH  He+ He Elastic > 7.5 eV Screened Rutherford + empirical Brenner-Zaider Excitation 7.5 eV – 10 keV A 1 B 1, B 1 A 1, Ryd A+B, Ryd C+D, diffuse bands 10 eV – 500 keV Dingfelder 500 keV – 10 MeV Emfietzoglou 100 eV – 10 MeV Dingfelder Effective charge scaling from same models as for proton Dingfelder Charge Change 100 eV – 10 MeV Dingfelder 100 eV – 10 MeV Dingfelder Ionisation 7 eV – 10 keV Emfietzoglou 1b 1, 3a 1, 1b 2, 2a 1 + 1a 1 100 eV – 500 keV Rudd 500 keV – 10 MeV Dingfelder (Born) 100 eV – 10 MeV Dingfelder

20. Maria Grazia Pia, INFN Genova Why these models? No emotional attachment to any of the models Toolkit: offer a wide choice among many available alternatives Complementary/alternative models No “one size fits all” Powerful design Abstract interfaces: the kernel is blind to any specific modelling The system is intrinsically open to multiple implementations Improvements, extensions, options Open system Collaboration is welcome (experimental/modelling/software)

21. Maria Grazia Pia, INFN Genova What is behind… A policy defines a class or class template interface Policy host classes are parameterised classes classes that use other classes as a parameter Advantage w.r.t. a conventional strategy pattern Policies are not required to inherit from a base class The code is bound at compilation time  No need of virtual methods, resulting in faster execution Policy-based class design Policies can proliferate w/o any limitation Syntax-oriented rather than signature-oriented New technique 1 st time introduced in Monte Carlo Weak dependency of the policy and the policy based class on the policy interface Highly customizable design Open to extension

22. Maria Grazia Pia, INFN Genova Geant4-DNA physics process Deprived of any intrinsic physics functionality Configured by template specialization to acquire physics properties Handled transparently by Geant4 kernel

23. Maria Grazia Pia, INFN Genova Development metrics Open to extension: what does it mean in practice? Implementation + unit test of a new physics model 5 to 7 hours ~ 5 to 7 hours (average computing experience) No integration effort at all Other software processes Peer review of the code Integration testing System testing Porting to other supported platforms User documentation Experimental validation Investment in software technology!

24. Maria Grazia Pia, INFN Genova IEEE Trans. Nucl. Sci., Vol. 54, no. 6, Dec. 2007 More details on both software and physics in IEEE Trans. Nucl. Sci., Vol. 54, no. 6, Dec. 2007

25. Maria Grazia Pia, INFN Genova Example of simulation Liquid water sphere 0.2 µm diameter 1000 electrons shot from central source E = 20 keV Geant4 physics processes: Elastic scattering Excitation Ionisation 0.2 µm Shower of particles at the nm / eV scale

26. Maria Grazia Pia, INFN Genova How accurate are Geant4-DNA physics models ? Both theoretical and experimental complexity in the very low energy régime Theoretical calculations must take into account the detailed dielectric structure of the interacting material Approximations, assumptions, semi-empirical models Experimental measurements are difficult Control of systematics Practical constraints depending on the phase

27. Maria Grazia Pia, INFN Genova Verification & Validation Verification Conformity with theoretical models Performed on all physics models Validation Against experimental data Lack of experimental data in liquid water in the very low energy range New measurements needed Evaluation of plausibility Only practical option at the present stage Comparison against experimental data in water vapour/ice Interesting also to study phase-related effects

28. Maria Grazia Pia, INFN Genova A selection of results Systematic comparison in progress Survey of literature: extensive collection of experimental data (goal: all!) No time to show all of them (  paper) Selection of a few interesting cases Highlight the complexity of the experimental domain Discuss physics modelling features S. Chauvie, S. Incerti, P. Moretto, M. G. Pia, Evaluation of Phase Effects in Geant4 Microdosimetry Models for Particle Interactions in Water, Proc. IEEE NSS 2007

29. Maria Grazia Pia, INFN Genova Electron elastic scattering Theoretical challenge to model accurately at very low energy Various theoretical approaches at different degrees of complexity From simple screened Rutherford cross section to sophisticated phase shift calculations No experimental data in liquid water Geant4-DNA Simple screened Rutherford cross section + semi-empirical model based on vapour data (Why so unsophisticated? Look at the experimental data…) Open to evolution along with the availability of new data

30. Maria Grazia Pia, INFN Genova Electron elastic scattering: total cross section Evident discrepancy of the experimental data Puzzle: inconsistency in recommended evaluated data from Itikawa & Mason, J. Phys. Chem. Ref. Data, 34-1, pp. 1-22, 2005. Geant4-DNA Better agreement with some of the data sets Hardly conclusive comparison, given the experimental status… Geant4-DNA elastic  Itikawa & Mason elastic (recommended) Itikawa & Mason total (recommended)  Danjo & Nishimura  Seng et al.  Sueoka et al.  Saglam et al. Recommended total cross section smaller than elastic only one! Not all available experimental data reported… the picture would be too crowded!

31. Maria Grazia Pia, INFN Genova Electron ionisation Semi-empirical model D. Emfietzoglou and M. Moscovitch, “Inelastic collision characteristics of electrons in liquid water”, NIM B, vol. 193, pp. 71-78, 2002 Based on dielectric formalism for the valence shells (1b1, 3a1, 1b2 and 2a1) responsible for condensed- phase effects Based on the binary encounter approximation for the K-shell (1a1)

32. Maria Grazia Pia, INFN Genova Electron ionisation: total cross section Different phases Geant4-DNA model: liquid water Experimental data: vapour Plausible behaviour of Geant4 implementation Phase differences appear more significant at lower energies Geant4-DNA Born ionisation  Itikawa & Mason ionisation (recommended)

33. Maria Grazia Pia, INFN Genova Proton ionisation Cross section based on two complementary models a semi-empirical analytical approach with parameters specifically calculated for liquid water for 100 eV < E < 500 keV a model based on the Born theory for 500 keV < E < 10 MeV M. Dingfelder et al., “Inelastic-collision cross sections of liquid water for interactions of energetic protons”, Radiat. Phys. Chem., vol. 59, pp. 255-275, 2000. M. E. Rudd et al., “Cross sections for ionisation of water vapor by 7-4000 keV protons”, Phys. Rev. A, vol. 31, pp. 492-494, 1985. M. E. Rudd et al., “Electron production in proton collisions: total cross sections”, Rev. Mod. Phys., vol. 57, no. 4, pp. 965-994, 1985.

34. Maria Grazia Pia, INFN Genova Proton ionisation: total cross section All measurements performed by the same team at different accelerators and time Even data taken by the same group exhibit inconsistencies ! systematic is difficult to control in delicate experimental conditions Geant4-DNA models look plausible Hard to discuss phase effects in these experimental conditions! Goodness-of-fit test Geant4 DNA model incompatible with experimental data (p-value < 0.001) Compatibility w.r.t. data fit?  Cramer-von Mises test: p-value = 0.1  Anderson-Darling test: p-value <0.001  PNL data  early Van de Graaff data late Van de Graaff data  early Univ. Nebraska-Lincoln data  late Univ. Nebraska-Lincoln data  tandem Van de Graaff data Geant4-DNA Fit to experimental data M. E. Rudd, T. V. Goffe, R. D. DuBois, L. H. Toburen, “Cross sections for ionisation of water vapor by 7-4000 keV protons”, Phys. Rev. A, vol. 31, pp. 492-494, 1985. Different phases Geant4-DNA model: liquid water Experimental data: vapour

35. Maria Grazia Pia, INFN Genova Proton and hydrogen charge change Cross section based on a semi-empirical approach Described by an analytical formula With parameters optimised from experimental data in vapour M. Dingfelder et al., “Inelastic-collision cross sections of liquid water for interactions of energetic protons”, Radiat. Phys. Chem., vol. 59, pp. 255-275, 2000. B. G. Lindsay et al., “Charge transfer of 0.5-, 1.5-, and 5-keV protons with H2O: absolute differential and integral cross sections”, Phys. Rev. A, vol. 55, no. 5, pp. 3945-3946, 1997. R. Dagnac et al., “A study on the collision of hydrogen ions H + 1, H + 2 and H + 3 with a water-vapour target”, J. Phys. B, vol. 3, pp. 1239-1251, 1970. L. H. Toburen et al., “Measurement of highenergy charge transfer cross sections for incident protons and atomic hydrogen in various gases”, Phys. Rev., vol. 171, no. 1, pp. 114-122, 1968

36. Maria Grazia Pia, INFN Genova Charge change cross section: proton and hydrogen Different phases Geant4-DNA model: liquid Experimental data: vapour Goodness-of-fit test Geant4-DNA model experimental data ( white symbols only)  Anderson-Darling test  Cramer-von Mises test  Kolmogorov-Smirnov test  Kuiper test  Watson test p-value > 0.1 from all tests … but some data were used to optimise the semi-empirical model!  Lindsay et al.  Dagnac et al.  Toburen et al.  Berkner et al.  Cable Koopman  Chambers et al. Large discrepancies among the data!

37. Maria Grazia Pia, INFN Genova Conclusion from comparisons Geant4-DNA models (liquid) look plausible when compared to available experimental data (vapour) More experimental data are needed In liquid water for simulation model validation In vapour and ice to study the importance of phase effects in modelling particle interactions with the medium control of systematicreproducibility With good control of systematic and reproducibility of experimental conditions! Hard to draw firm conclusions about phase effects Available experimental data exhibit significant discrepancies in many cases Some of these data have been already used to constrain or optimize semi- empirical models

38. Maria Grazia Pia, INFN Genova Exploiting the toolkit For the first time general-purpose Monte Carlo a general-purpose Monte Carlo system is equipped with functionality specific to the simulation of biological effects of radiation Geant4-DNA physics processes  User Interface Kernel Geometry Visualisation

39. Maria Grazia Pia, INFN Genova Microdosimetry in high resolution cellular phantoms with Geant4-DNA © IPB/CENBG

40. Maria Grazia Pia, INFN Genova Context Understanding the health effects of low doses of ionizing radiation is the challenge of today’s radiobiology research At the cell scale, recent results include the observation of  bystander effects  adaptive response  gene expression changes  genomic instability  genetic susceptibility ►May question the validity of health risk estimation at low doses of radiation ►Consequences for radiotherapy, environment exposure, space exploration… Dedicated worldwide experimental facilities to investigate the interaction of ionizing radiation with living cells  radioactive sources  classical beams  microbeams : allow a perfect control of the deposited dose in the targeted cell (e.g. the CENBG irradiation facility in France)

41. Maria Grazia Pia, INFN Genova AIFIRA equipped with a cellular irradiation microbeam line 3 MeV proton or  beam single cell & single ion mode Targeting accuracy on living cells in air: a few µm Able to quantify DNA damages like double strand breaks CENBG AIFIRA irradiation facility in Bordeaux, France © IPB/CENBG

42. Maria Grazia Pia, INFN Genova Realistic cellular geometries from confocal microscopy depth of field ability to control depth of field background information elimination of background information away from the focal plane (that leads to image degradation) optical sections collect serial optical sections from thick specimens © Olympus Confocal microscopy offers several advantages over conventional widefield optical microscopy

43. Maria Grazia Pia, INFN Genova Confocal microscopy Images of human keratinocyte cells HaCaT/(GFP-H2B)Tg acquired at CENBG cell line used in single cell irradiation at CENBG Cells fixed after 4 hours or 24 hours of incubation (cell irradiation conditions) Staining  Nucleus: Hoechst 33342 dye (DNA marker)  Cytoplasm: propidium iodide, (RNA and DNA marker).  Nucleoli (high chromatine and protein concentration regions): idem Acquisition 2D images acquired every 163 nm with a Leica® DMR TCS SP2 confocal microscope several 2D resolutions, up to 512 × 512 pixels Image reconstruction 3D stacking using the Leica Confocal Software® filtering and phantom geometry reconstruction with Mercury® Computer Systems, Inc. Amira® suite © IPB/CENBG

44. Maria Grazia Pia, INFN Genova Building cellular models Selection of four “phantoms” reconstructed from 128×128 2D confocal images. Incubation : 4 hours for cells a and b 24 hours for cells c and d The cytoplasm and nucleoli appear in red while the nucleus is shown in blue © IPB/CENBG a b c d

45. Maria Grazia Pia, INFN Genova Geometry modelling Not available in ad-hoc Monte Carlo codes Exploit the advantage of a general purpose Monte Carlo system Powerful Geant4 geometry package Use of functionality already existing in Geant4 Voxel geometries + Navigation optimisation techniques Direct benefit from investment in the Geant4 toolkit Realistic rendering of the biological systems Important for overall realistic simulation results Parameterised volumes Nested parameterisation

46. Maria Grazia Pia, INFN Genova Cellular phantoms in Geant4 Implemented either as parameterised volumes or nested geometries (faster navigation above 64x64 resolution) Composition: liquid water (compatible with Geant4 DNA models) microbeam These cellular models are publicly available in the Geant4 microbeam Advanced Example geant4/examples/advanced/microbeam

47. Maria Grazia Pia, INFN Genova 2.37 MeV  + hitting the cell Cellular phantom model 24h incubated cell Irradiated with a 2.37 MeV  + beam 64 x 64 x 60 resolution 0.36 x 0.36 x 0.16 µm 3 voxel size cytoplasm nucleus ~10 µm

48. Maria Grazia Pia, INFN Genova Shower in cellular phantom Charge decreaseCharge increase Elastic scattering Excitation Ionisation (unit: µm) 2.37 MeV  + delivered on targeted cell by the CENBG microbeam irradiation facility G4 DNA processes CPU ~45 min (preliminary timing) ZOOM

49. Maria Grazia Pia, INFN Genova Geant4 DNA capabilities With this Geant4 extension, it is now possible to study the energy deposit distribution produced by a primary particle and its secondaries inside a cell Access distributions in nucleus, cytoplasm, mitochondria… What you get in return is more than your own investment!

50. Maria Grazia Pia, INFN Genova Changing scale Large effort for microscopic modelling of interactions and biological systems in Geant4 Parallel approach: macroscopic modelling in Geant4 Concept of dose in a cell population Statistical evaluation of radiation effects from empirical data All this is possible in the same simulation environment (toolkit) Human cell lines irradiated with X-rays Courtesy E. Hall Example: modelling cell survival fraction in a population of irradiated cells

51. Maria Grazia Pia, INFN Genova Example Computation of dose in a cell population and estimation of survival fraction Monolayer V79-379A cells Proton beam E= 3.66 MeV/n Linear-Quadratic model Folkard et al., Int. J. Rad. Biol., 1996 α = 0.32 β = -0.039 Macroscopic cell survival models to be distributed in Geant4 (advanced example in preparation) Dose (Gy) Continuous line: LQ theoretical model with Folkard parameters Data points: Geant4 simulation results Survival

52. Maria Grazia Pia, INFN Genova Conclusion The Geant4 DNA processes are publicly available Can be applied to realistic cell geometries Full comparison against vapour/ice will be published evaluation of phase effects Thanks to the flexibility of policy-based code design of Geant4 DNA, any interaction model can be easily implemented in a few hours and automatically integrated in Geant4 ! Not limited to radiation biology…

53. Maria Grazia Pia, INFN Genova Perspectives Short term  Geant4 DNA processes  will be publicly available in Geant4 9.1 on 14 December 2007  Microdosimetry advanced example  will be available in the next Geant4 releases (presumably end of June 2008)  illustrates how to use the Geant4 DNA physics processes  Cellular survival advanced example  in preparation  Other physics models  thanks to the novel software design Longer term  Chemical phase : production of radical species  Geometry-dedicated development cycle : DNA geometry modelling  Biological phase : prediction of DNA damages (double strand breaks – fatal lesions, DNA fragments…) after irrradiation Other materials than liquid water: DNA bases, silicon etc.

54. Maria Grazia Pia, INFN Genova For discussion… Geant4-DNA proposes a paradigm shift Open source, freely available software Microdosimetry/radiobiology functionality in a general-purpose Monte Carlo code Availability of multiple models in the same environment Equal importance to functionality and software technology Foster collaboration within the scientific community  Theoretical modelling, experimental measurements, software technology Promote feedback from users of the software Comments and suggestions are welcome...

55. Maria Grazia Pia, INFN Genova Acknowledgment Thanks to M. Dingfelder and D. Emfietzoglou for theoretical support W. Friedland and H. Paretzke for fruitful discussions and suggestions P. Nieminen for motivation and support to the project through ESA funding COST-P9 for supporting short-term visits R. Capra, Z. Francis, G. Montarou for preliminary contributions at an early stage G. Cosmo and I. McLaren for support in the Geant4 system testing process K. Amako for support in releasing the Geant4-DNA code documentation Z. W. Bell (TNS Senior Editor) for his advice in the paper publication process CERN Library for providing many reference papers Thanks to Nigel Mason and CECAM for organizing this workshop and supporting our participation!