The Medical Device Directorate and Quantitative Magnetic Resonance

1. The Medical Device Directorate and Quantitative Magnetic Resonance Paul Tofts (1) and Geoff Cusick (2) Institute of Neurology, UCL Department of Medical Physics, UCLH IPEM November 12th 2004

2. qMRI (URL: qmri.org) • Paradigm shift from happy snappy MRI camera • scientific instrument measuring clinically relevant quantities. • MR pulse sequences • MR image analysis programs • Work-in-progress

3. MR pulse sequence = program • Three fields: • magnetic field Bo - static • Beware projectiles, implants • magnetic field gradients – switched • dB/dt – induces emf. Neural stimulation. Painful. • Radiofrequency fields – pulsed • Power deposition, heating, SAR • Data collection, reconstruction

4. Why should MR physicists be concerned with the MDD? • Reduce personal liability of physicists • Improve quality of the device • better science • fewer errors

5. (re)interpreting the MDD for qMR • Many Essential Requirements (n=96?) • Physicists hate ‘bureaucracy’ • Provide a friendly interface ☺ • only relevant ER’s visible (n=7)

6. MDD – 96 Essential Requirements (ER’s) identify MR-relevant ER’s Interface – response to each ER can be: N/A, SRm or GRn Specific Responses (SR’s) questionnaire General Responses (GR’s) Standard info Guidance notes

7. MR-relevant ER’s • The device (whether sequence or program) must be shown to work as intended [ER3, ER12.1] → SR1 • The device have an instruction manual [ER13.1] → SR2 • The device must give output with proper units [ER10.3] → SR3 • The accuracy of the device must be specified [ER10.1] → SR4 • The precision of the device must be specified [ER10.1] → SR5 • The limits of accuracy of the device must be specified [ER10.1] → SR6 • A sequence device must have safe RF power deposition SAR [ER1, ER9.2, ER11.1.1, ER12.1] → SR7 • A sequence device must operate with the lowest reasonable static field, SAR and dB/dt.→ GR8

8. Guidance notes - general • developing good practice. • errors are valuable! • analysed case studies and learn • modify procedures to at least prevent such known errors from taking place again. • devices should have ‘test modes’, where the likely errors can be anticipated • an independent person should look at the device and check its operation.

9. Guidance notes – general - 2 • qMR is a measuring instrument • follow traditions of measurement • specify accuracy and precision • uncertainty and uncertainty budget • Human error is always present. • recognition and acceptance • design test procedures to detect it

10. 1The device (whether sequence or program) must be shown to work as intended • technical description: Name the device. What type of device is it? describe the design of the device. Why was it developed? What kind of output does it give? How does it work? • anticipate the most likely errors (up to three) that could occur and how the chance of these happening can be minimised. Look at the case studies where errors have occurred. Recognise that human error is always present. • Provide test modes to anticipate problems (including those of human error through inadequate training). For a sequence, this could be to vary one or more of the user-set parameters (the ones that the user is expected to alter as part of using the device) and to monitor that the response is as expected. For programs, provide test image data and ensure the user can replicate the expected results (within given confidence limits).

11. 1The device (whether sequence or program) must be shown to work as intended - continued • Provide independent review of the device by an experienced person or persons (one physicist and maybe one non-technical user). • Monitor the device usage during a beta-test period. This could be for one month, or 20 measurements, after the device has been handed over to the user. • Through manufacturer upgrades (hardware or software) all these validation procedures will have to be repeated. • Quality Assurance (QA) phantom results and normal control values may be used to support the validity of the device • Accuracy and precision data (see elsewhere) also support validity

12. 2. The device have an instruction manual • write a (short) set of instructions for a non-technical user. Make this inbuilt to the device if possible, so it cannot get lost (for a pulse sequence ?? how can this be done? Link to a website? Could get broken; for a program, on-line usage and help). Test the manual with at least 2 users. • Anticipate potential problems and errors and include these in the manual

13. 3 the device must give output with proper units • give the output in proper SI units where possible (for example ms, percent units (pu), microseconds). • Stored integer values in calculated maps should be at good enough resolution so as not to degrade the data, whilst not coming near the 16-bit signed integer limit of 32767 ; this typically means values of between 1000-10,000. • Use the scaling factor facility in the display program (dispim) and in the (UNC) file header so that real floating point values can be used directly by the user, without seeing the integer values.

14. 4. The accuracy of the device must be specified • show that the quantity being produced is close to the truth, as far as possible. • For a pulse sequence, use a search coil to confirm aspects of a new pulse that may be crucial, particularly its amplitude. • For an analysis program, show that the quantity being measured is true in phantoms, if possible. [Some quantities, for example blood flow, may only meaningfully exist in the brain, since accurate enough phantoms do not (yet) exist. Others, such as volume, can meaningfully be tested in phantoms (test objects)].

15. 5. The precision of the device must be specified • measure the reproducibility by repeated measurements • use repeated scans if necessary • use paired measurements and the Bland Altman analysis to estimate standard deviation and 95% confidence limits

16. 6. The limits of accuracy of the device must be specified • Presumably means the 95% CL for total uncertainty (whether arising from systematic or random sources). • can be calculated from the mean inaccuracy, and the 95% confidence limit on repeated measurements, by combining the two quantities. • ‘uncertainty budget’, type A and B errors • See ‘QMRI of the brain’ page 68 for refs

17. 7. A sequence device must have safe RF power deposition SAR • this is an ongoing tricky subject • see elsewhere (general response GR5)

18. General responses • GR1. MR sequences are generally developed and used in ‘research mode’, and therefore do not, in general, have a blanket coverage arising from the manufacturer’s CE mark. Although the static field cannot be altered in research mode, the RF power, and possibly gradient switching rate, can be and therefore need to be considered in detail.

19. GR2. There are general safety guidelines from various bodies. In the UK, the relevant bodies are the National Radiation Protection Board (NRPB) and Health and Safety Executive (HSE). In Europe there may also be a body. In the USA, the FDA is relevant. • These guidelines affect the static field, the rate at which the gradients can be switched (dB/dt), and the Radiofrequency (RF) power deposition (SAR). • An additional issue is that the HSE seems to be recommending against anything above 2.0T. This seems to be a problem affecting MR in the whole UK, and has not been resolved. • In general the risk associated with MRI is very low, and there is a general move towards MRI and away from other (more risky) imaging techniques such X-ray Computed Tomography and nuclear medicine, both of which involve ionising radiation.

20. GR3 static field • At Queen Square, including associated Chalfont, there are clinical machines operating with ethical approval at 1.5T, 3.0T and 4.7T

21. GR4 The gradient switching rate • This determines the dB/dt (this increases with distance from the magnet isocentre). • In pulse sequences this is not usually increased above the manufacturer’s value • The consequences of a high dB/dt are stimulation of some muscles, usually in the chest wall, and are considered to be uncomfortable but not dangerous.

22. GR5 Radiofrequency (RF) Power deposition • defined by the Specific Absorption Rate (SAR) watts/kg • potentially the most hazardous factor. • Small amounts can cause a feeling of being warm; • large amounts could in principle cause local heating in tissues that do not have a blood supply, such as the vitreous humour or lens in the eye, and as a worst case a cataract could result. • The GE scanner has a variety of SAR checks, in software and hardware, some of which can be turned off in research mode. The software checks are complex; they attempt to take into account the mass of the subject, they make some assumptions about the distribution of the deposited power, and also set rules about the time course of the power deposition (i.e. controlling both instantaneous and time-averaged power deposition). • This is an area about which we are currently investigating, and where each scanner manufacturer will have a different Research Mode environment. We are currently considering starting a project to measure deposited power directly, in a phantom.

23. GR6 Acoustic noise • can be annoying • for many sequences ear plugs are offered to the subject. • The sound level is dependent primarily on the gradient switching rate and the number of gradient pulses per second • provided this is not increased (see above), the sound level is not expected to increase above that found in noisy sequences used in clinical mode.

24. GR7 Other factors • ferromagnetic projectiles, internal metal structures, or quenches • no more risky than when conventional sequence are used in clinical mode.

25. GR8. ALARA • A sequence device must operate with the lowest reasonable static field, SAR and dB/dt. • In general, the characteristics of the device would be degraded by going to lower static field, SAR and dB/dt. • The signal-to-noise ratio and hence precision would suffer. • SAR could not be reduced without removing or reducing RF pulses that are required for the sequence to work. • Reduced dB/dt would increase scanning time.

26. GR10 Image analysis programs • take MR data from the scanner (in fact these can be in the form of images or spectra). • The data include header information (such as echo time, patient ID). The accurate carrying through of header information must be checked. • Post 2004-upgrade scanner data are provided by GE in DICOM format, and then translated to UNC format by an in-house program (called Gedicom2unc ). • Old (pre-2004 upgrade) will be available from GE in DICOM format, although the exact DICOM implementation may be subtly different.

27. GR11. programming environment • is this in accordance with current good practice? • Controlling binaries. Version control. Authorship control. Keeping old ones etc. • computer system, manager. • What is current good software engineering practice?

28. Error case study 1 - B1 mapping sequence • History: • inexperienced scientist implemented a B1 mapping technique, which worked correctly under their use. (B1 = RF field) • handed over to a non-technical user, with an instruction sheet. • sheet had an error in it. • sequence was used incorrectly for several months • Learning: • experienced independent person should have oversight before handing over the device. • Inbuilt test mode would have forced the users to find the error (provided it was used!). For this device, reduce transmitter output by known amount, and remeasure B1 • Monitoring, by a technical person, of the device during its first weeks of use would probably have detected the error. • The manual is part of the device, and need to be tested! Silently watch how a naïve user uses the device.

29. Case study 2: qMT sequence • History: • A sequence to apply 3 different amplitudes of MT saturation pulse amplitude was written. • The resulting data appeared to fit a model, and were published in 3 places • An independent physicist, developing their own qMT sequence, found they could not reproduce the original data. • Several experienced physicists became involved, and suggested measuring the MT pulses directly. • The amplitude of one pulse was found to be wrong, and the explanation found. • A retrospective correction of old data could be made; the resulting corrected data were of higher quality, as judged by fitting the model, and also agreeing with those from other groups.

30. Magnetisation Transfer Freewater protons RF Bound protons 0 0 0 Saturated - Ss Unsaturated - Su Magnetisation Transfer Ratio

31. Original qMT sequencegaussian lineshape

32. qMT – corrected datasuper-lorenzian lineshape

33. Case study 2: qMT sequence cont • Learning: • Do not assume a new sequence is doing what you think. Recognise that pulse amplitudes may be wrong on a (GE) scanner. • Invent independent ways of testing the sequence • progressively increase Bsat and observe the signal. Do this in a phantom, and use Bsat values at least as high as in-vivo. Do this 20kHz off-resonance (where the behaviour of the imaging pulse is monitored), and signal should be constant, and 1khz off resonance, where a progressive reduction should be seen. • observe MT and imaging pulses with search coil for progressive experiment described above; measure amplitude (with confidence limits) relative to first imaging pulse. Measure its width, and estimate its area (and hence FA) relative to the imaging pulse. • We still need a way of testing the offset frequency, although errors in this are less likely • Ask an independent person – do you believe this sequence is doing what I have programmed it to do?

34. Error case study 3: MTR x10 • History: • MTR values are in the range 10-40pu; they are stored in computer files as integers (range 100-400) to obtain 0.1pu precision. • The clinical researcher was dealing with the integer values in all their analysis, including graphing • The integer values were passed to a statistician for complex analysis • The statistician estimated wrong values of difference and slope • An independent person recognised the factor of 10 error. • Learning: • Output all map values as floating point values, with proper units • No access for the user to the raw integer values. • Independent review works

35. conclusions • MR Safety is in a state of flux • More on good design practice • Lessons from electrical instruments, software • Acceptability to MR physicists? • Science will improve • “Every time I make a mistake I’m really pleased because I learnt something”