阅读说明：本技术 采用改进的数据处理技术对组织异常进行体素内不相干运动mri三维定量检测 (Three-dimensional quantitative detection of intra-voxel incoherent motion MRI of tissue abnormalities using improved data processing techniques ) 是由 王毅翔 陈蔚天 李瑶 邓敏 梁志信 于 2018-05-15 设计创作，主要内容包括：使用体素内不相干运动(IVIM)MRI技术可以检测肝纤维化。例如,可以使用弥散加权MRI成像序列对患者的肝脏进行扫描。可以将MRI扫描中获得的信号强度数据拟合为双指数模型信号衰减,该模型表示与灌注相关的“快速”部分及与组织中弥散相关的“慢速”部分的组合。这允许提取表示慢速和快速弥散速率的参数,以及快速和慢速部分的分数贡献。在多维空间(例如,三维空间)中对这些参数的组合进行分析产生了可以区分健康肝脏和纤维化肝脏的度量。(Liver fibrosis can be detected using the intra-voxel incoherent motion (IVIM) MRI technique. For example, a diffusion weighted MRI imaging sequence may be used to scan the patient's liver. The signal intensity data obtained in an MRI scan may be fitted to a bi-exponential model of the signal attenuation, which model represents a combination of a "fast" part related to perfusion and a "slow" part related to diffusion in the tissue. This allows extraction of parameters representing slow and fast diffusion rates, as well as fractional contributions of fast and slow parts. Analysis of the combination of these parameters in a multidimensional space (e.g., a three-dimensional space) yields a metric that can distinguish between healthy and fibrotic livers.)

1. A method, comprising:

acquiring Magnetic Resonance Imaging (MRI) data of a patient tissue, the MRI data corresponding to a diffusion-weighted (DW) MRI scan of the tissue, the MRI data comprising signal intensity data corresponding to a plurality of different b-values;

analyzing the MRI data to determine a set of diffusion parameter values, the set of diffusion parameter values including a true diffusion parameter (D) _Slow) Perfusion Fraction (PF) and fast diffusion parameter (D) _{Fast-acting toy}) A value of (d);

mapping the set of dispersion parameter values to points in three-dimensional space; and

determining a condition of the tissue from the point in the three-dimensional space.

2. The method of claim 1, wherein the tissue is liver tissue.

3. The method of claim 2, wherein determining the condition comprises classifying the liver tissue as healthy or fibrotic.

4. The method of claim 3, wherein for liver tissue classified as fibrotic, determining the condition further comprises assessing the severity of fibrosis.

5. The method of claim 1, wherein analyzing the MRI data comprises:

selecting a target area;

determining an average signal strength of the target area; and

determining the set of dispersion parameter values using the average signal strength.

6. The method of claim 1, wherein analyzing the MRI data comprises:

determining true diffusion parameters D using a fitting procedure applied to a portion of the signal strength data corresponding to a value of b greater than a threshold value of b _SlowA value of (d);

will use the determined D _SlowThe exponential curve defined by the values is extrapolated to a b value of zero;

determining a value of the perfusion fraction PF from the extrapolated exponential curve; and

using a determined D _SlowAnd PF values and fitting procedure applied to the signal strength data, determining a fast dispersion parameter D _{Fast-acting toy}The value of (c).

7. The method of claim 6, wherein the threshold b value is determined empirically based on maximizing a distance metric in three-dimensional space between a first plurality of sample points known to correspond to a healthy liver and a second plurality of sample points known to correspond to a fibrotic liver.

8. The method of claim 6, wherein the threshold b value is about 60s/mm ²。

9. The method of claim 6, wherein the threshold b value is about 200s/mm ²。

10. The method of claim 1, wherein determining the condition of the tissue is based on a position of the point relative to an interface defined in the three-dimensional space.

11. The method of claim 10, wherein the interface is defined such that a point corresponding to healthy tissue is located on one side of the interface and a point corresponding to fibrotic tissue is located on the other side of the interface.

12. The method of claim 11, wherein for a point corresponding to fibrotic tissue, determining the condition of the tissue further comprises determining a severity of fibrosis based on a distance from the point to the interface.

13. The method of claim 10, wherein the interface is defined such that a point corresponding to significantly fibrotic tissue is on one side of the interface and a point corresponding to not significantly fibrotic tissue is on the other side of the interface.

14. The method of claim 1, wherein the image data comprises DW image data collected for at least 10 different b-values.

15. The method of claim 1, further comprising, prior to analyzing the MRI data to determine the set of dispersion parameter values, performing an image cleaning operation to determine whether to exclude a particular image from the analysis based on a set of reliability criteria.

16. The method of claim 15, wherein performing the image cleaning operation comprises:

for each of a plurality of image slices of the MRI data, determining whether to exclude the image slice based on whether a particular anatomical structure is present;

for each of a plurality of image series of the MRI data, one of the image series consisting of a set of image slices of the same part of the individual imaged with different b-values:

grading the image quality of each image series according to the existence or nonexistence of b value inter-motion and b value intra-motion in the image series;

determining whether to exclude each of the series of images based on the ranking; and for at least some of the plurality of image series of MRI data:

determining a diffusion fit curve for each of the remaining image series;

evaluating the fitting quality of the dispersion fitting curve; and

determining whether to exclude each of the series of images based on the quality of fit.

17. A computer readable storage medium storing program instructions that, when executed by a processor of a computer system, cause the computer system to perform the method of any of claims 1-16.

18. A computer system, comprising:

a memory storing program code; and

a processor coupled to the memory, wherein the processor, in response to the program code, performs the method of any of claims 1-16.

Background

The present application relates generally to the detection of liver fibrosis, and in particular to the detection of tissue abnormalities, such as liver fibrosis, using intra-voxel incoherent motion (IVIM) Magnetic Resonance Imaging (MRI) and multidimensional (e.g., three-dimensional) analysis tools.

Chronic liver disease is a major public health problem worldwide. The growing trend of chronic liver disease is expected to be exacerbated by aging of the population, the growth of obese and non-alcoholic steatohepatitis, and chronic viral hepatitis, which may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma.

Liver fibrosis is a common feature of almost all chronic liver diseases, involving the accumulation of collagen, proteoglycans and other macromolecules in the extracellular matrix. Clinically, liver fibrosis is usually occult and progresses slowly over decades. Liver fibrosis, originally thought to be irreversible, is now thought to have a dynamic process with the potential to resolve, and a number of promising therapies have been developed to accelerate the resolution of liver fibrosis and promote liver regeneration. Such therapy is more effective in the early stages of liver fibrosis. Thus, early detection is beneficial to the health of the patient.

However, the current ability to detect early stage liver fibrosis is limited to biopsy, which is an invasive procedure with a number of contraindications and may cause various complications such as pain, bleeding, biliary peritonitis, abdominal splanchnic penetration, pneumothorax and even death. Therefore, non-invasive procedures are highly desirable.

Magnetic Resonance Imaging (MRI) provides a non-invasive procedure for imaging liver tissue, and many efforts have been made to use MRI to distinguish between healthy and fibrotic liver tissue. One MRI technique that has been investigated is the intra-voxel incoherent motion (IVIM) technique. IVIM is a form of Diffusion Weighted (DW) MRI in which the intensity of the acquired magnetic resonance signals depends on the self-diffusion of the excited spins, i.e. on microscopic random brownian molecular motion. The extent and direction of such molecular motion is influenced by the microstructure and organization of the biological tissue. One important factor is perfusion (movement of blood through a pseudo-random capillary network); another factor is the "true" dispersion of water within the tissue, depending on the composition of the tissue. IVIM reflects the random microscopic motion occurring in voxels (volume elements) of intracellular and/or extracellular water molecule MRI images and is involved in quantitatively separating tissue dispersivity and tissue microcapillary perfusion.

It is expected that water dispersion in fibrotic liver tissue (as compared to healthy liver tissue) will be limited by the presence of collagen fibers in the deformed leaflet structure. Liver fibrosis has also been observed to be associated with reduced liver perfusion. Therefore, there is interest in using IVIM technology to study diffuse liver diseases (e.g. liver fibrosis). To date, however, attempts to detect liver fibrosis using IVIM technology have not been successful.

Summary of The Invention

Certain embodiments of the invention relate to the detection of liver fibrosis using IVIM MRI techniques. In particular, the patient's liver may be scanned using a diffusion weighted MRI imaging sequence. The signal intensity data obtained in an MRI scan may be fitted to a bi-exponential model of the signal attenuation, which model represents a combination of a "fast" part related to perfusion and a "slow" part related to diffusion in the tissue. This allows extraction of parameters representing slow and fast diffusion rates, as well as fractional contributions of fast and slow parts. Analysis of the combination of these parameters in a multidimensional space (e.g., a three-dimensional space) yields a metric that can distinguish between healthy and fibrotic livers or between significantly fibrotic livers and healthy livers.

The following detailed description, together with the accompanying drawings, provide a better understanding of the nature and advantages of the claimed invention.

Brief description of the drawings

FIG. 1 illustrates an MRI system that may be used in connection with practicing some embodiments of the present invention.

Fig. 2 is a flow diagram of a method that can be used to detect liver fibrosis, according to an embodiment of the invention.

Fig. 3 shows an example of ROIs that may be selected for liver tissue according to an embodiment of the invention.

Fig. 4A-4C show one-dimensional scatter plots of determined liver tissue dispersion parameters for a group of test individuals with known liver fibrosis stages, according to an embodiment of the present invention.

Fig. 5A-5C illustrate three different perspective views of a 3D space into which the diffusion parameters of fig. 4A-4C may map, showing a distribution of points corresponding to tissues with different stages of liver fibrosis, according to embodiments of the invention.

Fig. 6A-6C show three different perspective views of the 3D space of fig. 5A-5C, with points corresponding to mildly fibrotic liver tissue removed.

Fig. 7A shows a two-dimensional distribution of diffusion parameters for healthy and significantly fibrotic liver tissue.

Fig. 7B shows a two-dimensional distribution of diffusion parameters for healthy, mildly fibrotic, and significantly fibrotic liver tissue.

Figures 8A-8C illustrate one-dimensional scatter plots of liver tissue dispersion parameters determined by various threshold b-values for a group of test individuals with known liver fibrosis stages, according to embodiments of the present invention.

Fig. 9A and 9B are bar graphs showing the calculated separation distance parameter for each threshold B value of the data of fig. 8A-8C. Fig. 9A shows a separation distance parameter for distinguishing healthy liver from mildly and significantly fibrotic liver, and fig. 9B shows a separation distance parameter for distinguishing healthy liver from significantly fibrotic liver.

FIG. 10 is a graph illustrating the results of a pair-wise comparison analysis of the data of FIGS. 8A-8C.

Fig. 11 is a flowchart of an image cleaning method according to an embodiment of the present invention.

FIG. 12 shows an example of a series of images that may be accepted for analysis based on the process of FIG. 11.

Detailed Description

Overview of IVIM

Intra-voxel incoherent motion (IVIM) is a Magnetic Resonance Imaging (MRI) technique, the basic concept of which was first developed by lebahan et al. (D.le Bihan et al, "MR imaging of intragenic associations: application to differentiation and perfusion in neurological disorders," Radiology 161: 401-7 (1986); D.le Bihan et al, "isolation of differentiation and perfusion in intragenic associations MR imaging," Radiology 168: 497-505 (1988)). IVIM measures the signal attenuation in response to a pair of gradient pulses (with a time interval between them) applied in opposite directions. To the extent that the target nuclei (usually hydrogen) do not move between gradient pulses, the net effect of the gradient pulses on the magnetization is expected to be zero. However, if the nuclei move (e.g., due to diffusion), the gradient will have a net effect of attenuating the signal. The signal attenuation can be characterized as:

SI(b)＝SI ₀[(1-PF)exp(-bD _slow)+PFexp(-bD _{Fast-acting toy})](1)

Where b is the IVIM b value (a standard parameter in the art characterizing the intensity, duration and time interval between gradient pulses, sometimes also referred to as the "b factor"), SI (b) is the signal intensity measured with a gradient pulse having a specified b value, SI ₀Without gradient pulses (b ═ 0 s/mm) ²) Measured signal intensity, PF is the diffusion fraction associated with microcirculation (perfusion), D _Slow(sometimes referred to in the art as "D" for short) is the "true" diffusion coefficient representing pure molecular diffusion, D _{Fast-acting toy}(sometimes also referred to in the art as D) is a pseudo-diffusion coefficient representing incoherent microcirculation (perfusion-related diffusion) within voxels.

Measurements of SI (b) may be made using MRI systems, which may generally be of conventional design. FIG. 1 illustrates an MRI system 100 that may be used in connection with practicing some embodiments of the present invention. The MRI system 100 includes a computer 102 communicatively connected to an MRI apparatus 104.

The computer 102 may be of generally conventional design and may include a user interface 106, a processor 108, a memory 110, a gradient controller 112, an RF controller 114, and an RF receiver 116. The user interface 106 may include components that allow a user (e.g., an operator of the MRI system 100) to enter instructions or data and view information. For example, the user interface 106 may include a keyboard, mouse, joystick, display screen, touch sensitive display screen, and the like. The processor 108 may include one or more general-purpose programmable processors capable of executing program code instructions to perform various operations. The memory 110 may include a combination of volatile and non-volatile storage elements (e.g., DRAM, SRAM, flash, magnetic disk, optical disk, etc.). Portions of the memory 110 may store program code that is executed by the processor 108. Examples of program code may include a control program 118 and an analysis program 120, the control program 118 may coordinate the operation of the MRI apparatus 104 to acquire data as described below, and the analysis program 120 may perform analysis algorithms on the data acquired from the MRI apparatus 104. The gradient controller 112, the RF controller 114, and the RF receiver 116 may incorporate standard communication interfaces and protocols to communicate with the components of the MRI apparatus 104, as described below.

The MRI apparatus 104 may be of generally conventional design and may include a magnet 130, one or more gradient coils 132, and RF coils 134, 136. The magnet 130 may be a magnet capable of generating a large constant magnetic field B in the longitudinal direction in a region where a patient may be placed ₀(e.g., 1.5T, 3.0T, etc.). The gradient coil 132 may be capable of following a constant magnetic field B ₀A gradient is generated in the direction of (c); the operation of the gradient coils 132 may be controlled by the computer 102 via the gradient controller 112. The RF coils 134, 136 may include a Transmitter (TX) coil 134 and a Receiver (RX) coil 136. In some embodiments, a single coil may serve as both a transmitter and a receiver. In some embodiments, the RF transmitter coil 134 may be placed at the location to be imaged when the RF receiver coil 136 is placed at other locations within the MRI device 104Around a portion of the individual's body. The preferred placement of the RF coils 134, 136 may depend on the particular part of the body to be imaged; those skilled in the art who review this application will be able to make appropriate selections.

In operation, the computer 100 may drive the gradient coils 132 using the gradient controller 112 to form a magnetic field around a region to be imaged. The computer 100 may use the RF controller 114 to drive the RF transmitter coil 134 to generate RF pulses at the resonant frequency of the target isotope to drive the spins of the nuclei into an excited state. When no RF pulse is generated, the RF receiver coil 136 may detect RF waves (or pulses) generated from spins relaxed from the excited state. The RF receiver 116 may include amplifiers, digital-to-analog converters, and other circuitry to generate digital data from the RF waves detected by the RF receiver coil 136. The RF receiver 116 may provide the data to the processor 108 for analysis.

The MRI system 100 is exemplary, and many variations and modifications are possible. Those skilled in the art are familiar with various MRI apparatus and basic principles of MRI data acquisition, including the use of gradient fields and RF pulses, as well as techniques for detecting signals responsive to RF pulses and processing those signals to generate image data.

Detection of liver fibrosis using IVIM

According to some embodiments of the invention, the MRI system 100 or other MRI apparatus may be used to generate pulse sequences suitable for Diffusion Weighted (DW) imaging of a particular organ or tissue, such as the liver, within a patient. The acquired data can be analyzed using IVIM-based techniques described below to detect abnormal conditions, such as liver fibrosis.

Fig. 2 is a flow diagram of a method 200 that can be used to detect liver fibrosis, according to an embodiment of the invention. The method 200 may be implemented using an MRI system (e.g., the system 100 of fig. 1). At block 202, an individual (in this example, a patient) whose tissue is to be imaged is positioned within an MRI apparatus. This may include having the patient assume a supine (or other suitable) position and aligning the patient within the MRI apparatus. In some embodiments, this may also include the positioning of RF and/or gradient coils; the specific positioning will depend on the tissue to be imaged.

At block 204, one or more preparation pulse sequences may be applied by operating the MRI apparatus. The preparation pulse sequence may include, for example, a magnetization reset sequence, a fat suppression sequence (e.g., Spectral Presaturation Inversion Recovery (SPIR)), and/or other suitable preparation pulse sequences.

At block 206, a data acquisition sequence may be applied. The data acquisition sequence may be, for example, a single-shot diffusion-weighted (DW) spin echo type echo planar imaging sequence as is known in the art. During this sequence, gradient pulses with a plurality of different b-factors (or b-values) may be applied. For example, in some embodiments, 10, 20, 40, 60, 80, 100, 15, 200, 400, and 800s/mm are used ²10 b-factors. The specific sequence, including the b-factor, can be varied as desired if the resulting data can be analyzed using the techniques described below.

At block 208, data collected during the data acquisition sequence may be analyzed to determine values for a set of diffusion parameters that characterize diffusion in the imaged tissue. In some embodiments, the set of dispersion parameters includes D as defined above with reference to equation (1) _Slow(true Dispersion coefficient), D _{Fast-acting toy}(perfusion factor) and PF (perfusion fraction).

Various analysis techniques may be used to determine the parameter values. For example, at block 210, one or more regions of interest (ROIs) within the image may be selected. In some embodiments, the ROI may be selected to minimize artifacts due to cardiac motion or proximity to other tissue. In the case of liver tissue, it may be preferable to select the ROI from the right lobe of the liver, since the image of the left lobe is more likely to be affected by artifacts due to heart motion and more susceptible to B due to its proximity to the stomach (with air inside) ₀The effect of the non-uniformity. Furthermore, the ROI may be selected to include target tissue, such as liver parenchyma, while avoiding vasculature regions (which may be more susceptible to artifacts). Fig. 3 shows an example of ROIs for liver tissue that may be selected according to an embodiment of the invention. Displayed is an image of liver tissue in which vasculature appearsDarker; the ROI is outlined with a light gray line.

At block 212, an average signal intensity of the ROI may be determined, for example, by averaging the signal intensity per pixel within the ROI. If multiple ROIs are selected, each ROI may be analyzed separately, and the results of the different ROIs may be merged at a later stage. It should be noted that parameter extraction may also be performed on a per-pixel basis (as described below). However, in the case where the signal-to-noise ratio of the DW image is low, the correlation parameter can be better estimated using the average signal strength.

At block 214, true dispersion parameters D may be obtained _SlowIs estimated. For example, if IVIM signal attenuation is modeled according to equation (1), D can be estimated using least squares linear fit of logarithmic image intensities at different b values to a linear equation _Slow. In some embodiments, a subset of the b-values of the acquired image data is used for D _SlowIs estimated. For example, 200s/mm may be used ²Or a larger b-value to minimize the contribution of the fast (perfusion) part. In some embodiments, the threshold b value may be selected to optimize the interval between healthy and fibrotic liver. An example is described below.

At block 216, a perfusion fraction PF may be estimated. For example, the fitted curve from block 214 may be extrapolated to determine an intercept at b-0, which reflects the expected signal intensity without perfusion. For b-0, the ratio between the intercept and the measured signal strength is extrapolated to yield an estimate of PF.

At block 218, a fast dispersion parameter D may be estimated _{Fast-acting toy}. For example, the estimated D may be _SlowSubstituting equation (1) (from block 214) and PF (from block 216) and a non-linear least squares fit (e.g., using Levenberg Marquardt algorithm or a variant thereof, such as the Trust Region algorithm) for all b values can be used to estimate D _{Fast-acting toy}。

At block 220, the parameter values determined (or estimated) in the analysis at block 208 may be used to determine a condition (or state) of the tissue, such as whether the liver tissue is fibrotic and/or to what extent the fibrosis isThe degree of seeding. For example, D may be _SlowPF and D _{Fast-acting toy}Is mapped to a point in three-dimensional (3D) space, and the position of the point can be used as an indicator of the condition of the tissue. One specific example is described below.

In some embodiments, at block 222, each parameter may be normalized to a range [0, 1] using a linear normalization technique, where a set of parameter values { x (i) } may be normalized to:

z(i)＝(x(i)-x _min)/(x _max-x _min) (2)

wherein x _minAnd x _maxAre the minimum and maximum values of the parameter x. At block 224, the normalized parameters may be mapped to points in 3D space. For example, each normalization parameter may be directly mapped to one of three coordinate axes of the 3D space.

At block 226, based on the points in the 3D space, the tissue may be classified to indicate its condition. For example, liver tissue can be classified as healthy (e.g., stage F0, described below) and fibrotic (e.g., stage F1-F4, described below), or healthy and significantly fibrotic (e.g., stage F2-F4, described below). For example, as described below, an interface in 3D space may be defined such that a point corresponding to normal liver tissue is on one side of the interface and a point corresponding to fibrotic liver tissue is on the other side of the interface. The separation interface may be defined from data of a group of individuals whose liver conditions are known from other sources. Once defined, the isolation interface can be used (e.g., in a clinical setting) to assess individuals whose liver condition is unknown.

It is understood that the method 200 is exemplary and that variations and modifications are possible. The particular pulse sequence, number of b values, and selection of particular b values may be modified. In some embodiments, prior to analysis, certain images may be excluded from analysis using image cleaning methods based on evidence of motion artifacts that may compromise data quality; an example of the image cleaning method is described below. Different analysis techniques may be used to determine parameter values characterizing diffusion from the acquired MRI data, and different techniques may be used to map the determined parameter values to points in the appropriate dimensional space. In addition, mapping to a point in space is not required; in some embodiments, the characteristic function may be defined such that the determined parameter value is an input term and the output term is a value (or set of values) indicating the likelihood that the tissue has a particular degree of fibrosis.

Example 1

A study was conducted to determine the feasibility of using multi-parameter analysis to distinguish between fibrotic and normal liver tissue using MRI data from the deep-Shen 2012/2013 dataset (described in P.X.Lu et al, "creation in molecular differentiation, fusion from and fusion-related differentiation in fibrous components: a productive clinical in vivo imaging modality," PLoS One 9(12): e113846 (2014)). The individuals included 16 individuals with normal liver (F0 fibrosis stage) and 33 individuals with viral hepatitis b and varying degrees of liver fibrosis (F1-F4 fibrosis stage). The fibrosis stage of each individual was determined according to conventional histology-based diagnosis. In this example, the labeling of fibrosis stages followed a conventional protocol, where stage F0 indicates no fibrosis; stage F1 indicates that only mild fibrosis is visible in the portal duct region; stage F2 indicates that fibrosis extends from the portal duct region, but there is little bridging between portal duct regions and there is no disruption of leaflet structure; stage F3 indicated severe fibrosis with significant fibrotic bridging between portal areas and central veins; stage F4 indicates the final stage of cirrhosis and formation of pseudolobules. Stages F0 and F1 are generally considered to show no significant liver fibrosis, while stages F2-F4 are considered to be significant liver fibrosis. At stage F2 or higher, liver fibrosis may be considered clinically significant (medical care should be taken); therefore, it may be useful to distinguish the F0 stage liver from the F2-F4 stage liver. Detection of fibrosis at stage F1 may also be of interest, for example, for early therapeutic intervention.

All individuals were MRI imaged using a Philips Achieva 1.5-T scanner (from Philips Healthcare, Best, the Netherlands). The IVIM DW imaging sequence is based on a single-shot DW spin echo type echo planar imaging sequence, and 10 b values are respectively10、20、40、60、80、100、150、200、400、800s/mm ². The SPIR technique (spectral pre-saturation inversion recovery) is used for fat suppression. MRI imaging parameters include: average TR is 1500 ms; TE is 63 ms; the thickness of the layer face is 7 mm; 124x97 matrix; a field of view (FOV) of 375mm x 302 mm; NEX ═ 2; the number of layers is 6.

The data obtained for each individual was analyzed to determine dispersion parameters in The manner described above with reference to fig. 2, and an algorithm was performed using MATLAB (obtained from The MathWorks, inc., Natick, MA). Specifically, for each individual, all 6 image slices were evaluated; the levels with significant motion artifacts and the levels showing significant abnormal behavior in the signal versus b-value relationship are discarded. Each individual was left with 2-5 levels, with an average of 3 levels per individual. For each slice, the ROI is defined similar to that shown in fig. 3. Using more than 200s/mm ²And the linear least squares fitting algorithm described above estimates the slow dispersion parameter D _Slow. As described above, the perfusion fraction PF is estimated using extrapolation. Estimation of fast dispersion parameters D using equation (1) and a non-linear least squares fitting algorithm as described above _{Fast-acting toy}. The values of the diffusion parameters determined in this way were found to be comparable to the values of the parameters measured in other studies.

4A-4C show one-dimensional scatter plots of each diffusion parameter (y-axis) versus fibrosis stage (x-axis) for each individual. FIG. 4A shows the perfusion fraction PF; FIG. 4B shows D _SlowFIG. 4C shows D _{Fast-acting toy}. The indicated p-values were determined using ANOVA and Mann-Whitney U test. It can be seen that using either of these parameters alone, liver fibrosis cannot be reliably diagnosed.

Mapping the diffusion parameters to 3D space, the axes corresponding to PF, D respectively _{Fast-acting toy}And D _Slow. Fig. 5A-5C show three different perspective views of a 3D space. Black spots correspond to healthy tissue (stage F0), gray spots correspond to mild fibrosis (stage F1), and white spots correspond to significant fibrosis (stages F2-F4). As can be seen from the figure, based on 3D analysis, fibrotic liver can be distinguished from normal liver. For example, as shown by the dashed lines in FIGS. 5A and 5B and the interface in FIG. 5C, it can be seen that there are cases in F0And clear separation between cases of significant fibrotic disease (stages F2-F4). The mild fibrotic case (F1) was also separated from the F0 (healthy) case. Fig. 6A-6C show perspective views of the same 3D space as fig. 5A-5C, but with the F1 case removed, which makes the separation between healthy cases and cases of significant fibrosis more clearly visible. For comparison, FIG. 7A shows D for the F0 (black dot) and F2-F4 (white dot) cases _SlowA two-dimensional (2D) plot with PF; fig. 7B shows a similar diagram including F1 (gray point) cases. In this 2D plot, there is no clear separation between mild fibrosis and normal liver tissue. Thus, it can be seen from these figures that 3D analysis provides a better distinction than 2D analysis: based on 3D analysis, fibrotic liver can be distinguished from normal liver.

A Support Vector Machine (SVM) method is used to quantitatively distinguish between the cases. In particular, an SVM lookup interface (parameterized as Ax + By + Cz + D0) can be used that can divide the data points into two groups By maximizing the sum D1+ D2, where for group i (i 1 or 2), D is the two group _iIs the distance from the closest point to the interface. In one analysis, an SVM lookup interface was used to separate healthy (F0) cases from fibrotic (F1-F4) cases. In another analysis, an SVM lookup interface was used to separate healthy (F0) cases from significantly fibrotic (F2-F4) cases.

For SVM analysis, the parameters PF, D are used as described above _SlowAnd D _{Fast-acting toy}And (6) carrying out normalization. The distinction between the F0 case and the F1-F4 case (as shown in fig. 5A-5C) is achieved by the following defined interface:

166.58*PF+8.90*D _slow-0.98*D _{Fast-acting toy}-19.71＝0， (3)

The minimum normalized distance for the F0 group was 0.0021 and the minimum normalized distance for the F1-F4 groups was 0.0026. The differentiation of the F0 case from the F1-F4 case (as shown in fig. 6A-6C) is achieved by the following defined interface:

29.56*PF+4.33*D _slow-0.12*D _{Fast-acting toy}-6.67＝0. (4)

The minimum normalized distance for the F0 set was 0.0149 and the minimum normalized distance for the F2-F4 sets was 0.0138.

Such as the bookExamples show based on PF and D _SlowAnd D _{Fast-acting toy}The combined analysis of (a) may provide a non-invasive technique for detecting liver fibrosis. Significant fibrosis (stage F2-F4) can be distinguished from healthy liver tissue (stage F0) and mild fibrosis (stage F1) can be distinguished from healthy liver tissue, which may aid in early therapeutic intervention. For example, in clinical applications, the MRI scan results of a patient may be used to determine the parameter values (PF, D) _Slow、D _{Fast-acting toy}) These parameter values may be used to calculate a metric, such as the left side of equations (3) and/or (4); comparing these metrics to zero (or assigning the patient's parameter values to one or the other side of the interface) may provide an indication of the likelihood of the patient developing fibrosis and/or the stage (mild or significant) of likely fibrosis.

In addition, the severity of fibrosis can be assessed by distance from the interface. On the side of the interface corresponding to the fibrotic tissue, points closer to the interface indicate less severe fibrosis, and points farther from the interface indicate more severe fibrosis. Generally, the greater the distance from the interface, the more severe the disease state.

It should be understood that the particular coefficients shown in equations (3) and (4) are not necessarily optimal. They are examples derived from MRI scans taken from a group of individuals with known fibrosis stages, the results of which may be affected by a small number of participants and/or by hepatitis b patients in all cases of liver fibrosis. Furthermore, the MRI data acquisition used in this analysis is not optimized for IVIM analysis. For example, the set of b values does not include b ═ 0. The data may not be optimal in other respects, which may affect the determined parameter values. Different parameters may result from studies on a larger population of individuals using the techniques described herein and MRI data acquisition optimized for IVIM analysis. It will also be appreciated by those skilled in the art that the histological diagnosis used to classify the tissues of an individual is not necessarily completely unequivocal; for example, a high-end F1 liver may be similar to a low-end F2 liver, and such classification ambiguity may also affect the optimization of the separation interface.

Optimizing the IVIM threshold b value

In the above embodimentsDetermining D from MRI data _Slow(e.g., at block 214 of the method 200 of fig. 2) is based on fitting the collected image intensity data to equation (1) using different b-values. It should be noted that a threshold value may be used to select the value of b to be used for this analysis phase to reduce the perfusion fraction D _{Fast-acting toy}The contribution of (c). In fact, due to D _{Fast-acting toy}Variation of contribution of D _SlowThe fit value of (a) depends on the threshold value. In the above embodiment, the threshold used was 200s/mm ²。

Some embodiments of the invention may be practiced by selecting for determining D _SlowThreshold b value of to develop a fitted D _SlowDependence on the threshold b value, which is expected to maximize the distance in the analysis space between the point corresponding to healthy liver tissue and the point corresponding to liver fibrosis liver tissue. Can be in one dimension (PF, D) _Slow、D _{Fast-acting toy}Any of the axes) or in the normalized 3-D space described above. The optimal threshold b value (e.g., the threshold that maximizes the distance metric) may be determined empirically using data collected from scans of normal and fibrotic liver individuals, for example, during training prior to clinical practice.

For example, a training method may be used to determine an optimal threshold b-value based on data collected from individuals known to have liver fibrosis stages. The analysis process of FIG. 6 may be repeated using different threshold b value selections; for each repetition, a distance metric may be calculated. Various distance metrics may be used; examples are as follows. A comparison of distance metric values obtained using different threshold b values may be used to select the best threshold b value. The selected optimal threshold b value can be used to generate a dispersion parameter D _SlowPF and D _{Fast-acting toy}The value of (c). These values can then be used to determine the separation interface in the normalized 3D space in the manner described above. In clinical applications, the same optimal threshold b value may be applied when performing a diagnostic analysis of a patient whose liver fibrosis stage is to be determined based on a separate interface.

For illustrative purposes, specific examples of optimizing the threshold b value are now described.