ISSLS PRIZE in Clinical Science 2023: comparison of degenerative MRI features of the intervertebral disc between those with and without chronic low back pain. An exploratory study of two large female populations using automated annotation

The relationship of degeneration to symptoms has been questioned. MRI detects apparently similar disc degeneration and degenerative changes in subjects both with and without back pain. We aimed to overcome these problems by re-annotating MRIs from asymptomatic and symptomatics groups onto the same grading system. We analysed disc degeneration in pre-existing large MRI datasets. Their MRIs were all originally annotated on different scales. We re-annotated all MRIs independent of their initial grading system, using a verified, rapid automated MRI annotation system (SpineNet) which reported degeneration on the Pfirrmann (1–5) scale, and other degenerative features (herniation, endplate defects, marrow signs, spinal stenosis) as binary present/absent. We compared prevalence of degenerative features between symptomatics and asymptomatics. Pfirrmann degeneration grades in relation to age and spinal level were very similar for the two independent groups of symptomatics over all ages and spinal levels. Severe degenerative changes were significantly more prevalent in discs of symptomatics than asymptomatics in the caudal but not the rostral lumbar discs in subjects < 60 years. We found high co-existence of degenerative features in both populations. Degeneration was minimal in around 30% of symptomatics < 50 years. We confirmed age and disc level are significant in determining imaging differences between asymptomatic and symptomatic populations and should not be ignored. Automated analysis, by rapidly combining and comparing data from existing groups with MRIs and information on LBP, provides a way in which epidemiological and ‘big data’ analysis could be advanced without the expense of collecting new groups. Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.


Introduction
Chronic low back pain (cLBP) is common. Its causes are mostly not well understood. Even though there is strong evidence that psycho-social factors can have a major contribution [1], the role of intervertebral disc degeneration is thought to be paramount with over 35,000 references in PubMed on the topic 'low back pain and intervertebral disc degeneration'. Demonstrating to what extent 'degenerative features' relate to low back pain (LBP) has been problematic; a systematic review, based on numerous studies, reported that such degenerative features are common in asymptomatic cohorts and that their prevalence increases with age. Moreover, the presence of degenerative features does not appear to predict future back pain in currently asymptomatic subjects [2]. Hence, it is suggested that abnormalities seen on MRI have little clinical significance [3].
However, should the possible clinical relevance of MRI findings of disc degeneration be discounted? Studies, including a systematic review, have found that overall prevalence of disc degeneration and of degenerative features, such as Modic changes [4], were significantly greater in those with LBP, than in asymptomatics [5][6][7]. But others find no such relationship [8,9]. The apparent lack of consensus on the question of whether disc degeneration is related to LBP is likely to have arisen in part because of differences in definitions of LBP and degenerative findings [5]. Definitions of degenerative changes are particularly variable and even when the same grading scheme is used, age-related prevalence of degeneration in asymptomatic populations can vary widely ( Fig S1).
Here, we aim to see if the relationship between degenerative changes seen on MRI and LBP can be clarified by overcoming heterogeneity in reporting imaging findings and in identification of those with LBP. We carried out an exploratory study analysing results for degenerative changes in relation to age and spinal level in two large symptomatic groups of patients with chronic LBP, and one large asymptomatic group. To avoid difficulties involved in reconciling differences in degenerative imaging findings between groups, we re-annotated MRIs of the lumbar spine onto a single objective grading system, independent on their original reporting or grading system. We used the validated automatic imaging software SpineNet [10] (See Supplementary Material) to report on Pfirrmann degeneration gradings. We compared prevalence of degenerative features between symptomatic and asymptomatic groups in relation to age for both the upper and lower lumbar spine.

Participants and settings
All subjects were recruited with ethical approval and consent and fully anonymised but were not directly involved in study design. The study size was constrained by the groups available. As the asymptomatic group (TwinsUK) was 91% female, we selected only female subjects from all groups to avoid sex bias.

Quantitative variables and automated MRI analysis
SpineNet annotated the sagittal T2 sequences of the lumbar MRIs of OSCLMRIC and TwinsUK with degeneration scored on the 5-point Pfirrmann scale. Binary characterisation of selected degenerative features: (herniation, central canal stenosis, marrow signs (all Modic types collapsed to present/ absent), and endplate changes) was reported [11]. From these data, we calculated prevalence of 'none/mild' (Pfirrmann grades 1 + 2), of 'severe' degeneration (Pfirrmann Grades 4 + 5), and of each degenerative feature in relation to spinal level and to age group by decade [12]. We analysed the averages of the rostral (L1/L2 and L2/L3) levels, the mid-lumbar (L3/L4) level, and caudal (L4/L5 and L5/S1) lumbar intervertebral discs separately. We compared prevalence in symptomatic and asymptomatic subjects both with and without relation to age and spinal level and calculated risks of features being symptomatic as odds ratios with 95% confidence intervals. We then combined the rostral and caudal pairs of discs to maximise the odds ratios distinguishing symptomatic and asymptomatic cohorts. We omitted the mid-lumbar disc where prevalence was equal in both cohorts age > 40yrs. (Fig. 1).

Fig. 1
Prevalence of intervertebral disc degeneration: average Pfirrmann Score versus age for caudal and rostral lumbar discs in allfemale cohorts. a, b Shows the average scores in a the caudal (L4/5, L5/S1) and b rostral (L1/2, L2/3) lumbar discs for 2 symptomatic groups with chronic low back pain (Genodisc and OSCLMRIC). c, d Shows scores of a symptomatic (OSCLMRIC) group and an asymptomatic (Twins UK) group; c for the caudal and in d for the rostral lumbar discs. Mean scores are shown as a solid line; one standard deviation is shown in the relevant colour and demonstrate the extent of overlap; variances are higher in the lower end of the age group because of the lower sample size. a and b Show the strong similarity of the 2 cohorts of chronic back pain patients, one recruited in six different European countries and the other in several centres in the UK. c Shows an obvious difference of average caudal disc degeneration between 2 groups, one symptomatic, the other asymptomatic both recruited in the UK. d Shows close similarity in rostral disc degeneration of these two cohorts

Statistical methods
The prevalence of each feature by age and level in OSCLMRIC and TwinsUK (Tables S1-S4) was calculated as the percentage of discs in each decade and spinal level with feature(s) present. For marrow signs and endplate change, we calculated the average of the binary scores of the rostral and caudal lumbar levels.
Odds ratios (OR), 95% confidence intervals (CI) and P values were used to determine the probability of an individual belonging to a group with MRI features present, being symptomatic or asymptomatic [13,13]. We omitted OR calculation from the mid-lumbar level (L3/L4) as it was non-discriminatory for symptomatic/asymptomatic participants. (Fig. 8-S). Venn diagrams were constructed in-house in PowerPoint®, based on the prevalence of each feature in the caudal lumbar discs, with overlaps showing the prevalence of discs containing both features.
Because of the low prevalence of degenerative features in the asymptomatic group, we found that once age and disc level were considered, the study was underpowered for regression analysis, or for refining degradative changes such as type of herniation or marrow change, degree of stenosis, or extent of endplate defect or of marrow signs. We have used the STROBE Checklist to structure this report (https:// www. strobe-state ment. org/).

Results
We analysed the results reported from re-annotating all MRIs from the two symptomatic and one asymptomatic group onto the same system. All results, pooled for age by decade, are given in Supplementary Data (Tables 1-5) and those presented graphically are detailed below.
1. Intervertebral Disc Degeneration; change in mean Pfirrmann score with age and spinal level.
For two independent female symptomatic groups (Genodisc, OSCLMRIC), we show the age dependence of Pfirrmann score, averaged between the two caudal ( Fig. 1a) and the two rostral ( Fig. 1b) lumbar discs. The change in score with age was similar for these two groups, with the caudal two lumbar discs were already relatively degenerate at 30-40yrs (Fig. 1a). The rostral lumbar discs were only mildly degenerate at 30-40 years, but degeneration severity prevalence increased steeply with age ( Fig. 1b).
For a female symptomatic group (OSCLMRIC) and a female asymptomatic group (TwinsUK), we show the age dependence of Pfirrmann score, averaged between the two caudal ( Fig. 1c) and the two rostral ( Fig. 1d) lumbar discs. In the caudal lumbar discs, the average scores of symptomatics were distinctly higher than those of asymptomatics, particularly < 60yrs (Fig. 1c). In the rostral lumbar discs, the age-related mean scores were similar in both symptomatic and asymptomatic groups (Fig. 1d).
2. Prevalence of age-related disc degeneration scores for symptomatic (OSCLMRIC) and asymptomatic (Twin-sUK) female subjects in the caudal and rostral lumbar discs.
The prevalence of discs with minimal degeneration was compared between symptomatics than asymptomatics and was lower for asymptomatics at all ages in the caudal lumbar spine (Fig. 2a). This difference was less obvious in the rostral lumbar spine (Fig. 2b). The prevalence of severe disc degeneration (Pfirrmann grades 4 + 5) in the caudal lumbar discs was lower in asymptomatics but increased with age for both groups with the differences decreasing with age ( Fig. 2c). The prevalence of severe disc degeneration was lower in the rostral spine, with little difference between the symptomatic and asymptomatic groups (Fig. 2d).
3. Odds Ratios ± 95% Confidence Intervals for the relative prevalence of caudal lumbar disc degeneration between the symptomatic and asymptomatic cohorts by age.

Prevalence with age and disc level of degenerative fea-
tures in symptomatic and asymptomatic subjects.
The prevalence of disc herniation (Fig. 4a), central canal stenosis (Fig. 4b), marrow change ( Fig. 4c) and endplate defect (Fig. 4d) is shown in regard to age and disc level. For all features, prevalence was markedly greater in symptomatic than in asymptomatic subjects, particularly at younger ages, and, apart from endplate defect, greater in the caudal than the rostral lumbar spine. For instance, in the caudal lumbar spine at 40-49 years, around 30% of discs were herniated in symptomatics compared to 9% of asymptomatic discs (p < ·0001, Fig. 4a, Table S5(iii)). Over the same age range, marrow change was present in 32% of symptomatic compared to 11% of asymptomatic discs (p < ·00,001, Fig. 4c; Table S5(v)); for endplate defects, prevalence was lower being 8% for symptomatics and 3% in asymptomatics (p < ·00,001, Fig. 4d, Table S5(vi)). The prevalence of herniation, marrow changes and central canal stenosis in the rostral lumbar discs was very low, < 10%, and was similar in both groups (Tables S1, S2 and S4, respectively). For endplate defects, however, prevalence was greatest in the rostral spine, similar in both groups and increased with age ( Fig. 4d; Table S3, Table S5b(v)). 5. Odds Ratios ± 95% Confidence Intervals for the relative prevalence of degenerative features in caudal discs between the symptomatics and asymptomatics by age.
6. Co-existence of severe disc degeneration and individual degenerative features; variation with age and spinal level.
Most degenerative features, in both symptomatics and asymptomatics, were found in discs with severe disc degeneration in both the caudal and rostral spines, whatever the overall prevalence of the feature (Fig. 6a-d).

Fig. 2
Prevalence of intervertebral disc degeneration: variation with age and spinal level of prevalence (%) of discs with minimal and severe disc degeneration in asymptomatics and symptomatics. Figure 2 Shows the prevalence of disc degeneration in a symptomatic (OSCLMRIC) group and asymptomatic (TwinsUK) cohort. It shows the prevalence of normal or mildly degenerate discs ('Low'; Pfirrmann 1 + 2) in the caudal (a) and rostral discs (b). Prevalence of severe disc degeneration ('High'; Pfirrmann 4 + 5) is shown in the caudal (c) and rostral discs (d). Caudal lumbar discs = (L4/5, L5/S1); Rostral discs = (L1/2, L2/3). (Symptomatic = red; Asymptomatic = green; Severe degeneration = solid; Minimal degeneration = striped). Drawn from Data in Table S5 More than 90% of marrow changes were seen in severely degenerate discs for both symptomatic and asymptomatic subjects at most ages and spinal levels. The low (2%) prevalence of spinal stenosis in symptomatics < 50 years (compared with 0% in asymptomatics) had no apparent association with disc degeneration, possibly reflecting an alternative aetiology, such as developmental stenosis [15] ( Fig. 4b. Table S5b(iv)). There is a separate interaction of spinal stenosis and symptomatic disc herniation.
7. Co-existence of degenerative features in symptomatics and asymptomatics.
As shown by a Venn diagram (Fig. 7), for 40-49y subjects, only 5.6% of the 18% total discs with severe disc degeneration (Pfirrmann 4 + 5) in the asymptomatic cohort and 7.2% of the 43% with severe disc degeneration in the symptomatic cohort had no other degenerative features. Around 14% of symptomatic and 12% of asymptomatic severe degenerate discs had only a single degenerative feature. Marrow signs (Modic changes) alone were seen in only 0.5% of symptomatic discs. Similar co-existence of degenerative features was seen at all ages (Tables S1-S4). At 30-40 years, around 30% of the symptomatic group had no/mild degeneration (Pfirrmann 1 + 2), and no identified degenerative features (Table 1). Such coexistence suggests that using individual degenerative features as biomarkers for presence or absence of symptoms should be avoided. Alternatively combining degenerative features may be a stronger biomarker for a symptomatic spine [16].

(a) None/Mild degeneration -Low Pfirrmann grade (1+2): Caudal Lumbar Spine
Odds ratios and 95% Confidence intervals Odds ratios and 95% Confidence intervals Fig. 3 Prevalence of intervertebral disc degeneration: Odds Ratios and 95% Confidence Intervals for disc degeneration scores in the caudal spine by decade and pooled. a Shows Odds ratios and Confidences intervals for comparisons of disc degeneration in symptomatics (OSCLMRIC) with asymptomatics (TwinsUK) with low Pfirrmann (1 + 2) gradings. b Shows Odds ratios and Confidences intervals for comparisons of prevalence of disc degeneration in symptomatics (OSCLMRIC) with asymptomatics (TwinsUK) for high Pfirrmann (4 + 5) gradings. The Odds Ratios for prevalence of a Pfirrmann Grades (1 + 2) and b Pfirrmann grades (4 + 5) in Symptomatic vs. Asymptomatic subjects are shown by decade (years) and all ages pooled. The red squares indicate the odds ratio and the blue lines show 95% confidence intervals for the degenerative features in the caudal lumbar discs (L4/5, L5/S1) for each decade (30-80 years). OR for all age groups are significant (i.e. 95% CI do not cross OR = 1) except the elderly (70-79 years). Pooled odds ratios and confidence interval are shown on the same figure. The red broken lines show the odds ratios (pooled) and the grey broken lines the overall 95% confidence intervals, pooled over all ages and spinal levels drawn from data given in Table S6a Discussion Here, we used a rapid automated MRI analysis system (SpineNet) to re-annotate images of large groups of those with and without back pain onto the same grading system independent of their original annotations. The groups could then be compared directly in relation to age-and spinal level-related degenerative changes, and the results agree with other findings in the literature.
We showed that two independent groups of chronic back pain patients (OSCLMRIC, Genodisc) had very Fig. 4 Prevalence of other degenerative features (herniations, central stenosis, marrow signs, endplate defects) in symptomatics and asymptomatics in relation to age and spinal level. Figure 4 show the prevalence of a herniations (present/absent), b central canal stenosis (present/absent), c marrow signs (present/absent), d endplate defects in the caudal and rostral lumber discs of symptomatics (OSCLMRIC) and asymptomatics (TwinsUK) in relation to ages ranges, shown by decade. Figures were drawn from data in Table S5. Symptomatics = red; Asymptomatic = green; Caudal discs = solid line, Rostral discs = broken line similar patterns of degeneration, with degeneration increasing with age and with lower levels of degeneration in the rostral than in the caudal spine. In the caudal but not the rostral spine, levels of degeneration were distinctly lower in asymptomatics than in symptomatics (Fig. 1). The prevalence of disc degeneration (Fig. 2) and of all degenerative features examined (Fig. 4) increased with age and was significantly greater in symptomatics than in asymptomatic subjects in the caudal but not the rostral spine, particularly at younger ages (Figs. 3, 5). Many degenerative features co-existed with severe disc degeneration (Figs. 6,  7). However, in our study, 30% of symptomatic subjects, aged 30-50 years with chronic backpain, had no degenerative features detectable on MRI (Table 1) suggesting this group should be identified and alternative mechanisms discovered.
Why degenerative changes appear to be strongly related to pain in some subjects, and why others, with apparently similar degenerative changes, remain pain-free is still unclear. Studies have found that that type of herniations can distinguish symptomatic from asymptomatic discs [17]. Unbiased analyses of degeneration, or MRI sequences other than T2, might also be better able to discriminate between painful and non-painful discs [18,19]. However, even advances in MRI  Table S6b imaging protocols may not be able to differentiate between some asymptomatic and symptomatic subjects. Axially loaded MRIs appear able to differentiate between those with and without pain in some instances [20] but load-induced effects [21] cannot be detected by conventional spinal MRIs. Moreover, current conventional MRIs are unable to detect important factors associated with low back pain such as genetic architecture [22], augmented pain processing [23] or psycho-social factors [1,24]. Differences between painful and non-painful degenerative changes could also be masked by annotation practices. Large differences in age-related prevalence of disc degeneration are reported even in asymptomatic subjects (Fig. S1). To what extent such differences arise from annotation practices rather than environmental and genetic differences between populations can only be resolved if comparisons are made on similarly annotated images. Automated analysis can also overcome the considerable challenges facing experts in annotating complex imaging and provide objective means of unravelling differences in discs from symptomatic and non-symptomatic subjects. Moreover, by rapidly re-annotating large groups, previously annotated by different MRI analysis systems onto the same objective system, it enables data from large pre-existing groups to be compared or combined. Collection of new groups is expensive and time consuming. Automated analysis provides a way in which epidemiological analysis could be advanced by combining and comparing data from existing groups with MRIs and information on back pain. Spinal MRIs, by distinguishing between spines with and without structural degenerative changes, could provide a means of stratifying patients for further research into causes and treatments of low back pain.

Limitations
The prevalence of degenerative changes reported here is specific to our study populations. Degenerative changes in our group of chronic back pain patients recruited in secondary care may differ from those in the totality of low back pain Age-related percentage of caudal lumbar discs with severe degenerative changes combined with other specific degenerative features. The per cent of all caudal lumbar discs with severe disc degeneration (Pfirrmann 4 + 5) (y-axis) which also have the specific degenerative features a herniations, b central canal stenosis, c endplate defects, d marrow signs. Percentages are shown in relation to age for the symptomatics (OSCLMRIC) (red) and asymptomatics (TwinsUK) (green). The solid bars are (%) degenerate discs in the caudal lumbar spine combined with each degenerative feature. Absent solid bars reflect no degenerate discs in this category. The diagonal-lined bars are percentage of degenerate discs combined with each degenerative feature in the rostral lumbar spine, red lines for symptomatics, green for asymptomatics. Absent shaded bars are when there no discs present with severe disc degeneration. Data are calculated from Tables S1-S5. Marrow changes in particular are closely associated with degenerate discs in both asymptomatics and symptomatics in both the caudal and rostral discs patients seen in primary care, or in back pain reported in population cohorts.
Our initial analysis of degeneration uses (i) an average of the 1-5 categoric Pfirrmann scale (Fig. 1), which conceals important information, and (ii) an analysis of grades 1 + 2 versus 4 + 5 which identifies populations with either disc 'normal' or disc 'very degenerate'. It omits changes in grade 3 discs, which are non-discriminatory in around 25% of the total discs in both groups at some ages (Tables S1a, b). (iv) We also omitted the L3/4 disc because it was non-discriminatory. (v) Degenerative features were characterised only as present or absent as our study was underpowered for further analysis if also considering age-and spinal levels. Larger datasets could allow a sensitivity analysis of these issues and allow refining the characterisation of degenerative features.

Conclusions
Here, in an exploratory study, we found results obtained by re-annotating existing large groups of MRIs. We were able to provide quantitative information on differences in prevalence of degenerative changes between those with and without back pain and showed these were very dependent on age and spinal level. Hence, reporting MRI features of spinal pathology in relation to symptoms, without taking age or spinal level into account, can be very misleading.    [16]. The prevalence of central canal stenosis is very low in this young/middleaged group (Fig. 4) and absent in the asymptomatic group so is not shown. In this age group, it may represent developmental stenosis rather than degenerative stenosis. Data are taken from Tables S1-S5

Conflict of interest
The author declare that they have no conflict of interest.
Data availability statement OSCLMRIC Data are available upon reasonable request-deidentified participant data are available via corresponding author. Other data sets are available via the websites quoted.

Patient and public involvement statement
At what stage in the research process were patients/the public first involved in the research and how? Automated annotation has been presented through BackCare patients' charity and in a public question and answer session at the Back Pain Show, Birmingham May 2017 and subsequent interactive podcasts. The symptomatic group and asymptomatic cohort have had PPI input in their clinical and research settings. The Oxford Spine Clinic is a serial recruiting setting for clinical studies with regular interactions with large numbers of patients concerning back pain research (EB). How were the research question(s) and outcome measures developed and informed by their priorities, experience, and preferences? MRI is considered essential by many patients and current guidance discourages the use of imaging for the investigation of back pain (EB). How were patients/the public involved in the design of this study? Not Table 1 Percentage of discs with mild degeneration and no identified degenerative features in relation to age; lower lumbar ((L4/L5) and (L5/S1)) discs which have no degenerative features identified here (viz. herniations, central canal stenosis, marrow signs, endplate defects) and only mild degeneration (Pfirrmann 1+2) The percentage of asymptomatic and symptomatic lower lumbar ((L4/L5) and (L5/S1)) discs which have no degenerative features identified here (herniations, central canal stenosis, marrow signs, endplate defects) and only mild degeneration (Pfirrmann 1 + 2). It also shows the percentage with moderate degeneration (Pfirrmann 1 + 2 + 3). The disc numbers analysed are given in parentheses directly, but epidemiology issues were raised in public discussions. How were they involved in the recruitment to and conduct of the study? These subjects were recruited anonymously based on reporting back pain and having suitable imaging. TwinsUK has a full explanation of its history and recruitment on its website: https:// twins uk. ac. uk/. It is stated in the Methods that subjects were not involved in the design of this study. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.