Abstract
Background
Effectiveness of Occipital Nerve Stimulation (ONS) in refractory chronic cluster headache (rCCH) is supported by series of cases and a unique controlled trial, and its risk/benefit ratio has been questioned. Our objective was to identify predictive factors of ONS effectiveness in rCCH patients, to optimize this risk/benefit ratio and better select eligible patients.
Methods
We analyzed 125 patients (43 women, mean age 46,4) included prospectively in the “French ONS registry”, suffering from rCCH, treated by ONS for more than one year, and with data concerning putative preoperative predictive factors of effectiveness, including demographic, CCH characteristics and severity, treatment use and co-morbidities. We studied factors associated with ONS response, defined as a ≥ 50% reduction of weekly attack frequency (WAF) between baseline and one year follow-up.
Results
Factors predictor of good response to ONS were high preoperative WAF (p = 0.0003), high number of days with attack treatment use (p = 0.0006) and absence of epilepsy (p = 0.019). The best cut-off to predict ONS effectiveness was a WAF of 14 attacks/w. ONS response’s rates were 77.0% and 37.3% in patients with WAF ≥ 14/w and WAF < 14/w, respectively. However, in both groups, quality of life was significantly improved after ONS (p < 0.001).
Conclusion
Preoperative WAF was the main predictive factors of ONS response in rCCH, with a cut-off of 14 attacks/w, which may help to select patients and increase the ONS risk/benefit ratio. However, this threshold should be used with caution, as patients with WAF < 14/w also benefited from ONS.
Registration
The study has been registered (clinicaltrials.gov identifier NCT01842763).
Introduction
Neuromodulation techniques have emerged twenty years ago as promising therapies for patients suffering from chronic cluster headache (CCH), especially occipital nerve stimulation (ONS) [1, 2]. In open series of cases [1–10], and in controlled clinical trial [11, 12] about 50% to 70% of the patients did respond to ONS, a responder being usually defined when weekly attack frequency decreased by more than 50%. Consequently, ONS has been considered as an option in several European recommendations for refractory CCH management [13–15]. However, as ONS efficacy is not currently supported by high level of evidence, ONS is still not validated and reimbursed in most countries and its risk / benefit ratio has been questioned [16].
To optimize this risk/benefit ratio, it is crucial to better select patients eligible for ONS, by identifying predictive factors of response ONS. Few studies tried to identify such factors, failing to propose preoperative factors that are really meaningful in daily clinic [10, 17, 18].
The objective of this study was to identify predictive factors of ONS effectiveness in refractory CCH patients included in the multicentric French ONS registry.
Methods
Patients
All patients were included prospectively in the “French Occipital Nerves Stimulation Observatory” between 2013 and 2024, a multicentric registry collecting data of chronic headache patients undergoing ONS (clinicaltrials.gov identifier NCT01842763). All the patients signed an informed consent for data collection and the registry obtained all the required legal and ethical approval. All patients were assessed and treated in tertiary multi-disciplinary centers. Criteria for treating refractory CCH by ONS followed the French recommendations [13], which differ slightly from the European Headache Federation definition of refractory CCH [19]. Criteria to be included in the French ONS observatory were: (i) chronic cluster headache [20]; (ii) disease duration greater than 1 year, (iii) refractory to pharmacological prophylactic treatment, including verapamil up to 960 mg/day, lithium with plasma level from 0.6 to 1 mEq/l and association of both, in absence of adverse events [13], (iiii) treatment by ONS. The ONS surgical technique and hardware have been already described and could vary across centers but followed the key recommendations [9]: continuous tonic stimulation inducing comfortable paresthesias in the occipital region, via subcutaneously implanted occipital electrodes connected to a generator. Stimulation parameters (intensity 1,5–9 V or mA; frequency 30–100 Hz) varied across patients and could vary over time. At the time this present study was initiated, 168 patients were included in the French ONS registry. Criteria to be further included in the present study were: (i) previous inclusion in the French ONS registry, (ii) follow up superior to one year after ONS implantation; (iii) complete or nearly complete data concerning putative preoperative predictive factors of efficacy. All the patients included in this study have already been included in previously published studies [9, 10, 21].
Collected data
Data were prospectively collected, before surgery (baseline) and at last follow-up after ONS using the same multidimensional questionnaire and the patient’s agenda. Baseline criteria that could influence ONS efficacy and that were analyzed as predictive factors of efficacy were: age, gender, professional status (activity versus no activity including sick-leave, with disability pension, unemployment); history of epilepsy, sleep apnea, high blood pressure, diabetes, asthma, thyroid dysfunction, anxiety, depression, obesity and smoking; duration of the disease, duration of the chronic form of CH; laterality (strictly unilateral versus preferentially unilateral or bilateral; right versus left side); number of headache days during the month preceding inclusion; number of CH attacks during the last week preceding the visit, mean attacks intensity (assessed by numeric scale from 0 to 10), mean attack duration and number of days with attack treatment use during the week preceding inclusion; medication taken during the week preceding inclusion; sumatriptan and oxygen resistance (due to inefficacy or intolerance) ; HIT-6 score [22, 23] HAD-D and HAD-A [24, 25] scores (total scores and 3 categories distinguishing absent (sub-score ≤ 7), mild (8–10), moderate to severe (≥ 11) symptoms, the Migraine Disability Assessment (MIDAS) questionnaire grades [26, 27] and quality of life was assessed by the French version of EQ-5D-3 L health questionnaire [28, 29] (utility score and visual analogue scale (EQ VAS)).
Definition of ONS effectiveness
ONS effectiveness was evaluated by changes occurring after one year of continuous chronic stimulation compared to baseline, the primary endpoint being the weekly attack frequency. In this study, we defined ONS effectiveness by a ≥ 50% reduction of weekly attack frequency between baseline and one year follow-up.
Statistical analysis
Results are presented as means (SD) and medians for quantitative variables and relative frequencies for qualitative variables.
The predictive factors of attack frequency decrease ≥ 50% were studied using Student t-test or Wilcoxon-Mann-Whitney test for quantitative variables and Chi2 test or Fisher exact test for qualitative variables. Receiver operating characteristic (ROC) curves were constructed to assess weekly attack frequency between reduction of attack frequency. The area under the curve (AUC) was shown. The best cut-off was identified. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were measured. To compare post-operative scores to baseline (HAD-Anxiety, HAD-Depression, Eq. 5D utility and ED5D VAS), Wilcoxon signed-rank test were used for patients with preoperative attack frequency < 14/week and for patients with preoperative attack frequency ≥ 14/w.
All tests were 2-sided and the significance level was set at 5%. Analyses were performed with R-4.5.1 software.
Results
One hundred and twenty-five patients (82 men, 43 women, gender ratio 1,9) were included in the study. The mean age was 46,4 ± 11,4 years. Characteristics of the study population is described in Table 1. Attack frequency decrease at last follow-up was ≥ 50% compared to baseline in 76 patients (60.8%).
Table 1.
Characteristics of the patients treated by occipital nerve stimulation for refractory chronic cluster headache
| Patients’ characteristics | N | mean | SD |
|---|---|---|---|
| Age | 121 | 46,4 | 11,4 |
| Disease duration | 110 | 12,4 | 9,0 |
| Chronic form duration | 119 | 6,4 | 5,2 |
| Number of headache days (last month) | 122 | 26,9 | 7,0 |
| Number of CH attacks (last week) | 125 | 21,8 | 20,1 |
| Mean attacks intensity (last week) | 121 | 8,0 | 2,0 |
| Mean attack duration (minutes) (last week) | 110 | 54,5 | 98,5 |
| Number of days with attack treatment use (last week) | 116 | 5.8 | 2.1 |
| Score HIT 6 | 112 | 67,6 | 5,7 |
| Score HAD-D | 113 | 10,4 | 4,4 |
| Score HAD-A | 115 | 11,0 | 6,6 |
| 5D utility score | 115 | 0,4 | 0,2 |
| 5D - VAS | 109 | 39,2 | 20,6 |
| N | n | % | |
| Gender | 125 | ||
| Women | 43 | 34,4 | |
| Men | 82 | 65,6 | |
| Professional status | 111 | ||
| Active | 49 | 44,1 | |
| Sick leave | 21 | 18,9 | |
| Disability pension | 32 | 28,8 | |
| Unemployment | 9 | 8,1 | |
| Attack location | 121 | ||
| Strictly unilateral | 86 | 71,1 | |
| Preferentially unilateral or bilateral | 35 | 28,9 | |
| Attack side | 118 | ||
| Right | 64 | 54,2 | |
| Left | 48 | 40,7 | |
| Across attacks | 6 | 5,1 | |
| MIDAS - Grade | 101 | ||
| 1 | 6 | 5,9 | |
| 2 | 3 | 3,0 | |
| 3 | 3 | 3,0 | |
| 4 | 89 | 88,1 | |
| Medical history | |||
| Epilepsy | 111 | 4 | 3,6 |
| Sleep apnea | 110 | 7 | 6,4 |
| High blood pressure | 110 | 9 | 8,2 |
| Diabetes | 110 | 2 | 1,8 |
| Asthma | 110 | 6 | 5,5 |
| Thyroid dysfunction | 110 | 3 | 2,7 |
| Anxiety | 110 | 15 | 13,6 |
| Mood disorders | 111 | 21 | 18,9 |
| Obesity | 110 | 26 | 23,6 |
| Smoking | 112 | 74 | 66,1 |
| Medication intake for CH (last week) | |||
| Preventive treatments | |||
| Beta Blockers | 119 | 5 | 4,2 |
| Verapamil | 119 | 80 | 67,2 |
| Antiepileptics | 119 | 36 | 30,3 |
| Antidepressants | 119 | 35 | 29,4 |
| NSAID | 119 | 7 | 5,9 |
| Lithium | 119 | 35 | 29,4 |
| Others | 119 | 7 | 5,9 |
| Transitional treatments | |||
| Steroids | 119 | 14 | 11,8 |
| Acute treatments | |||
| Sumatriptan (subcutaneous) | 125 | 86 | 68,8 |
| Oxygen | 122 | 76 | 62,3 |
| Acute treatment resistance | |||
| Sumatriptan resistance (intolerance or inefficacy) | 125 | 24 | 19,2 |
| Oxygen resistance (intolerance or inefficacy) | 122 | 37 | 30,3 |
SD: standard deviation. HAD: Hospital Anxiety and Depression Scale, which includes sub-scores for anxiety (HAD-A) and depression (HAD-D). EQ-5D: EQ-5D health questionnaire, which encompasses the EuroQol-5D utility score and the EuroQol Visual Analogue Scale (EQ-VAS). HIT-6: Headache Impact Test
In univariate analysis, factors correlated with long-term reduction of attack frequency ≥ 50%, and consequently predictor of good response to ONS (Table 2) were absence of epilepsy (p = 0.019), preoperative weekly attack frequency (p = 0.0003) and number of days with attack treatment use (p = 0.0006). The higher the number of weekly attacks was, the better was the response to the ONS. The higher the number of days with attack treatment use was, the better was the response, however 69% of the patients used an acute treatment 7 days per week. Other factors (age, gender, other medical history, disease duration, patient reported outcomes) did not have a significant influence on the outcome.
Table 2.
Predictive factors of response (attack frequency decrease ≥ 50%) to occipital nerve stimulation in patients treated for refractory chronic cluster headache
| Baseline characteristics | Weekly attack frequency decrease ≥ 50% | ||||
|---|---|---|---|---|---|
| No - n = 49 | Yes - n = 76 | ||||
| mean | SD | mean | SD | p-value* | |
| Age | 47,3 | 12,2 | 45,9 | 10,9 | 0,495 |
| Disease duration | 12,3 | 8,5 | 12,4 | 9,3 | 0,836 |
| Chronic form duration | 5,6 | 4,2 | 6,9 | 5,7 | 0,172 |
| Number of headache days (last month) | 24,8 | 9,2 | 28,3 | 4,6 | 0,078 |
| Number of CH attacks (last week) | 15,9 | 19,6 | 25,5 | 19,6 | 0,0003 |
| Mean attacks intensity (last week) | 7,8 | 2,2 | 8,2 | 1,9 | 0,444 |
| Mean attack duration (minutes) (last week) | 45,5 | 37,2 | 60,6 | 123,5 | 0,219 |
| Number of days with attack treatment use (last week) | 5.0 | 2.5 | 6.3 | 1.5 | 0.0006 |
| Score HIT 6 | 66,9 | 6,3 | 68,1 | 5,3 | 0,272 |
| Score HAD-D | 11,0 | 4,9 | 9,9 | 3,9 | 0,215 |
| Score HAD-A | 11,7 | 9,0 | 10,5 | 4,3 | 0,880 |
| 5D utility score | 0,4 | 0,3 | 0,4 | 0,2 | 0,284 |
| 5D - VAS | 40,8 | 22,0 | 37,9 | 19,5 | 0,504 |
| n | % | n | % | p-value** | |
| Gender | 0,659 | ||||
| Women | 18 | 41,9 | 25 | 58,1 | |
| Professional activity | 0,656 | ||||
| Active | 15 | 30,6 | 34 | 69,4 | |
| Pain location | 0,807 | ||||
| Strictly unilateral | 34 | 39,5 | 52 | 60,5 | |
| Preferentially unilateral or bilateral | 13 | 37,1 | 22 | 62,9 | |
| Pain side | 0,161 | ||||
| Right | 26 | 40,6 | 38 | 59,4 | |
| MIDAS – Grade | 0,564 | ||||
| 1–3 | 3 | 25,0 | 9 | 75,0 | |
| 4 | 39 | 43,8 | 50 | 56,2 | |
| HAD A category | 0,817 | ||||
| ≤ 7 - Absent | 11 | 39,3 | 17 | 60,7 | |
| 8–10 - Mild | 15 | 45,5 | 18 | 54,5 | |
| ≥ 11 Moderate to severe | 21 | 38,9 | 33 | 61,1 | |
| HAD D category | 0,501 | ||||
| ≤ 7 - Absent | 10 | 32,3 | 21 | 67,7 | |
| 8–10 - Mild | 12 | 41,4 | 17 | 58,6 | |
| ≥ 11 Moderate to severe | 24 | 45,3 | 29 | 54,7 | |
| Medical history | |||||
| Epilepsy | 4 | 100,0 | 0 | 0,0 | 0,019 |
| Sleep apnea | 1 | 14,3 | 6 | 85,7 | 0,248 |
| HBP | 5 | 55,6 | 4 | 44,4 | 0,298 |
| Diabetes | 2 | 100,0 | 0 | 0,0 | 0,144 |
| Asthma | 2 | 33,3 | 4 | 66,7 | 1,000 |
| Thyroid dysfunction | 1 | 33,3 | 2 | 66,7 | 1,000 |
| Anxiety | 4 | 26,7 | 11 | 73,3 | 0,323 |
| Mood disorders | 8 | 38,1 | 13 | 61,9 | 0,978 |
| Obesity | 11 | 42,3 | 15 | 57,7 | 0,620 |
| Smoking | 27 | 36,5 | 47 | 63,5 | 0,757 |
| Medication | |||||
| Verapamil | 29 | 36,3 | 51 | 63,8 | 0,440 |
| Antiepileptics | 14 | 38,9 | 22 | 61,1 | 0,973 |
| Antidepressants | 11 | 31,4 | 24 | 68,6 | 0,296 |
| Lithium | 12 | 34,3 | 23 | 65,7 | 0,527 |
| Steroids | 5 | 35,7 | 9 | 64,3 | 0,810 |
| Sumatriptan | 37 | 43,0 | 49 | 57,0 | 0,194 |
| Oxygen use | 31 | 40,8 | 45 | 59,2 | 0,509 |
| sumatriptan resistance (yes) | 6 | 25,0 | 18 | 75,0 | 0,113 |
| Oxygen resistance (yes) | 13 | 35,1 | 24 | 64,9 | 0,612 |
HAD: Hospital Anxiety and Depression Scale anxiety (HAD-A) and depression (HAD-D) sub-scores. EQ-5D: EQ-5D health questionnaire, utility score and Visual Analogue Scale (EQ-VAS). HIT-6: Headache Impact Test. * T test of Student or Wilcoxon-Mann-Whitney test. ** Chi2 test or exact Fisher test
* Student t-test or Wilcoxon-Mann-Whitney test
** Chi2 test or Fisher exact test
The ROC curve showed that the best cut-off to predict ONS efficacy was a weekly attack frequency of 14 per week (Fig. 1). The AUC was 0.693. The number of ONS responders was 57/74 (77.0%) patients with weekly attack frequency ≥ 14/w and 19/51 (37.3%) patients with attack frequency < 14/w. This cut-off of 14 attacks/w defined preoperative weekly attack frequency as a predictive factor of ONS efficacy with a sensitivity of 65.3%, a specificity of 75.0%, positive predictive value of 62.5% and negative predictive value of 77.0%.
Fig. 1.
Receiver operating characteristic (ROC) curve assessing response to ONS (attack frequency decrease ≥ 50%) according to preoperative weekly attack frequency
When comparing post-operative scores to baseline, we observed a significant improvement of HAD-A (p < 0.001), HAD-D (p < 0.001), Eq. 5D-utility (p < 0.001) and Eq. 5D-VAS (p < 0.001) scores in the group of patients with preoperative attack frequency ≥ 14/w (Fig. 2). In this group, 16.2% and 29.7% of the patients did not use sumatriptan or oxygen, respectively, due to intolerance or inefficacy. We also observed a significant improvement of the HAD-A, HAD-D, Eq. 5D utility and VAS scores (p = 0.001, p = 0.002, p < 0.001, p < 0.001, respectively) in the group of patients with preoperative attack frequency < 14/w. Improvements were slightly lower in this later group compared with the former, but the difference between groups was not significant. In this group 23.5% and 31.2% of the patients did not use sumatriptan or oxygen, respectively.
Fig. 2.
Evolution of anxiety, depression and quality of life in chronic cluster headache patients treated by occipital nerve stimulation according to their preoperative weekly attack frequency < 14/week or ≥ 14/week. HAD: Hospital Anxiety and Depression Scale anxiety (HAD-A) and depression (HAD-D) sub-scores. EQ-5D: EQ-5D health questionnaire, utility and Visual Analogue Scale (EQ-VAS) scores. * p < 0,01
Discussion
In this study, main factors significantly associated with good response to ONS were preoperative weekly attack frequency and number of days with attack treatment use. Considering preoperative weekly attack frequency, the best threshold to predict ONS efficacy was 14 attacks per week.
Co-morbid epilepsy also appeared associated with poor ONS response, but this result was probably biased by the small number of patients (4 cases, all distributed in the non-responder group) with such comorbidity. We have no further hypotheses to explain this association. We did not perform a multivariate analysis because, among the 3 predictive factors identified in the univariate analysis, epilepsy concerned only a few cases and the other two, namely the frequency of attacks and the use of attack treatments, were clearly linked to each other. In addition, a substantial proportion of patients did not use any acute treatment (Table 1), and 69% of patients who used acute treatments did so seven days a week, making this criterion poorly relevant. Acute treatment resistance was not a factor associated with response to ONS.
Three similar studies have previously identified factors potentially associated with ONS success or failure in 59 [10], 61 [18], 88 [17] patients, respectively. Membrilla et al. [17] suggested that early onset of CH and smoking were associated with ONS failure, but these associations were not confirmed in our study and in the data from the Icon study [18]. Brandt et al. showed an association between early (24 weeks) response to ONS with positive long-term response [18]. We did not study this particular factor because we focused on preoperative factors that could be used to select the best candidates for ONS treatment. In a previous study, we identified a positive relation between good long-term outcome and preoperative low depression (HAD-D) score [10]. Such relation was not found in the current study. This could be explained by the fact that our previous study only analyzed ONS response at last follow-up, which was variable among patients and by the lower number of patients included. Baseline mean weekly attack frequency, that appears in our study as the main factor related to ONS response, was not considered by Membrilla et al., and not found as such by Brandt et al. [17, 18]. However, Brandt used a model studying the effectiveness of ONS as the relative difference in attack frequency from baseline at 2 and 5 years after ONS, as a continuous variable, whereas we studied this effectiveness dichotomously, considering responders who had a reduction in attack frequency greater than 50% at 1 year.
Despite that baseline weekly attack frequency reflected the preoperative severity of CH disease, other patient reported outcome measures (PROM), as the HIT, MIDAS, HAD, EQ-5D scores, also reflecting CH severity, were not found associated with ONS response. This discrepancy may be explained by the generic nature of these PROMs, not specific to CCH. Moreover, the use of these scales is limited by a saturation effect because all these patients, suffering from a refractory form of CCH and candidates for ONS, have very high and poorly discriminating preoperative values. The use of more specific measures for these severe forms, such as the recent CHIC scale, could resolve this bias [30]. However, we can also hypothesize that ONS has a specific effect on forms of CCH that manifest as a very high frequency of attacks, that might be associated with a higher degree of central sensitization.
Our model allowed us to identified a threshold of 14 attacks per week as having the best sensitivity and specificity ratios to predict ONS response. This finding reinforces the recent International Headache Society recommendations to consider severe CCH patients according to the frequency of attacks, by distinguishing patients having more than 14 attacks per week on average [31]. This 14 attack/w threshold is also coherent with the limitations of sumatriptan injection use. Selecting patients based on this threshold may increase the risk/benefit ratio of ONS and its cost-effectiveness [32], and may be considered in future revisions of the guidelines on neuromodulation use in primary headaches [14]. However, caution is advised and one should not be too strict in the use of this threshold, which could lead to a loss of chance for patients resistant to acute treatments (about one third of the patients in this group). Indeed, our analysis showed that patients with less than 14 attacks/w also benefited substantially from ONS, leading to significant decreases of functional and emotional impacts of the disease and to a significant improvement of their quality of life.
Our study has some limitations, such as the fact that our criteria for defining refractory CCH and proposing ONS differ from the EHF recommendations [19]. It cannot be ruled out that variations in the attack frequency were related to spontaneous or seasonal variations, spontaneous remission of the disease, a placebo effect (although unlikely after one year of stimulation) or biased by a recall bias. The main limitation of this study is the low number of patients included, which is also the limit of previous studies, due to rarity of the disease and of the therapy indication. This limitation weakens the robustness of statistical models. This argues for pooling data from the different teams working on this subject in international collaborative studies.
Conclusion
In this study, the preoperative weekly attack frequency and the number of days with attack treatment use were factors significantly associated with response to ONS, namely of attack frequency decrease ≥ 50%. The best threshold of preoperative attack frequency to predict ONS efficacy was 14 attacks per week, with a sensitivity of 65.3%, a specificity of 75.0%. However, patients with less than 14 attacks/w also benefited substantially from ONS, with significant improvement of their quality of life.
Author contributions
Study design: DF, MLM Data collection: DF, AL, AD, JR, AB, CL, ND, SR, SD, BJ, CC, SC, JM, SCC, FC, PR, GD, ES, MLM Data analysis: DF, MLM Statistics: RF Manuscript writing: DF, MLM, RF, ALW All authors reviewed the manuscript.
Funding
This research was supported by the University Hospital of Nice, as part of the FHU INOVPAIN consortium (Nice, France). While Medtronic and St Jude Medical-Abbott provided financial support for the study, these companies were not involved in its design, data collection, analysis, data interpretation and in the manuscript writing.
Data availability
Anominyzed data is available for research purpose, on request to the corresponding author.
Declarations
Competing interests
This research was supported by the University Hospital of Nice, as part of the FHU INOVPAIN consortium (Nice, France). While Medtronic and St Jude Medical-Abbott provided financial support for the study, these companies were not involved in its design, data collection, analysis, interpretation and in the manuscript writing. Denys Fontaine is consultant for Medtronic, Boston scientific and Abbott and has received research grants from Abbott and Medtronic, outside and for the present study. Aurelie Leplus has received speaker fees from Boston Scientific and is consultant for Abbott. Sylvie Raoul reports grants and personal fees from Medtronic, Abbott and Boston Scientific, outside the submitted work. Anne Balossier is consultant for Medtronic and Abbott and reports personal fees from Medtronic and Abbott, outside the submitted work. Sylvie Raoul received consulting fees from Medtronic, Abbott and Boston Scientific. Jimmy Voirin is consultant for Medtronic, Boston Scientific and Abbott and has received fees from Medtronic and Boston Scientific. Philippe Rigoard reports research grants and speaker fees from Medtronic, Abbott and Boston Scientific. Geneviève Demarquay has received financial support from Allergan-Abbvie, Lilly, Lundbeck, Novartis, Pfizer, Teva, not related to the present study. Emile Simon reports fees from Medtronic and Boston Scientific, outside the submitted work. Michel Lanteri-Minet is consultant for Medtronic and has received research grants from Abbott and Medtronic, outside and for the present study; he is also Associate Editor for the Journal of Headache and Pain. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Anominyzed data is available for research purpose, on request to the corresponding author.