Comparison of the diagnostic accuracy of whole-body diffusion-weighted imaging and ¹⁸F-prostate-specific membrane antigen-1007 positron emission tomography combined with computed tomography for detecting bone metastases in prostate cancer

Full Text

BACKGROUND

Positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals is increasingly widely used in clinical practice for prostate cancer staging. PET/CT has become the preferred approach in the diagnosis of biochemical recurrence in prostate cancer [1, 2]. Several clinical studies have confirmed that PET/CT with PSMA-targeting radiopharmaceuticals outperforms magnetic resonance imaging (MRI), CT, and radiolabeled choline in detecting biochemical recurrence [3, 4]. Furthermore, PSMA improves the accuracy of primary staging in intermediate- and high-risk prostate cancer [5].

In the United States and Europe, gallium-68 is the most commonly used isotope in PSMA-targeting radiopharmaceuticals. Specifically, ⁶⁸Ga-PSMA-11 was the first PET radiopharmaceutical approved in the United States for patients with prostate cancer [6]. With advancements in radiopharmacy, ¹⁸F-PSMA ligands, such as ¹⁸F-PSMA-1007, have become widely used.

The main technical advantages of ¹⁸F-PSMA ligands over ⁶⁸Ga-PSMA include a longer half-life (110 min vs. 68 min) and the possibility of cyclotron production. Moreover, ¹⁸F-PSMA has lower positron emission energy than ⁶⁸Ga-PSMA (0.6 MeV vs. 2.3 MeV), increasing the spatial resolution of phantom scans [7]. Another advantage of ¹⁸F-PSMA-1007 is the radiopharmaceutical's low background activity in the urinary tract [8].

However, as ¹⁸F-PSMA-1007 becomes more widely used, reports of false-positive findings in bones increase [9]. This can lead to an unreasonable overestimation of the disease stage, resulting in an ineffective treatment strategy.

The key advantages of MRI, which was introduced as a diagnostic tool several decades ago, include excellent soft tissue contrast and the absence of radiation exposure.

Diffusion-weighted imaging (DWI) is an MRI mode that measures the microscopic movement of water molecules at the cellular level. DWI provides both quantitative (e.g., apparent diffusion coefficient) and qualitative (e.g., signal intensity) data for the differential diagnosis of benign and malignant neoplasms [10].

DWI was initially used in brain diseases, including to detect cerebral infarction zones based on diffusion restriction. Technical advances introduced in the late 1990s, such as diffusion-weighted imaging with background suppression (DWIBS), made it possible to use DWI to diagnose extracranial disorders. The key advantage of DWIBS is quick, free-breathing whole-body imaging, which opens up new prospects for cancer staging [10].

However, given its low resolution, DWIBS alone is insufficiently effective. The fundamental advantage of DWIBS is that it detects lesions based on high signal intensity at high b values [11]. To accurately determine the anatomic site of the detected lesion, whole-body DWI must be supplemented by basic MRI sequences, such as T1 weighted images (T1WI), short tau inversion recovery (STIR), and some others [12].

DWI is currently used to visualize metastases. Malignant tumors typically have a more intense DWI signal than benign ones. Diffusion restriction by tumor tissues may be caused by a greater number of cells per unit volume, resulting in smaller intercellular spaces. The advantages of whole-body DWI include a short scan time (approximately 20 minutes), no ionizing radiation, and no need for intravenous contrast. Furthermore, DWI is a clarifying MRI sequence in whole-body examinations in cancer, including the diagnosis of distant metastases [13].

AIM

The work aimed to assess the diagnostic accuracy of whole-body PET/CT with ¹⁸F-PSMA-1007 compared to whole-body and pelvic DWI in patients with prostate cancer.

METHODS

Study Design

A retrospective, single-center study was conducted.

Eligibility Criteria

Inclusion criteria:

• Prostate cancer with signs of biochemical recurrence;
• Multiparametric prostate MRI;
• Whole-body DWI;
• Whole-body PET/CT with ¹⁸F-PSMA-1007;
• Interval between MRI and PET of no more than 14 days.

Non-inclusion criteria: absence of one or more diagnostic markers of prostate cancer.

Exclusion criteria: significant artifacts of pelvic DWI, whole-body DWI, or whole-body PET/CT with ¹⁸F-PSMA-1007, preventing proper assessment of findings.

Study Setting

Patients who underwent PET/CT with ¹⁸F-PSMA-1007, whole-body DWI, and prostate MRI were enrolled at the private healthcare facility European Medical Center.

Study Duration

The study used electronic medical records obtained between January 1, 2023, and June 1, 2023.

Intervention

Two datasets were generated at the first stage of the study:

• PET/CT with ¹⁸F-PSMA-1007 and whole-body DWI;
• PET/CT with ¹⁸F-PSMA-1007 and pelvic DWI.

The interval between MRI and PET was no more than 14 days.

At the second stage, the number of metastatic bone lesions at various anatomic sites was assessed using PET with ¹⁸F-PSMA-1007 and MRI findings.

A Biograph^® mCT scanner (Siemens Healthineers, Germany) was used for PET/CT with ¹⁸F-PSMA-1007. Whole-body (head-to-toes) PET/CT was performed. The radiopharmaceutical activity was calculated as 3.0–4.0 MBq per 1 kg body weight (mean: 250–350 MBq). After receiving the radiopharmaceutical, patients rested for 60 minutes. Oral hydration with 500 mL of water was performed. The scan time per axial field of view (the area corresponding to the patient's position on the scanner bed) was 3 minutes.

PSMA-RADS-3,¹ PSMA-RADS-4,² and PSMA-RADS-5³ lesions are classified as doubtful or positive based on PET findings [14]. To be classified as true-positive, a lesion must be confirmed by additional MRI sequences, including:

• Axial in-phase and out-of-phase T1WIs, HASTE T2WIs,⁴ and sagittal T1WIs of the spine for whole-body MRI findings;
• Axial in-phase and out-of-phase T1WIs, HASTE T2WIs,⁴ and dynamic contrast-enhanced T1WIs for pelvic MRI findings [15].

The scanning used a head coil, two flexible body coils, and a spine coil. The overall scan time was determined by the patient's anthropometric characteristics, but did not exceed 50 minutes. Table 1 shows protocols for prostate MRI and whole-body DWI.

 

Table 1. Protocols of whole-body and prostate diffusion-weighted magnetic resonance imaging

MRI sequence	Slice orientation	TE/TR, ms	Field of view, mm	Slice thickness, mm / overlap, %
Multiparametric magnetic resonance imaging of the prostate
TSE T2-weighted image	Sagittal	120/3800	250×250	3/0.3
TSE T2-weighted image	Axial	110/3938	180×180	2.5/0
SS-EPI diffusion-weighted image	Axial	87/2425	160×160	3/0.3
SS-EPI diffusion-weighted image	Axial	59/5400	200×200	3/0
TSE T2-weighted image	Coronal	110/2500	160×160	2.5/0
Dynamic contrast-enhanced T1-weighted image, temporal resolution 15 s	Axial	2.3/4.6	250×250	3/0
T1-weighted image after contrast enhancement	Axial	1.3/2.3	400×350	4/0
Whole-body diffusion-weighted magnetic resonance imaging
SS-EPI diffusion-weighted image	Axial	76/15 600	380×285	5/0
TSE T1-weighted image	Sagittal	12/630	340×340	4/0
HASTE T2-weighted image	Axial	91/1400	385×313	6/0
VIBE DIXON T1-weighted image	Axial	6.69/2.39–4.77	380×309	4/
TIRM T2-weighted image	Axial	86/7200	230×201	5/0
Note. TSE, turbo spin echo; SS-EPI, single-shot echo planar imaging; HASTE, half-Fourier acquisition single-shot turbo spin echo; VIBE DIXON, volumetric interpolated breath-hold examination with the Dixon method; TIRM, turbo inversion recovery magnitude; TE, echo time; TR, repetition time.

 

Main Study Outcome

Detection of metastatic bone lesions using PET/CT with ¹⁸F-PSMA-1007 and whole-body and pelvic diffusion-weighted imaging findings, confirmed by additional MRI sequences.

Subgroup Analysis

All findings were divided into two groups:

• Group 1: PET/CT with ¹⁸F-PSMA-1007 and whole-body DWI findings;
• Group 2: PET/CT with ¹⁸F-PSMA-1007 and pelvic DWI findings.

Outcomes Registration

The number of detected lesions was entered into a table, indicating the anatomic site. To assess the distribution by anatomic sites, metastases to cranial bones, scapulas, ribs, pelvic bones, and vertebrae were counted individually. Moreover, metastases to pelvic bones were counted individually for whole-body and pelvic MRI findings.

Each lesion detected using PET/CT with ¹⁸F-PSMA-1007 and whole-body and pelvic DWI findings was compared with a reference test (MRI scans with additional MRI sequences). Only lesions that met the diagnostic criteria for metastases based on additional MRI sequences were classified as true-positive. The additional MRI sequences included frequency-selective fat suppression (in-phase and out-of-phase T1WIs) for reliable detection of a metastatic lesion and a red marrow reconversion zone [16, 17].

Ethics Approval

The study was approved by the Independent Ethics Committee of the Center for Diagnostics and Telemedicine (Minutes No. 10/2023 dated December 21, 2023).

Statistical Analysis

Sample size calculation

Given the lack of data for accurately predicting expected effects, the sample size was calculated using the estimated average effect size of 0.5 [18]. According to the Altman nomogram, with the effect size of 0.5, significance level of 0.05, and power of 0.8, the required sample size will be 120 patients [19].

Statistical methods

The diagnostic accuracy of the studied techniques was assessed by calculating their sensitivity and specificity.

• Sensitivity (Se) was assessed as the proportion of true-positive findings:

$Se=\frac{TP}{TP+FN}$, (1)

where ТР is the number of true-positive findings; FN is the number of false-negative findings.

• Specificity (Sp) was assessed as the proportion of true-negative findings:

$Sp=\frac{TN}{TN+FP}$, (2)

where TN is the number of true-negative findings; FP is the number of false-positive findings.

The number of true-positive findings was defined as the number of lesions at the examined anatomic site, confirmed by additional MRI sequences. The number of true-negative findings was defined as the number of patients without lesions at the examined anatomic site according to index and reference tests. If the number of lesions at the examined anatomic site based on the index test exceeded the number based on the reference test, the difference was regarded the number of false-positive findings. Otherwise, the difference was interpreted as the number of false-negative findings. The sensitivity and specificity of each index test for each anatomic site are shown with 95% confidence intervals (CIs). The overall sensitivity and specificity of each index test are presented as means and interquartile ranges. The McNemar's test was used to compare index and reference tests.

R 4.2.1⁵ was used for all calculations [20].

RESULTS

Participants

The study included findings for 119 patients:

Group 1: 40 data pairs of PET/CT with ¹⁸F-PSMA-1007 and whole-body DWI findings;

Group 2: 79 data pairs of PET/CT with ¹⁸F-PSMA-1007 and pelvic DWI findings.

Table 2 shows the total number of metastatic lesions in group 1, confirmed by additional MRI sequences.

 

Table 2. Number of metastatic bone lesions detected in group 1

Anatomic site	PET/CT with 18F-PSMA-1007, n	Whole-body DWI, n	Lesions confirmed by other MRI sequences, n
Skull	53	50	35
Scapulas	59	55	46
Ribs	240	218	167
Vertebrae	225	220	176
Pelvis	135	131	114
Extremities	22	29	20
Note. PET/CT, positron emission tomography/computed tomography; PSMA, prostate-specific membrane antigen; DWI, diffusion-weighted image; MRI, magnetic resonance imaging.

 

Table 3 shows the total number of metastatic lesions in group 2, confirmed by additional MRI sequences. In addition to bone metastases, group 2 showed signs of prostate cancer recurrence near the vesicourethral anastomosis in 31 patients and signs of pelvic lymph node involvement in 59 patients. In group 1, signs of recurrence near the vesicourethral anastomosis were found in 17 patients, and signs of retroperitoneal and pelvic lymph node involvement in 28 patients.

 

Table 3. Number of metastatic lesions detected in group 2

Anatomic site	PET/CT with 18F-PSMA-1007, n	Whole-body DWI, n	Lesions confirmed by other MRI sequences, n
Pelvis	118	80	79
Extremities	30	18	18
Note. PET/CT, positron emission tomography/computed tomography; PSMA, prostate-specific membrane antigen; DWI, diffusion-weighted image; MRI, magnetic resonance imaging.

 

Primary Results

The distribution (%) of metastatic lesions by anatomic sites was as follows:

• 5% in cranial bones
• 5% in the spine
• 5% in the ribs
• 5% in the scapulas
• 5% in pelvic bones, and
• 5% in the extremities.

The maximum sensitivity and specificity of whole-body DWI were 93.22 (95% CI: 87.67–97.81) and 58.10% (95% CI: 31.54–74.62), respectively. The maximum sensitivity and specificity of whole-body PET/CT with ¹⁸F-PSMA-1007 were 97.55 (95% CI: 95.13–100.00) and 51.06% (95% CI: 20.35–76.59), respectively. Table 4 shows the calculated diagnostic parameters for selected anatomic sites. In group 2, the sensitivity was 100% for both techniques, whereas the sensitivity was 85.18% for whole-body PET/CT with ¹⁸F-PSMA-1007 and 100% for pelvic DWI (see Table 5).

 

Table 4. Diagnostic accuracy parameters in group 1

Anatomic site	PET/CT with 18F-PSMA-1007		Whole-body DWI		χ2	p-value
	Se, % (95% CI)	Sp, % (95% CI)	Se, % (95% CI)	Sp, % (95% CI)
Skull	100 (90.11–100)	64 (50.14–75.86)	100 (90.11–100)	69.39 (55.47–80.48)	0.129	0.720
Scapulas	100 (91.62–100)	63.83 (49.54–76.03)	91.3 (71.68–96.57)	71.11 (56.63–82.27)	0.800	0.372
Ribs	98.74 (95.53–99.65)	19.42 (12.94–28.1)	98.74 (95.53–99.65)	31.46 (22.75–41.7)	3.645	0.057
Vertebrae	95.93 (91.84–98.01)	20 (12.51–30.41)	95.93 (91.84–98.01)	27.63 (18.84–38.58)	0.275	0.601
Pelvis	96.36 (91.02–98.58)	38.3 (25.79–52.57)	96.36 (91.02–98.58)	46.81 (33.33–60.77)	0.444	0.505
Extremities	94.44 (74.24–99.01)	85.29 (69.87–93.55)	94.44 (74.24–99.01)	72.09 (57.31–83.25)	4.455	0.035
Note. PET/CT, positron emission tomography/computed tomography; PSMA, prostate-specific membrane antigen; DWI, diffusion-weighted image; Se, sensitivity; Sp, specificity; CI, confidence interval; χ2, McNemar's test.

 

Table 5. Diagnostic accuracy parameters in group 2

Anatomic site	PET/CT with 18F-PSMA-1007		Whole-body DWI		χ2	p-value
	Se, % (95% CI)	Sp, % (95% CI)	Se, % (95% CI)	Sp, % (95% CI)
Таз	98.73 (93.17–99.78)	52.94 (42.43–63.19)	100 (95.36–100)	98.28 (90.86–99.69)	35.103	<0.001
Конечности	100 (82.41–100)	85.19 (75.87–91.32)	100 (82.41–100)	100 (95–100)	11.000	<0.001
Note. PET/CT, positron emission tomography/computed tomography; PSMA, prostate-specific membrane antigen; DWI, diffusion-weighted image; Se, sensitivity; Sp, specificity; CI, confidence interval; χ2, McNemar's test.

 

DISCUSSION

Summary of Primary Results

The main study outcome is a relatively low specificity of both PET/CT with ¹⁸F-PSMA-1007 and whole-body DWI in detecting bone metastases. Pelvic DWI obtained by multiparametric prostate MRI showed higher specificity. Whole-body DWI showed the highest specificity in detecting skull, scapula, and femur metastases.

Discussion of Primary Results

The findings indicate low specificity of PET/CT with ¹⁸F-PSMA-1007 and whole-body DWI in detecting bone metastases, which is confirmed by recent clinical studies, including multicenter studies. Grünig et al. [21] reported that PET/CT with ¹⁸F-PSMA-1007 detected hyperfixation foci in bones in 51.4% of patients, which are difficult to interpret due to their unclear origin. One of the first published works comparing the diagnostic accuracy of PET/CT with ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-11 found significant differences in false positive rates in the bones (48% vs. 14.7%). This is traditionally explained by the longer half-life of ¹⁸F compared to ⁶⁸Ga, which increases spatial resolution and improves signal-to-noise ratio [9]. Immunohistochemistry found PSMA not only in prostate tissues, but also in inflammation and neoangiogenesis foci [22]. Furthermore, PSMA-based radiopharmaceuticals can target benign bone lesions (see Fig. 1), such as red marrow hyperplasia, which is frequently detected in the ribs [23] and vertebral hemangiomas [24]. The interpretation of magnetic resonance images of vertebral hemangiomas is rarely challenging, and they are easily distinguished from prostate cancer metastases. However, atypical hemangiomas frequently require histological confirmation [25]. The exact mechanism of PSMA-based radiopharmaceutical fixation in benign bone lesions is unknown.

 

Fig. 1. Patient A., 56 years old, with mixed neuroendocrine prostate cancer T3aN1Mx, Gleason 8 (4 + 4). Condition after radical prostatectomy. Total serum prostate-specific antigen elevated to 1.87 ng/mL. Tumor recurrence near the vesicourethral anastomosis: а, axial positron emission tomography/computed tomography scan: a radiopharmaceutical hyperfixation focus in the left ilium, suspicious for metastasis; b and с, no focal lesions in the left ilium according to diffusion-weighted (b) and Т1-weighted images without fat suppression (с); d, a signal void corresponding to red marrow reconversion in the radiopharmaceutical hyperfixation focus according to the T1-weighted image, without abnormal bone marrow infiltration; e, a hyperfixation focus near the vesicourethral anastomosis according to positron emission tomography/computed tomography with ¹⁸F-prostate-specific membrane antigen-1007.

 

Restricted diffusion in benign lesions, such as red marrow reconversion zones, is a significant challenge for radiologists when interpreting bone DWI findings. T1-weighted Dixon MRI sequences with frequency-selective fat suppression can be used for differential diagnosis of these lesions [26, 27]. Furthermore, degenerative changes in the spine are frequently associated with signs of restricted diffusion (see Fig. 2). MRI sequences with frequency-selective fat suppression reliably detect metastases and Schmorl's nodes [28].

 

Fig. 2. Patient B., 77 years old, with prostate adenocarcinoma T4N2M0, Gleason 8 (4 + 4). Condition after comprehensive treatment, several lines of hormone therapy, chemotherapy, and radiotherapy of the prostate and regional lymph nodes. Total serum prostate-specific antigen elevated to 0.4 ng/mL. Example of a false-positive finding: а, axial positron emission tomography/computed tomography with ¹⁸F-prostate-specific membrane antigen-1007: a radiopharmaceutical hyperfixation focus in the right LV arch, suspicious for metastasis; b and с, ― diffusion-weighted (b) and Т2-weighted magnetic resonance images (с): signs of arthritis of the right LV-SI facet joint with joint effusion and moderate trabecular edema of adjacent articular surfaces.

 

Whole-body DWI is widely used in primary staging of cancers with high risk for bone metastases, including prostate cancer. According to Hottat et al. [29], the diagnostic accuracy in detecting bone metastases can reach 92%. Whole-body DWI is not inferior to PET/CT with ¹⁸F-choline and outperforms bone scintigraphy in detecting bone metastases in prostate cancer [30]. A meta-analysis by Liu et al. demonstrated comparable diagnostic accuracy of PET/CT with ⁶⁸Ga-PSMA and whole-body MRI [31]. Furthermore, international publications indicate that whole-body DWI alone can be used to detect bone metastases [32]. Sun et al. [33] conducted a study in patients with different cancers and reported comparable sensitivity, as well as positive and negative prognostic value, of whole-body DWI and PET/CT with ¹⁸F-fluorodeoxyglucose. The diffusion coefficient in benign bone lesions was significantly higher than in metastases. Combined rapid free-breathing MRI sequences without contrast are widely used for cancer staging in all body systems. A combination of T1WI, STIR, and DWI is typically used. Larbi et al. [34] compared different combinations of MRI sequences for detecting bone metastases in prostate cancer and found that the diagnostic value of T1WI + DWI was comparable to that of T1WI + STIR.

We found significant (p < 0.001) differences in diagnostic accuracy between whole-body PET/CT with ¹⁸F-PSMA-1007 and pelvic DWI, which could be attributed to the broader field of view in pelvic DWI (see Table 1). According to Park et al. [27], pelvic DWI allowed for the differentiation of pelvic bone metastases in prostate cancer from benign lesions, with significant differences.

Study Limitations

There is currently no non-invasive gold standard for the compared techniques, making it difficult to eliminate the effect of concordant findings on the results [21, 35, 36]. Notably, multiparametric MRI is not the preferred method for detecting bone metastases; therefore, the use of other MRI sequences as a reference test to assess the diagnostic accuracy of PET/CT with ¹⁸F-PSMA-1007 and DWI is a significant limitation of this study. Histological confirmation of all identified metastatic lesions is impossible for technical reasons. However, the approach used in this study is frequently applied in international research. For example, Freitag et al. [37] and Chen et al. [35] assessed the concordance between the findings.

This retrospective study only included patients with confirmed prostate cancer; therefore, the distribution of normal and abnormal findings in the sample did not match the actual distribution in this patient population. Whole-body DWI, which was used to clarify the nature of suspicious findings obtained by PET/CT with ¹⁸F-PSMA-1007, did not rule out the radiologist's bias in assessing the identified lesions.

CONCLUSION

Despite its well-known advantages, PET/CT with ¹⁸F-PSMA-1007 has high false positive rates in the bones, primarily the ribs, vertebrae, and pelvic bones. DWI cannot be used alone to clarify doubtful findings of PET/CT with ¹⁸F-PSMA-1007. Multiparametric whole-body MRI is recommended to prevent unreasonable overestimation of the disease stage.

ADDITIONAL INFORMATION

Author contributions: P.B. Gelezhe, R.V. Reshetnikov: conceptualization, formal analysis, writing—original draft, writing—review & editing; I.A. Blokhin, M.R. Kodenko: formal analysis, writing—original draft, writing—review & editing. All the authors approved the version of the manuscript to be published and agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval: The study was approved by the Independent Ethics Committee of State Budget-Funded Health Care Institution of the City of Moscow Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department (Meeting Minutes No. 10/2023 dated December 21, 2023).

Consent for publication: All patients signed a written informed consent form that included a clause on the possible publication of anonymized data, including diagnostic images, for scientific purposes.

Funding sources: This article is part of the research project Opportunistic Screening for Socially Significant and Other Common Diseases (Unified State Information Accounting System No. 123031400009-1), in accordance with Order No. 1196 dated December 21, 2022, On Approval of State Assignments Funded by the Budget of the City of Moscow for State Budgetary (Autonomous) Institutions Under the Jurisdiction of the Moscow City Health Department for 2023 and the Planned Period of 2024–2025, issued by the Moscow City Health Department.

Disclosure of interests: The authors have no relationships, activities, or interests for the last three years related to for-profit or not-for-profit third parties whose interests may be affected by the content of the article.

Statement of originality: No previously published material (text, images, or data) was used in this work.

Data availability statement: The editorial policy regarding data sharing does not apply to this work.

Generative AI: No generative artificial intelligence technologies were used to prepare this article.

Provenance and peer review: This paper was submitted unsolicited and reviewed following the standard procedure. The peer review process involved an external reviewer, two members of the editorial board, and the in-house science editor.

 

¹ PSMA-RADS-3 (Prostate-Specific Membrane Antigen Reporting and Data System 3): equivocal malignancy requiring further evaluation, according to the standardized system for interpretation of imaging findings obtained with radiopharmaceuticals.

² PSMA-RADS-4 (Prostate-Specific Membrane Antigen Reporting and Data System 4): high likelihood of malignancy, according to the standardized system for interpretation of imaging findings obtained with radiopharmaceuticals.

³ PSMA-RADS-5 (Prostate-Specific Membrane Antigen Reporting and Data System 5): very high likelihood of malignancy; high probability of clinically significant cancer, according to the standardized system for interpretation of imaging findings obtained with radiopharmaceuticals.

⁴ HASTE (Half-Fourier Acquisition Single-shot Turbo Spin Echo): a rapid sequence that enables acquisition of the entire image in a single radiofrequency pulse.

⁵ R 4.2.1 [Internet]. R: The R Project for Statistical Computing; 2022. Available at: https://www.r-project.org/. Accessed on: April 10, 2024.

About the authors

Pavel B. Gelezhe

Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies; European Medical Center

Author for correspondence.
Email: gelezhe.pavel@gmail.com
ORCID iD: 0000-0003-1072-2202
SPIN-code: 4841-3234

MD, Cand. Sci. (Medicine)

Russian Federation, Moscow; Moscow

Roman V. Reshetnikov

Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies

Email: ReshetnikovRV1@zdrav.mos.ru
ORCID iD: 0000-0002-9661-0254
SPIN-code: 8592-0558

Cand. Sci. (Physics and Mathematics)

Russian Federation, Moscow

Ivan A. Blokhin

Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies

Email: BlokhinIA@zdrav.mos.ru
ORCID iD: 0000-0002-2681-9378
SPIN-code: 3306-1387
Russian Federation, Moscow

Maria R. Kodenko

Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies

Email: KodenkoM@zdrav.mos.ru
ORCID iD: 0000-0002-0166-3768
SPIN-code: 5789-0319

Cand. Sci. (Engineering)

Russian Federation, Moscow

References

Supplementary files