Error mitigation enables PET radiomic cancer characterization on quantum computers.

BACKGROUND: Cancer is a leading cause of death worldwide. While routine diagnosis of cancer is performed mainly with biopsy sampling, it is suboptimal to accurately characterize tumor heterogeneity. Positron emission tomography (PET)-driven radiomic research has demonstrated promising results when predicting clinical endpoints. This study aimed to investigate the added value of quantum machine learning both in simulator and in real quantum computers utilizing error mitigation techniques to predict clinical endpoints in various PET cancer patients. METHODS: Previously published PET radiomics datasets including 11C-MET PET glioma, 68GA-PSMA-11 PET prostate and lung 18F-FDG PET with 3-year survival, low-vs-high Gleason risk and 2-year survival as clinical endpoints respectively were utilized in this study. Redundancy reduction with 0.7, 0.8, and 0.9 Spearman rank thresholds (SRT), followed by selecting 8 and 16 features from all cohorts, was performed, resulting in 18 dataset variants. Quantum advantage was estimated by Geometric Difference (GDQ) score in each dataset variant. Five classic machine learning (CML) and their quantum versions (QML) were trained and tested in simulator environments across the dataset variants. Quantum circuit optimization and error mitigation were performed, followed by training and testing selected QML methods on the 21-qubit IonQ Aria quantum computer. Predictive performances were estimated by test balanced accuracy (BACC) values. RESULTS: On average, QML outperformed CML in simulator environments with 16-features (BACC 70% and 69%, respectively), while with 8-features, CML outperformed QML with + 1%. The highest average QML advantage was + 4%. The GDQ scores were ≤ 1.0 in all the 8-feature cases, while they were > 1.0 when QML outperformed CML in 9 out of 11 cases. The test BACC of selected QML methods and datasets in the IonQ device without error mitigation (EM) were 69.94% BACC, while EM increased test BACC to 75.66% (76.77% in noiseless simulators). CONCLUSIONS: We demonstrated that with error mitigation, quantum advantage can be achieved in real existing quantum computers when predicting clinical endpoints in clinically relevant PET cancer cohorts. Quantum advantage can already be achieved in simulator environments in these cohorts when relying on QML.

Ultra-Widefield OCT Angiography.

Optical Coherence Tomography Angiography (OCTA), a functional extension of OCT, has the potential to replace most invasive fluorescein angiography (FA) exams in ophthalmology. So far, OCTA's field of view is however still lacking behind fluorescence fundus photography techniques. This is problematic, because many retinal diseases manifest at an early stage by changes of the peripheral retinal capillary network. It is therefore desirable to expand OCTA's field of view to match that of ultra-widefield fundus cameras. We present a custom developed clinical high-speed swept-source OCT (SS-OCT) system operating at an acquisition rate 8-16 times faster than today's state-of-the-art commercially available OCTA devices. Its speed allows us to capture ultra-wide fields of view of up to 90 degrees with an unprecedented sampling density and hence extraordinary resolution by merging two single shot scans with 60 degrees in diameter. To further enhance the visual appearance of the angiograms, we developed for the first time a three-dimensional deep learning based algorithm for denoising volumetric OCTA data sets. We showcase its imaging performance and clinical usability by presenting images of patients suffering from diabetic retinopathy.

Clinical data classification with noisy intermediate scale quantum computers.

Quantum machine learning has experienced significant progress in both software and hardware development in the recent years and has emerged as an applicable area of near-term quantum computers. In this work, we investigate the feasibility of utilizing quantum machine learning (QML) on real clinical datasets. We propose two QML algorithms for data classification on IBM quantum hardware: a quantum distance classifier (qDS) and a simplified quantum-kernel support vector machine (sqKSVM). We utilize these different methods using the linear time quantum data encoding technique ([Formula: see text]) for embedding classical data into quantum states and estimating the inner product on the 15-qubit IBMQ Melbourne quantum computer. We match the predictive performance of our QML approaches with prior QML methods and with their classical counterpart algorithms for three open-access clinical datasets. Our results imply that the qDS in small sample and feature count datasets outperforms kernel-based methods. In contrast, quantum kernel approaches outperform qDS in high sample and feature count datasets. We demonstrate that the [Formula: see text] encoding increases predictive performance with up to + 2% area under the receiver operator characteristics curve across all quantum machine learning approaches, thus, making it ideal for machine learning tasks executed in Noisy Intermediate Scale Quantum computers.

Akinetic all-semiconductor programmable swept-source at 1550 nm and 1310 nm with centimeters coherence length.

We demonstrate, for the first time, OCT imaging capabilities of a novel, akinetic (without any form of movement in the tuning mechanism), all-semiconductor, all-electronic tunable, compact and flexible swept source laser technology at 1550 nm and 1310 nm. To investigate its OCT performance, 2D and 3D ex vivo and in vivo OCT imaging was performed at different sweep rates, from 20 kHz up to 200 kHz, with different axial resolutions, about 10 µm to 20 µm, and at different coherence gate displacements, from zero delay to >17 cm. Laser source phase linearity and phase repeatability standard deviation of <2 mrad (<160 pm) were observed without external phase referencing, indicating that the laser operated close to the shot noise limit (~2 × factor); constant percentile wavelengths variations of sliding RIN and ortho RIN <0.2% could be demonstrated, ~5 times better as compared to other swept laser technologies.

Simultaneous dual wavelength eye-tracked ultrahigh resolution retinal and choroidal optical coherence tomography.

We demonstrate an optical coherence tomography device that simultaneously combines different novel ultrabroad bandwidth light sources centered in the 800 and 1060 nm regions, operating at 66 kHz depth scan rate, and a confocal laser scanning ophthalmoscope-based eye tracker to permit motion-artifact-free, ultrahigh resolution and high contrast retinal and choroidal imaging. The two wavelengths of the device provide the complementary information needed for diagnosis of subtle retinal changes, while also increasing visibility of deeper-lying layers to image pathologies that include opaque media in the anterior eye segment or eyes with increased choroidal thickness.

Miniature spectrometer and beam splitter for an optical coherence tomography on a silicon chip.

Optical coherence tomography (OCT) has enabled clinical applications that revolutionized in vivo medical diagnostics. Nevertheless, its current limitations owing to cost, size, complexity, and the need for accurate alignment must be overcome by radically novel approaches. Exploiting integrated optics, we assemble the central components of a spectral-domain OCT system on a silicon chip. The spectrometer comprises an arrayed-waveguide grating with 136-nm free spectral range and 0.21-nm wavelength resolution. The beam splitter is realized by a non-uniform adiabatic coupler with its 3-dB splitting ratio being nearly constant over 150 nm. With this device whose overall volume is 0.36 cm(3) we demonstrate high-quality in vivo imaging in human skin with 1.4-mm penetration depth, 7.5-µm axial resolution, and a signal-to-noise ratio of 74 dB. Considering the reasonable performance of this early OCT on-a-chip system and the anticipated improvements in this technology, a completely different range of devices and new fields of applications may become feasible.

Spectroscopic measurements with dispersion encoded full range frequency domain optical coherence tomography in single- and multilayered non-scattering phantoms.

In this study, depth resolved measurements of absorption profiles in the wavelength range of 800 nm with a bandwidth of 140 nm are demonstrated using high speed spectroscopic frequency domain OCT(SOCT) and a full range reconstruction algorithm (dispersion encoded full range, DEFR). The feasibility of the algorithm for SOCT is tested in simulation and experiment. With proper calibration, SOCT with DEFR is able to extract absolute, depth resolved absorption profiles over the whole wavelength range at once without the need of tuning and performing measurements at single wavelengths sequentially. The superior acquisition speed and better phase stability in frequency domain as compared to time domain results in a better reproducibility and practicability for spectroscopic measurements. In addition, high acquisition speed in excess of 20 kHz allows to measure absorption dynamics with 50 micros time resolution, which might be useful for the investigation of pharmacokinetics or pharmacodynamics. SOCT of approximately 600 microm thick single- and multilayered, weakly scattering phantoms with varying absorption in the range of 5-80 cm(-1), equivalent to blood absorption in capillaries, is presented. SOCT measurements are compared with those using a spectrometer in transmission mode. For Indocyanine Green (ICG), a dynamic absorption measurements are demonstrated.

Patients with active rheumatoid arthritis but only few tender and swollen joints: a subgroup with impaired short term outcome.

The disease activity score of 28 joints (DAS28) is now commonly used for the guidance of treatment decisions in rheumatoid arthritis (RA). The goal of this work was to determine whether patients with DAS28 > 3.2 but less than 2 swollen and 2 tender joints respond differently to treatment than patients with a higher number of active joints. One hundred and ninety two patients with active RA treated in a rheumatology hospital as in-patients were studied prospectively. At admission (T1), release (T2) and 3 months after release (T3) disease activity (DAS28-CRP at T1 + 2, RADAI at T1 + 3), pain (numeric scale at T1 - 3) and function (FFbH at T1 + 3) were measured. A total of 148 patients had two or more (group 1) and 44 less than 2 swollen and tender joints at admission (group 2) but both groups had similar over all DAS28-scores. The groups significantly differed in their outcome after 3 months: group 1 had a significant better reduction of disease activity, pain and functional deficit (p < 0.001 for the fulfilment of defined response criteria and p < 0.05 for comparison of the mean values for pain and function) in comparison to group 2. Although the numbers were small sub-analysis suggested that the differences might be due to a better response to newly administered DMARD and TNF-alpha-inhibitor therapy in group 1. Active RA patients with less than 2 swollen and 2 tender joints represent a subgroup with lower response to treatment with DMARD or TNF-alpha-inhibitors. This has to be taken into account in the management of these patients.

Effects of change in intraocular pressure on axial eye length and lens position.

PURPOSE: To quantify the biometric changes of ocular dimensions with mechanical elevation of intraocular pressure (IOP) in vivo, to get a better understanding of the elastic properties of the human ocular structures that may play a role in the pathogenesis of various diseases such as myopia or glaucoma. METHODS: Changes in IOP were induced by a suction cup in 18 eyes under cycloplegia. Axial eye length (AEL) and anterior chamber depth (ACD) were measured with non-invasive laser interferometry during elevation of the IOP 10 and 20 mmHg over baseline values and after a 10-min resting period. RESULTS: IOP elevation of 10 and 20 mmHg respectively caused a significant increase of AEL of 23 mum (95% confidence interval: 14-34 microm) and 39 microm (confidence interval (CI): 28-51 microm). After mechanical oculopression, which resulted in an IOP reduction of -5.1 mmHg (CI: -6.3 to -4.0 mmHg) vsbaseline, a significant shortening of -7 microm (CI: -13 to 0 microm) was observed. The change in AEL correlated with the change in IOP (r=0.66, P=0.005). Furthermore, a significant increase in ACD of 30 microm (CI: 24-36 microm) was detected with IOP reduction after oculopression, but no change was seen during IOP elevation. CONCLUSIONS: Biometric changes of the human eye as a response to IOP changes were assessed in vivo. The correlation between change in AEL and IOP found emphasizes the need of in vivoocular rigidity measurements in the human eye.

Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography.

Noncontact, depth-resolved, optical probing of retinal response to visual stimulation with a <10-microm spatial resolution, achieved by using functional ultrahigh-resolution optical coherence tomography (fUHROCT), is demonstrated in isolated rabbit retinas. The method takes advantage of the fact that physiological changes in dark-adapted retinas caused by light stimulation can result in local variation of the tissue reflectivity. fUHROCT scans were acquired from isolated retinas synchronously with electrical recordings before, during, and after light stimulation. Pronounced stimulus-related changes in the retinal reflectivity profile were observed in the inner/outer segments of the photoreceptor layer and the plexiform layers. Control experiments (e.g., dark adaptation vs. light stimulation), pharmacological inhibition of photoreceptor function, and synaptic transmission to the inner retina confirmed that the origin of the observed optical changes is the altered physiological state of the retina evoked by the light stimulus. We have demonstrated that fUHROCT allows for simultaneous, noninvasive probing of both retinal morphology and function, which could significantly improve the early diagnosis of various ophthalmic pathologies and could lead to better understanding of pathogenesis.

Stimulus-driven versus pilocarpine-induced biometric changes in pseudophakic eyes.

PURPOSE: Most trials that study the lens movement of accommodative intraocular lens (IOLs) use pilocarpine to stimulate ciliary muscle contraction. The aim of this study is to assess in vivo whether a more physiologic, stimulus-driven accommodation is comparable to pilocarpine-induced IOL movement. DESIGN: Controlled patient- and examiner-masked clinical trial. PARTICIPANTS: The study population included 38 eyes with accommodative IOL implants (1CU) and a control group of 28 eyes with conventional open-loop IOLs. METHODS: A high-precision biometry technique, partial coherence interferometry, was used to measure IOL position. Anterior chamber depth was measured during physiologic (near point) and pharmacological (pilocarpine 2%) stimulation. In a subgroup of 14 1CU eyes, IOL position was determined repeatedly within 90 minutes after pilocarpine administration. A different subgroup was investigated as to the effect of cyclopentolate on IOL position. Best-corrected distance visual acuity (VA), best-corrected near VA, and distance-corrected near VA (DCNVA) were assessed using logarithm of the minimum angle of resolution charts. MAIN OUTCOME MEASURES: Anterior chamber depth change under pilocarpine and near-point-driven accommodation. RESULTS: Near-point accommodation did not induce movement of either the accommodating 1CU or the control IOLs. Pilocarpine induced a 201+/-0.137-mm anterior movement of the 1CU IOL (P<0.001), compared with no movement within the control IOL groups (P>0.05). There was no significant (P>0.05) difference in DCNVA between the accommodative and open-loop IOLs. No correlation between near point- or pilocarpine-stimulated IOL movement and DCNVA was found. Concerning the time course of movement after pilocarpine administration, most of the 1CU IOLs showed some movement 30 minutes after application. Cyclopentolate-induced ciliary muscle relaxation caused a posterior IOL movement, as compared with the relaxed state, when focusing on a distant target. CONCLUSION: Pilocarpine-induced ciliary muscle contraction seems to overestimate IOL movement relative to a monocular near-driven stimulus. Therefore, concerning IOL movement, pilocarpine may act as a superstimulus and may not adequately simulate daily life performance of accommodative IOLs. However, it may be helpful to evaluate the maximum potential of an accommodating IOL.

In vivo retinal optical coherence tomography at 1040 nm - enhanced penetration into the choroid.

For the first time in vivo retinal imaging has been performed with a new compact, low noise Yb-based ASE source operating in the 1 microm range (NP Photonics, lambdac = 1040 nm, Deltalambda = 50 nm, Pout = 30 mW) at the dispersion minimum of water with ~7 microm axial resolution. OCT tomograms acquired at 800 nm are compared to those achieved at 1040 nm showing about 200 microm deeper penetration into the choroid below the retinal pigment epithelium. Retinal OCT at longer wavelengths significantly improves the visualization of the retinal pigment epithelium/choriocapillaris/choroids interface and superficial choroidal layers as well as reduces the scattering through turbid media and therefore might provide a better diagnosis tool for early stages of retinal pathologies such as age related macular degeneration which is accompanied by choroidal neovascularization, i.e., extensive growth of new blood vessels in the choroid and retina.

Adaptive-optics ultrahigh-resolution optical coherence tomography.

Merging of ultrahigh-resolution optical coherence tomography (UHR OCT) and adaptive optics (AO), resulting in high axial (3 microm) and improved transverse resolution (5-10 microm) is demonstrated for the first time to our knowledge in in vivo retinal imaging. A compact (300 mm x 300 mm) closed-loop AO system, based on a real-time Hartmann-Shack wave-front sensor operating at 30 Hz and a 37-actuator membrane deformable mirror, is interfaced to an UHR OCT system, based on a commercial OCT instrument, employing a compact Ti:sapphire laser with 130-nm bandwidth. Closed-loop correction of both ocular and system aberrations results in a residual uncorrected wave-front rms of 0.1 microm for a 3.68-mm pupil diameter. When this level of correction is achieved, OCT images are obtained under a static mirror configuration. By use of AO, an improvement of the transverse resolution of two to three times, compared with UHR OCT systems used so far, is obtained. A significant signal-to-noise ratio improvement of up to 9 dB in corrected compared with uncorrected OCT tomograms is also achieved.

[Methodological advancements. Ultrahigh-resolution OCT]. / Methodische Weiterentwicklungen. Hochauflösende OCT.

Development of ultrabroad bandwidth light sources has recently enabled significant improvement of ophthalmic axial OCT imaging resolution, demonstrating the potential of ultrahigh resolution OCT (UHR OCT) to perform noninvasive optical biopsy, i.e., the in vivo visualization of microstructural morphology in situ, which had previously only been possible with histopathology. Therefore, UHR OCT allows detection of intraretinal changes that can be used for diagnosis of retinal disease in its early stages when treatment is most effective and irreversible damage can be prevented or delayed. Furthermore, it may provide a better understanding of the pathogenesis of several macular pathologies as well as contribute to the development of new therapy approaches. Future developments of ophthalmic OCT include high speed, three-dimensional retinal imaging, combining adaptive optics and UHR OCT, spatially resolved spectroscopic OCT, functional imaging, and OCT imaging with enhanced penetration into the choroid by employing novel wavelength regions.

Advances in broad bandwidth light sources for ultrahigh resolution optical coherence tomography.

Novel ultra-broad bandwidth light sources enabling unprecedented sub-2 microm axial resolution over the 400 nm-1700 nm wavelength range have been developed and evaluated with respect to their feasibility for clinical ultrahigh resolution optical coherence tomography (UHR OCT) applications. The state-of-the-art light sources described here include a compact Kerr lens mode locked Ti:sapphire laser (lambdaC = 785 nm, delta lambda = 260 nm, P(out) = 50 mW) and different nonlinear fibre-based light sources with spectral bandwidths (at full width at half maximum) up to 350 nm at lambdaC = 1130 nm and 470 nm at lambdaC = 1375 nm. In vitro UHR OCT imaging is demonstrated at multiple wavelengths in human cancer cells, animal ganglion cells as well as in neuropathologic and ophthalmic biopsies in order to compare and optimize UHR OCT image contrast, resolution and penetration depth.

Precision of extracting absorption profiles from weakly scattering media with spectroscopic time-domain optical coherence tomography.

The feasibility of spectroscopic optical coherence tomography (SOCT) to quantify spatially localized absorption profiles of chromophores embedded in weakly scattering media with a single measurement over the full spectral bandwidth of the light source was investigated by using a state-of-the-art ultra-broad bandwidth Ti:Al(2)O(3) laser (lambdac = 800 nm, Deltalambda = 260 nm, P(out) = 120 mW ex-fiber). The precision of the method as a function of the chromophore absorption, the sample thickness, and different parameters related to the measurement procedure was evaluated both theoretically and experimentally in single and multilayered phantoms. It is demonstrated that in weakly scattering media SOCT is able to extract mua(lambda) as small as 0.5 mm-1 from 450 mum thick phantoms with a precision of ~2% in the central and ~8% at the edges of the used wavelength region. As expected, in phantoms with the same absorption properties and thickness ~180 mum the precision of SOCT decreases to >10% in the central wavelength region.

Ultrahigh resolution Fourier domain optical coherence tomography.

We present, for the first time, in vivo ultrahigh resolution (~2.5 microm in tissue), high speed (10000 A-scans/second equivalent acquisition rate sustained over 160 A-scans) retinal imaging obtained with Fourier domain (FD) OCT employing a commercially available, compact (500x260mm), broad bandwidth (120 nm at full-width-at-half-maximum centered at 800 nm) Titanium:sapphire laser (Femtosource Integral OCT, Femtolasers Produktions GmbH). Resolution and sampling requirements, dispersion compensation as well as dynamic range for ultrahigh resolution FD OCT are carefully analyzed. In vivo OCT sensitivity performance achieved by ultrahigh resolution FD OCT was similar to that of ultrahigh resolution time domain OCT, although employing only 2-3 times less optical power (~300 microW). Visualization of intra-retinal layers, especially the inner and outer segment of the photoreceptor layer, obtained by FDOCT was comparable to that, accomplished by ultrahigh resolution time domain OCT, despite an at least 40 times higher data acquisition speed of FD OCT.

Compact, low-cost Ti:Al2O3 laser for in vivo ultrahigh-resolution optical coherence tomography.

A compact, low-cost, prismless Ti:Al2O3 laser with 176-nm bandwidth (FWHM) and 20-mW output power was developed. Ultrahigh-resolution ophthalmic optical coherence tomography (OCT) ex vivo imaging in an animal model with approximately 1.2-microm axial resolution and in vivo imaging in patients with macular pathologies with approximately 3-microm axial resolution were demonstrated. Owing to the pump laser, this light source significantly reduces the cost of broadband OCT systems. Furthermore, the source has great potential for clinical application of spectroscopic and ultrahigh-resolution OCT because of its small footprint (500 mm x 180 mm including the pump laser), user friendliness, stability, and reproducibility.

Compact, broad-bandwidth fiber laser for sub-2-microm axial resolution optical coherence tomography in the 1300-nm wavelength region.

A novel, compact, user friendly fiber laser with a broad emission bandwidth (MenloSystems, lambdac = 1375 nm, deltalambda = 470 nm, Pout = 4 mW) was used to achieve unprecedented sub-2-microm axial resolution optical coherence tomography (OCT) in nontransparent biological tissue in the 1300-nm wavelength region. Fresh human skin and arterial biopsies were imaged ex vivo with approximately 1.4-microm axial and approximately 3-microm lateral resolution and 95-dB sensitivity, demonstrating the great potential for clinical OCT applications of this stable, low-cost, and turn-on-key fiber laser.

Enhanced visualization of choroidal vessels using ultrahigh resolution ophthalmic OCT at 1050 nm.

In this article the ability of ultrahigh resolution ophthalmic optical coherence tomography (OCT) to image small choroidal blood vessels below the highly reflective and absorbing retinal pigment epithelium is demonstrated for the first time. A new light source (lambdac= 1050 nm, Deltalambda = 165 nm, Pout= 10 mW), based on a photonic crystal fiber pumped by a compact, self-starting Ti:Al2O3 laser has therefore been developed. Ex-vivo ultrahigh resolution OCT images of freshly excised pig retinas acquired with this light source demonstrate enhanced penetration into the choroid and better visualization of choroidal vessels as compared to tomograms acquired with a state-of-the art Ti:Al2O3 laser (Femtolasers Compact Pro, lc= 780 nm, Deltalambda= 160 nm, Pout= 400 mW), normally used in clinical studies for in vivo ultrahigh resolution ophthalmic OCT imaging. These results were also compared with retinal tomograms acquired with a novel, spectrally broadened fiber laser (MenloSystems, lambdac= 1350 nm, Deltalambda= 470 nm, Pout = 4 mW) permitting even greater penetration in the choroid. Due to high water absorption at longer wavelengths retinal OCT imaging at ~1300 nm may find applications in animal ophthalmic studies. Detection and follow-up of choroidal neovascularization improves early diagnosis of many retinal pathologies, e.g. age-related macular degeneration or diabetic retinopathy and can aid development of novel therapy approaches.