Random Aberrations Research Articles

Multi-image blending holographic encryption system based on multi-source coherent diffraction and frequency-domain attention learning

The multi-image encryption method has the advantage of large information encryption capacity, which is conducive to the development of high-throughput cryptosystems. However, for multi-image encryption, the low PSNR caused by the crosstalk between images restricts the development of multi-image encryption methods. In our method, a novel optical multi-image encryption method based on multi-image coherent diffraction and frequency-domain attention learning is proposed. For encrypting, random aberrations brought about by diffraction are used instead of random phase masks to encrypt multiple source images into a single holographic ciphertext image based on holography and coherent diffraction imaging. A specially designed deep learning decryption network based on physical prior is proposed, which is used to resolve the source images of each channel respectively. Highlights and advantages include lower computational cost algorithm, higher real-time performance and better decryption quality. The feasibility, noise immunity, security and robustness of the proposed method are investigated through simulations and experiments. It is believed that the method we propose here can promote the further development of multi-optical image encryption systems.

Sixty-Nine-Element Voice Coil Deformable Mirror for Visible Light Communication

To overcome the atmospheric turbulence aberration, and improve the quality of light beam in visible light communication (VLC), a compact 69-element deformable mirror (DM) using micro voice coil actuators was designed based on systematic theoretical analysis. The structural parameters of the micro voice coil actuator were optimized by electromagnetic theory and the finite element method. The DM was optimized from the aspects of thermal deformation, response time, coupling coefficient, and other parameters. Finally, wavefront fitting and residual calculation were completed according to the influence function. The optimized voice coil deformable mirror (VCDM) has a large phase stroke, good thermal stability, a short response time of less than 0.7 ms, and a large first resonance of 2045 Hz. The fitting residuals of the VCDM for the first 10 Zernike modes with a PV value of 8 μm are all below 10 nm (RMS). Compared with a similar DM, the obtained results from our compact VCDM indicate that it has a higher wavefront fitting precision. VCDM corrected complex random aberrations in the VLC scenario and improved the coupling efficiency of the signal beam, proving that the compact VCDM with high performance and low cost has a good application prospect in VLC systems.

Simulation analysis and comparison of the effects of aberrations on multiphoton fluorescent light sheets

Multi-photon scanning light-sheet microscope, which combines the advantages of light-sheet illumination and multi-photon excitation, has high axial resolution, low photobleaching, and a large field of view. However, as the light sheet goes deeper into the biological tissue, biological optical aberrations caused by the uneven refractive index inside the organism become non-negligible factors that dramatically increase the thickness and decrease the light intensity of the light sheet. This paper theoretically deduces and simulates the influence of aberrations on the intensity and thickness of the two-, three-, and four-photon fluorescent light sheet. A clear general trend is obvious. With the increasing amplitude of aberration, the effect of aberration on the light sheet thickness and intensity increases in each multiphoton light sheet. In terms of thickness, the impact of high-order aberrations diminishes from the two-photon to the four-photon light sheet. However, in terms of intensity, the impact of high-order aberrations increases from the two-photon to the four-photon light sheet. The number of items to be corrected for each multiphoton light sheet is given and compared under random aberrations with different amplitudes. The results provide important guidance for the design and evaluation of adaptive optics in multi-photon light sheet microscopes.

Interferometric imaging of reflective micro-objects in the presence of strong aberrations.

Some imaging techniques reduce the effect of optical aberrations either by detecting and actively compensating for them or by utilizing interferometry. A microscope based on a Mach-Zehnder interferometer has been recently introduced to allow obtaining sharp images of light-transmitting objects in the presence of strong aberrations. However, the method is not capable of imaging microstructures on opaque substrates. In this work, we use a Michelson interferometer to demonstrate imaging of reflecting and back-scattering objects on any substrate with micrometer-scale resolution. The system is remarkably insensitive to both deterministic and random aberrations that can completely destroy the object's intensity image.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adolescents with GATA2-Related Myelodysplastic Syndrome

Background GATA2 deficiency is an inherited immunodeficiency and predisposition syndrome with a high risk of developing myelodysplastic syndrome (MDS) early in life. Allogeneic hematopoietic stem cell transplantation (HSCT) is presently the only curative therapy for affected patients (pts), but to date there has been no larger study examining in detail outcomes after HSCT for GATA2-related pediatric MDS. Here we report the results of an analysis of pts with a germline GATA2 mutation undergoing HSCT for a diagnosis of MDS enrolled in the registry of the European Working Group of MDS in Childhood (EWOG-MDS). Patients and transplantation procedure Of the 87 pts with GATA2 deficiency registered before the age of 18 years, 66 underwent HSCT between 01/1997 and 11/2018. One pt had to be excluded from the analysis due to lack of data. The 65 remaining pts (34 males/31 females) were transplanted at a median age of 13.5 (4.6-19.9) years. Twenty-seven pts were transplanted for refractory cytopenia of childhood (RCC), while 38 pts had advanced disease. The highest bone marrow (BM) blast percentage prior to HSCT was 5-19% (n=23), 20-29% (n= 9) or >30% blasts (n=5); in one pt with myelofibrotic MDS a blast count was not attainable. Karyotypes included monosomy 7 (n=44), der (1;7) (n=4), trisomy 8 (n=4), random aberration (n=1) or a normal karyotype (n=12). Five of the 38 pts with an increased blast percentage had received intensive AML-type therapy prior to HSCT. Pts were grafted from a matched sibling donor (MSD; n=17), unrelated donor (UD; n=40) or a mismatched family donor (MMFD; n=8). The stem cell source was BM (n=37), peripheral blood (n=27) or cord blood (n=1). Pts were prepared with a busulfan-based (n=35), treosulfan-based (n=21), total body irradiation-based (n=5) or an alternative conditioning regimen (n=4). Results At 5 years the probability of overall survival (pOS) and disease-free survival (DFS) was 0.74 [0.62-0.86] and 0.69 [0.57-0.81], respectively, non-relapse mortality was 0.15 [0.08-0.27] and the cumulative incidence of relapse was 0.16 [0.09-0.29]. All pts engrafted initially. The cumulative incidence of acute graft versus host disease (GVHD) grade II-IV and III-IV was 0.34 [0.24-0.48] and 0.12 [0.06-0.24], respectively, and of overall and extensive chronic GVHD 0.25 [0.16-0.39] and 0.08 [0.03-0.20]. The most common post-transplant infections were viral (39 of the 43 pts with infections) with one pt each with EBV-related post-transplant lymphoproliferative disease and primary CMV disease. There were no mycobacterial infections. The most common non-infectious complications were hepatobiliary (13 pts, including 3 with veno-occlusive disease) and pulmonary (10 pts, 5 of whom had been prepared with a busulfan-based conditioning regimen). Pts with >20% BM blasts showed a trend towards a poorer DFS (0.52 [0.24-0.80]) compared to pts with 5-19% blasts (0.72 [0.53-0.91]) or pts with RCC (0.80 [0.64-0.96]; p=0.15). Examining the influence of karyotype in pts with RCC, there were a total of 2 relapses and 3 deaths (1 after relapse) among the 12 pts with monosomy 7, while there was one event among the 15 RCC pts with a normal karyotype (n=10, 1 death), trisomy 8 (n=3), der (1;7) (n=1) or random aberration (n=1). Limiting the analysis to 9/10 or 10/10 HLA matched-donors, DFS was comparable for pts transplanted from an UD (0.73 [0.55-0.91]) versus a MSD (0.82 [0.64-1.00]). Of the 8 pts transplanted from a MMFD, one patient died after secondary graft failure. No major difference in outcome was seen according to age at HSCT, gender, time from diagnosis to HSCT or stem cell source. Of the five pts who had received AML-type therapy prior to HSCT, three died of a transplant-related cause or relapse. Conclusions and perspectives In summary, HSCT resulted in a pOS of 0.74 in this cohort of children and adolescents with GATA2 deficiency and MDS. Pts with increased blasts had a tendency towards poorer outcomes. The high risk of developing advanced MDS and the better outcome in early stages of the disease indicates that HSCT should be performed early in the clinical course of children diagnosed with GATA2 deficiency and MDS. Of note, there was no indication of excessive toxicity, disease-associated comorbidities or an increased risk of GVHD. The HSCT outcomes of children and adolescents with MDS and GATA2 deficiency are similar to what has been previously published for pts transplanted for MDS in the absence of GATA2 germline disease. Disclosures Bader: Amgen (Brasil), Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy; Medac: Patents & Royalties, Research Funding; Riemser, Neovii: Research Funding. Locatelli:Miltenyi: Honoraria; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Niemeyer:Celgene: Consultancy.

Analysis of aberrations and performance evaluation of adaptive optics in two-photon light-sheet microscopy

Abstract Two-photon light-sheet microscopy (TP-LSM) system performance is greatly degraded by specimen-induced aberrations in illumination path, which limit the field of view, axial resolution and excitation efficiency of the system. Adaptive optics (AO) is an effective method for attenuating these effects. For the design and evaluation of an AO system, a comprehensive analysis of the effects of aberrations is needed. In this paper, a TP-LSM system is simulated, and new indexes based on integral intensity are introduced for the evaluation of an aberrated light-sheet. Then, the influences of each Zernike mode and random aberrations on the illumination path of the TP-LSM system are investigated with a numerical simulation method. Results show that high-order aberrations have little effect on the axial resolution and excitation efficiency of the system and only low-order components require correction. The random aberrations varied in strength with the depth of the specimens, so the number of corrected Zernike modes is variable. A general formula is generated for the estimation of the number of modes that should be detected and corrected under different aberrations and different numerical aperture of the objective. The results can provide important guidance in the design and evaluation of AO units for TP-LSM systems.

Modal Diversity for Robust Free-Space Optical Communications

Modal diversity is an important advance in free-space optics, where propagation distances are limited by effects such as atmospheric turbulence. This experimental demonstration shows that orthogonal, coaxially propagating spatial modes of light from different bases are able to mitigate the effects of atmospheric turbulence. The different modes experience different perturbations, even when traveling along the same path, which removes the conventional need for physical separation of the transmitters, while also showing a significant improvement in bit-error rate. This approach could be applicable to a wide range of physical systems that are adversely affected by random aberrations.

A new performance metric on sensorless adaptive optics imaging system

Sensorless adaptive optics (AO) imaging systems have been widely studied in recent years. To reach optimum results, such systems require an efficient performance metric. In this paper, a new performance metric applied to sensorless AO system based on stochastic parallel gradient descent (SPGD) algorithm is presented. This new metric has better performance of stability and correction ability compared with other three performance metrics (i.e. Strehl Ratio, Power-In-Bucket and Image Sharpness), and similar with mean radius (MR) metric but easier to measure by a photo-detector using a mask which can be simply-manufactured. Numerical simulations of AO corrections of various random aberrations are performed. The results show the superiority of the new metric.

Four-phase closure algorithm for coherent field imaging

According to the realization principle of phase closure in coherent field imaging, a new four-phase closure (FPC) algorithm is proposed for T-array multi-beam transmitter system. A type of four-item measurement radio of closure phase is first defined, and then the validity of FPC is confirmed in cancelling out the random atmospheric phase aberrations as well as eliminating atmospheric scintillation effect on degradation of the reconstructed image. Simulations prove the effectiveness of FPC, providing a new approach in removing atmospheric aberrations for multi-beam coherence field imaging.

Phase retrieval and Zernike decomposition using measured intensity data and the estimated electric field

A new direct search phase retrieval technique for determining the optical prescription of an imaging system in terms of Zernike coefficients is described. The technique provides coefficient estimates without the need to defocus point source images to generate phase diversity by using electric field (E-field) estimates in addition to intensity data. Numerical analysis shows that E-field patterns in the image plane produced by the Zernike polynomials are less correlated with each other than the intensity patterns. Therefore, the E-field pattern provides more information for Zernike coefficient estimation than the intensity pattern alone. The phase retrieval is accomplished through an iterative process that uses the measured point source data to estimate the E-field pattern in the image plane with the Gerchberg-Saxton (GS) algorithm. The estimated E-field is correlated with a modeled E-field to produce estimates of the Zernike coefficients. Then the coefficients that minimize the error between measured data and the intensity model are selected. By using E-field estimates rather than phase estimates from the GS algorithm, the limitations of phase unwrapping for Zernike decomposition are avoided. Simulated point source data shows the new phase retrieval algorithm avoids getting trapped in local minima over a wide range of random aberrations. Experimental point source data are used to demonstrate the phase retrieval effectiveness.

Comparative analysis for measurement precision of phase retrieval wavefront sensor

In order to analyze the performance of phase retrieval wavefront sensor (PRWS), an experimental based on the PRWS method has been built. In this paper, we utilize liquid crystal space light modulator (LC-SLM) to produce single aberration and random aberration, and validate the ability of PRWS measurement for any aberrations. Mathematic model of phase retrieval measurement is constructed based on the diffraction theory, and solved using gradient based optimization algorithm. Experimental results demonstrate that good agreement is obtained among the errors distribution, PV value and RMS value of ZYGO interferometer. The measurement precision of wavefront is 3/1000 wavelength RMS. Therefore, the feasibility and accuracy of the proposed method can be confirmed.

Algorithm for Ronchigram recovery with random aberrations coefficients

We present the validation for Ronchigram recovery with the random aberrations coefficients (ReRRCA) algorithm. This algorithm was proposed to obtain the wavefront aberrations of synthetic Ronchigrams, using only one Ronchigram without the need for polynomial fits or trapezoidal integrations. The validation is performed by simulating different types of Ronchigrams for on-axis and off-axis surfaces. In order to validate the proposed analysis, the polynomial aberration coefficients that were used to generate the simulated Ronchigrams were retrieved. Therefore, it was verified that the coefficients correspond to the retrieved ones by the algorithm. The results show that the ReRRCA algorithm retrieves the aberration coefficients from the analyzed Ronchigram with a maximum error of 9%.

Errata: Segmented vortex telescope and its tolerance to diffraction effects and primary aberrations

The segmented large millimeter telescope (LMT/GTM) is the largest spatial light modulator capable of producing vortex beams of integer topological charge. This observing mode could be applied for direct exoplanet searches in the millimeter or submillimeter regimes. The stability of the vortex structure against aberrations and diffraction effects inherent to the size and segmented nature of the collector mirror was studied. In the presence of low-order aberrations, the focal distribution of the system remains stable. Results show that these effects depend on the topological charge of the vortex and the relative orientation of the aberration with respect to the antenna axis. Coma and defocus show no large effects in the image at the focal plane; however, the system is very sensitive to astigmatism. Heat turbulence, simulated by random aberrations, shows that the system behaves in a similar way as astigmatism dissociating the vortices. The segmented vortex telescope is proposed as a novel approach for the detection of giant planets outside circumstellar disks around nearby stars. Since results are applicable to other facilities with segmented surfaces, it is suggested that this idea should be considered as a regular observation mode complementary to interferometric methods.

Segmented vortex telescope and its tolerance to diffraction effects and primary aberrations

The segmented large millimeter telescope (LMT/GTM) is the largest spatial light modulator capable of producing vortex beams of integer topological charge. This observing mode could be applied for direct exoplanet searches in the millimeter or submillimeter regimes. The stability of the vortex structure against aberrations and diffraction effects inherent to the size and segmented nature of the collector mirror was studied. In the presence of low-order aberrations, the focal distribution of the system remains stable. Results show that these effects depend on the topological charge of the vortex and the relative orientation of the aberration with respect to the antenna axis. Coma and defocus show no large effects in the image at the focal plane; however, the system is very sensitive to astigmatism. Heat turbulence, simulated by random aberrations, shows that the system behaves in a similar way as astigmatism dissociating the vortices. The segmented vortex telescope is proposed as a novel approach for the detection of giant planets outside circumstellar disks around nearby stars. Since results are applicable to other facilities with segmented surfaces, it is suggested that this idea should be considered as a regular observation mode complementary to interferometric methods.

HIGH-CONTRAST IMAGING VIA MODAL CONVERGENCE OF DEFORMABLE MIRROR

For extremely high contrast imaging, such as direct observation of faint stellar companions, an adaptive optics system is required to produce low-halo and low-speckle regions in the focal plane. A method for deformable mirror control is proposed to achieve this goal. The method relies on a modal convergence of the deformable mirror driven by a focal-plane metric. The modal sets are derived from the Walsh functions. The Walsh-function modes serve two purposes: the expansion of the actuator displacements and the expansion of the phase functions. Taking advantage of the unique properties of the modal functions, a universal control algorithm is devised for the realization of high-contrast focal planes with and without the help of conventional coronagraphy. Numerical modeling is conducted to simulate complete imaging systems under various scenarios. It is shown that the proposed method reliably produces high-contrast focal planes using either a segmented or a membrane mirror. In the presence of random aberration the method is shown to be able to maintain high-contrast focal planes. Requiring neither retrieval of electric fields nor detailed knowledge of the deformable mirrors, this technique may allow high-contrast imaging in real time.

Therapy-Related Myelodysplastic Syndrome Following Treatment for Childhood Acute Lymphoblastic Leukemia: Outcome of Patients Registered in the EWOG-MDS 98/06 Studies,

Abstract 4130 Objective:Therapy-related myelodysplastic syndrome (tMDS) following treatment of childhood acute lymphoblastic leukemia (ALL) is one of the most frequently observed secondary malignancies in survivors of childhood cancer. Allogeneic stem cell transplantation (SCT) is the only curative treatment. This analysis was performed to asses the outcome of patients with tMDS following treatment for childhood ALL reported to the EWOG-MDS study group. Patients and Transplant Procedure:Forty-three patients (19 male/24 female) were diagnosed with tMDS between August 1989 and August 2009. The median age at diagnosis was 8.9 yrs (3.4–20.5). The median interval from diagnosis of ALL to the diagnosis of tMDS was 3.3 yrs (1.7–7.0). Five patients did not receive SCT and died due to progressive disease at a median of 5.6 mo after diagnosis. Thirty-eight patients were transplanted. One patient was excluded from the analysis due to insufficient data. In the 37 patients karyotype analysis revealed the following results: normal karyotype (5), abnormalities of chromosome 7 +/− additional aberrations (10), random aberrations (9), structurally complex karyotype (9), failed analysis (4). The highest WHO type was refractory cytopenia (RC) in 4 patients, whereas 33 patients had advanced AML like therapy prior to SCT was employed in 11 patients. Donors were matched siblings (13), matched unrelated volunteers (15), or mismatched or insufficiently typed family or unrelated donors (9). Conditioning consisted of busulfan, cyclophosphamide and melphalan (Bu/Cy/Mel) (23), an alternative busulfan based regimen (6), a radiation based regimen (5) or others (3). Results:After a median follow up of 4.1 (0.5 – 9.4) years, 14 patients are alive in first complete remission (CR). Seventeen patients developed relapse after a median time of 266 days (28 days – 3.4 years). Of these, three patients are alive in CR after a second allograft. Six patients died of transplant-related complications after first (4) or second (2) SCT. In summary, SCT for tMDS following ALL resulted in a probability of event-free and overall survival at 5 years of 0.34 and 0.42, respectively. In univariate analysis, the presence of a structurally complex karyotype, SCT from a mismatched donor and a preparative regimen other than Bu/Cy/Mel were factors predicting a decreased probability of event-free survival. The use of intensive chemotherapy prior to SCT resulted in a trend towards better survival due to a reduction in relapse incidence. In multivariate COX-analysis, a conditioning regimen other than BuCyMel remained the only variable associated with a high risk of treatment failure. Conclusion:Allogeneic SCT with a preparative regimen consisting of Bu/Cy/Mel is feasible and effective in patients developing tMDS following treatment for childhood ALL. Relapse is the main cause of treatment failure and intensive chemotherapy prior SCT may possibly contribute to an improved outcome. Disclosures:Hasle:Pfizer: Research Funding.

Abstract LB-314: Array comparative genomic hybridization of thymic epithelial tumors identifies loss of CDKN2A as a prognostic factor and BCL2 family members as targets for therapy

Abstract Background: Thymic epithelial tumors (TETs) are rare and the genomic aberrations relevant to TET biology are unknown. The goal of this study was to identify recurrent genomic aberrations in TETs. Materials and Methods: From a series of 132 TET resected patients we selected 59 formalin fixed paraffin embedded (FFPE) samples with more than 80% of cancer cells in order to perform high-resolution array-CGH. We used ULS labeling kit (Agilent) and 105A array (Agilent) for 20 and 180K array (Agilent) for 39 samples. For the immunohistochemistry we used a tissue micro-array built from FFPE samples of the 132 patients. The viability assay MTS (Promega) was used to evaluate cytotoxicity of Gx15–070 and ABT-263 (Selleck Chemicals) in T1889, TY82 and T1682 TET cell lines. Results: Chromosome arm level copy number (CN) aberrations were considered those chromosome arms with more than 80% of their length affected by either CN gain or loss. Rare non-recurrent chromosome arm-level CN aberrations were observed in type A thymomas, whereas types B3 and thymic carcinomas shared frequent gains of chromosomes 1q, 5 and 7, as well as losses of chromosomes 6 and 13q. In addition, thymic carcinomas presented frequent losses of chromosomes 16p and 17q. We applied the GISTIC algorithm to the whole set of CN aberrations in order to distinguish aberrations driving the cancer phenotype from the background level of random CN aberrations. 72 CN gain and 54 CN loss peaks were identified (q<0.25). Only two peaks were associated with a significant (p<0.05) poor disease related survival and time to progression. These two peaks represented one CN gain (log2 ratio > 0.3) containing BCL2 locus and one high-level CN loss (log2 ratio < −0.7) containing CDKN2A/B loci. None of the samples with CDKN2A CN loss (5/59) expressed the related proteins p16INK4 and p14ARF. Patients with CDKN2A-negative immunohistochemistry results (85/119) had a poorer disease related survival (LogRank p=0.041). TET cell lines did not have CDKN2A CN loss or BCL2 CN gain, none of them expressed CDKN2A proteins and T1682 and TY82 expressed BCL2. All TET cell lines expressed multiple BCL2 anti-apoptotic family members including MCL1, and were resistant to ABT-263, a BCL2, BCL-XL and BCL-W inhibitor, but sensitive to Gx15–070, a pan BCL2 anti-apoptotic family member (IC50: range 35.8–99.6 nM). Conclusion: Our data indicate that TET histotypes differ by distribution of chromosome arm level CN aberrations. Loss of CDKN2A is prognostic in TETs, whereas Bcl-2 family members may be valuable targets for treatment of this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-314. doi:10.1158/1538-7445.AM2011-LB-314

Wavefront sensorless adaptive optics: a general model-based approach

Wavefront sensorless adaptive optics (AO) systems have been widely studied in recent years. To reach optimum results, such systems require an efficient correction method. In this paper, a general model-based correction method for a wavefront sensorless AO system is presented. The general model-based approach is set up based on a relationship wherein the second moments (SM) of the wavefront gradients are approximately proportionate to the FWHM of the far-field intensity distribution. The general model-based method is capable of taking various common sets of functions as predetermined bias functions and correcting the aberrations by using fewer photodetector measurements. Numerical simulations of AO corrections of various random aberrations are performed. The results show that the Strehl ratio is improved from 0.07 to about 0.90, with only N + 1 photodetector measurement for the AO correction system using N aberration modes as the predetermined bias functions.

Monte Carlo simulations on corneal and total aberrations before and after LASIK

Previous Monte Carlo simulations which manipulate each Zernike coefficient of total aberrations of human eyes indicate that interactions among wave-front aberrations can provide better visual quality for both pre-LASIK eyes and post-LASIK eyes. In this paper, we go a step further for Monte Carlo simulations which are not only on total aberrations but also on corneal aberrations, before and after LASIK, for a set of eyes. The corneal aberrations after LASIK are acquired through a new reliable method. Then a series of Monte Carlo simulations (including sign simulation, value simulation and meridional simulation) are performed by manipulating each Zernike coefficient (second through sixth-order) of total aberrations as well as corneal aberrations. The results are evaluated by modulation transfer function (MTF) ratio. Total aberrations for post-LASIK eyes still show MTF advantage over randomized aberrations, with slightly change as compared to that for pre-LASIK eyes. However, true corneal aberrations before and after LASIK have no MTF advantage over random aberrations. From this research, we draw conclusions: there is apparent advantage for the complete eye's true aberrations over random aberrations, whether pre-LASIK or post-LASIK, which does not exist for any biological optical surfaces in isolation, and the ability of adaptive mechanism of human eyes, increases after LASIK.

Identification of Gene Expression Signatures Accurately Predicting Cytogenetic Subtypes in Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease, which is classified according to the WHO classification, based on morphology, immunophenotyping and non-random genetic aberrations. AML is hypothesized to arise from two different types of genetic aberrations, i.e. type-I (proliferation enhancing) mutations and type-II (differentiation impairing) mutations. To detect genetic aberrations multiple techniques such as conventional karyotyping, FISH and RT-PCR are being used. In addition to conventional karyotyping, the latter two techniques revealed a higher frequency of aberrations. Still, failures or false negative results should be taken into account. Recent studies have focused on the potential of gene expression profiling (GEP) to classify acute leukemias. To study the clinical value of classification by GEP, we first used a double-loop cross validation (CV) to avoid over-fitting of GEP data and, subsequently, addressed whether the identified GEP was suitable to classify pediatric AML cases in a second independent group of cases. Affymetrix Human Genome U133 plus 2.0 microarrays were used to generate gene expression profiles of 257 children with AML, with high blast counts, if necessary, after enrichment (~80% or more) and good quality RNA. Probe set intensities were normalized using the variance-stabilizing normalization (VSN) implemented in R (version 2.2.0). The patient group was divided into a test cohort (n=170) and an independent validation cohort (n=87). The test cohort was used to construct the classifier using two levels of CV:the minimum number of predictive genes was estimated using a 10-fold CV on random subsets of about 113 (~2/3 of total) patients;the accuracy of the obtained classifier is estimated on the remaining 57 (~1/3) patients. Candidate genes to represent the GEP in the classifier were those genes that discriminated AML subtypes according to an empirical Bayes linear regression model (Bioconductor package: Limma).To construct a reliable classifier it was sufficient to use 75 probe sets, representing the top 15 discriminating probe sets for MLL-gene rearranged AML, t(8;21), inv(16), t(15;17) and t(7;12). These subtypes represented ~50% of the included patients. The remaining patients either had normal cytogenetics, random aberrations or no data available (cytogenetic failure). Due to the heterogeneity of these remaining groups discriminative probe sets were not found. This classifier could reliably predict the 5 subtypes with a median accuracy of 93%. Validation of the classifier on the independent cohort confirmed that the sensitivity and accuracy was more than 99%. No gene expression signatures could be found for the molecular aberrations NPM1, CEBPa, MLL-PTD, FLT3, C-KIT, RAS or PTPN1, possibly due to the small number of cases. However, specific gene expression signatures were found for FLT3-ITD within the subset of cases with t(15;17) or normal cytogenetics. Importantly, a high expression of HOXB-cluster related genes was found in cases with FLT3-ITD and normal cytogenetics. In conclusion, GEP can correctly predict several important cytogenetic subtypes of pediatric AML, including cases that are currently classified using different cytogenetic techniques and cases with failed cytogenetic analysis. Prospective studies are needed to validate the use of GEP in the classification of pediatric AML, especially to provide information on its utility in clinical practice. Increasing numbers in rare subtypes may result in the discovery of genes discriminative for them, and may foster GEP as a new diagnostic tool.