Concordance of copy number abnormality detection using SNP arrays and Multiplex Ligation-dependent Probe Amplification (MLPA) in acute lymphoblastic leukaemia

In acute lymphoblastic leukaemia, MLPA has been used in research studies to identify clinically relevant copy number abnormality (CNA) profiles. However, in diagnostic settings other techniques are often employed. We assess whether equivalent CNA profiles are called using SNP arrays, ensuring platform independence. We demonstrate concordance between SNP6.0 and MLPA CNA calling on 143 leukaemia samples from two UK trials; comparing 1,287 calls within eight genes and a region. The techniques are 99% concordant using manually augmented calling, and 98% concordant using an automated pipeline. We classify these discordant calls and examine reasons for discordance. In nine cases the circular binary segmentation (CBS) algorithm failed to detect focal abnormalities or those flanking gaps in IKZF1 probe coverage. Eight cases were discordant due to probe design differences, with focal abnormalities detectable using one technique not observable by the other. Risk classification using manually augmented array calling resulted in four out of 143 patients being assigned to a different CNA risk group and eight patients using the automated pipeline. We conclude that MLPA defined CNA profiles can be accurately mirrored by SNP6.0 or similar array platforms. Automated calling using the CBS algorithm proved successful, except for IKZF1 which should be manually inspected

Randomization in substance abuse clinical trials

BACKGROUND: A well designed randomized clinical trial rates as the highest level of evidence for a particular intervention's efficacy. Randomization, a fundamental feature of clinical trials design, is a process invoking the use of probability to assign treatment interventions to patients. In general, randomization techniques pursue the goal of providing objectivity to the assignment of treatments, while at the same time balancing for treatment assignment totals and covariate distributions. Numerous randomization techniques, each with varying properties of randomness and balance, are suggested in the statistical literature. This paper reviews common randomization techniques often used in substance abuse research and an application from a National Institute on Drug Abuse (NIDA)-funded clinical trial in substance abuse is used to illustrate several choices an investigator faces when designing a clinical trial. RESULTS: Comparisons and contrasts of randomization schemes are provided with respect to deterministic and balancing properties. Specifically, Monte Carlo simulation is used to explore the balancing nature of randomization techniques for moderately sized clinical trials. Results demonstrate large treatment imbalance for complete randomization with less imbalance for the urn or adaptive scheme. The urn and adaptive randomization methods display smaller treatment imbalance as demonstrated by the low variability of treatment allocation imbalance. For all randomization schemes, covariate imbalance between treatment arms was small with little variation between adaptive schemes, stratified schemes and unstratified schemes given that sample sizes were moderate to large. CONCLUSION: We develop this paper with the goal of reminding substance abuse researchers of the broad array of randomization options available for clinical trial designs. There may be too quick a tendency for substance abuse researchers to implement the fashionable urn randomization schemes and other highly adaptive designs. In many instances, simple or blocked randomization with stratification on a major covariate or two will accomplish the same objectives as an urn or adaptive design, and it can do so with more simply implemented schedules and without the dangers of overmatching. Furthermore, the proper analysis, fully accounting for the stratified design, can be conducted

Comparison of ground‐based and Total Ozone Mapping Spectrometer erythemal UV doses at the island of Lampedusa in the period 1998–2003: Role of tropospheric aerosols

The Total Ozone Mapping Spectrometer (TOMS) has the longest time series of globally distributed estimates of UV irradiance at the Earth's surface. The proper interpretation of TOMS estimated irradiances relies on well‐calibrated and well‐maintained spectrometers at the Earth's surface. In this study, daily erythemal irradiances measured by a Brewer spectrophotometer at the island of Lampedusa (35.5°N, 12.6°E), in the Mediterranean are compared with TOMS observations in the period January 1998 to August 2003. The comparison, also because of the peculiar conditions at Lampedusa, a very good site for ground‐based validation of satellite observations, allows us to recognize how the space‐borne observations are influenced by the presence of atmospheric aerosols. Two TOMS data sets, derived applying different algorithms to retrieve ozone and UV irradiance from the backscattered radiance, are used in this study: Version 7 (V7) and the recently developed version 8 (V8), which uses new climatologies for ozone and temperature profiles and accounts for the attenuation by tropospheric aerosols through the aerosol index (AI). As shown in previous studies performed with V7 TOMS data, satellite‐derived erythemal doses systematically overestimate ground‐based measurements, mainly because of uncorrected absorption by aerosols in the troposphere. The bias between the TOMS and Brewer doses for all‐sky conditions is (9.4 ± 19.8)% for V7 and (7.3 ± 20.0)% for V8 and decreases to (5.6 ± 8.0)% for V7 and (3.4 ± 8.4)% for V8 for the cloud‐free cases. The large standard deviations for all‐sky conditions are due to nonhomogeneity in the cloud cover within the sensor field of view, while those for cloud‐free days are caused by the large aerosol variability occurring at Lampedusa. The biases for cloud‐free days have been related to differences in the TOMS AI UV attenuation algorithm and to the aerosol optical depth (AOD) at 415.6 nm measured with a Sun photometer at Lampedusa since 2001. The mean bias between the V7 TOMS and Brewer doses progressively increases with AI and AOD at 415.6 nm, from ± 3% for low AI and AOD up to 21% for 1.5 ≤ AI < 2.5 and 0.5 ≤ AOD < 0.6. The bias calculated with V8 data set varies between +6% for 0 ≤ AI < 1 and about −8% for 4 ≤ AI < 5, well within the respective uncertainties of the Brewer and TOMS measurements. TOMS V8 data show a smaller dependency on the aerosol absorption, indicating that the implemented corrections produce more reliable estimated doses. For very low aerosol loading (AOD at 415.6 nm below 0.2), the TOMS‐to‐Brewer erythemal dose ratio, both for V7 and V8, is approximately 1, indicating that the radiometric calibration of the Brewer instrument is consistent with the TOMS estimated irradiances from derived ozone and Rayleigh scattering attenuation

Steady and Stable: Numerical Investigations of Nonlinear Partial Differential Equations

Excerpt: Mathematics is a language which can describe patterns in everyday life as well as abstract concepts existing only in our minds. Patterns exist in data, functions, and sets constructed around a common theme, but the most tangible patterns are visual. Visual demonstrations can help undergraduate students connect to abstract concepts in advanced mathematical courses. The study of partial differential equations, in particular, benefits from numerical analysis and simulation

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

A Distinctive Pattern of Diversity for the TAS2R38 Gene in North Africa

The TAS2R38 gene is involved in bitter taste perception. This study documents the distinctive diversity patterns in Northern Africa of functional SNPs rs713598 and rs1726866 at the TAS2R38 locus and places those patterns in the context of global TAS2R38 diversity. We analyzed data previously genotyped with Taqman Applied Biosystem for rs713598 and rs1726866 for 375 unrelated subjects (305 Tunisians from seven locations: Mahdia, Sousse, Kesra, Nebeur, Kairouan, Smar and Kerkennah plus 70 Libyans). Data were analyzed to present haplotypes and genotypes and were compared to the data from worldwide populations. We provide information about TAS2R38 diversity in a part of the world that is relatively under-studied. Considering respectively the two SNPs rs713598 and rs1726866, the (C-A) nucleotide haplotype leading to PV amino acid haplotype is extremely rare almost everywhere, but it is relatively frequent (between 6% and 10%) in Northern Africa where it does coexist with the globally common haplotypes (PA, AA and AV). Given its higher frequency in Northern Africa, we propose the (C-A) haplotype as a biogeographic marker for forensic purposes