Case report on trial: Do you, Doctor, swear to tell the truth, the whole truth and nothing but the truth?

We are in the era of "evidence based medicine" in which our knowledge is stratified from top to bottom in a hierarchy of evidence. Many in the medical and dental communities highly value randomized clinical trials as the gold standard of care and undervalue clinical reports. The aim of this editorial is to emphasize the benefits of case reports in dental and oral medicine, and encourage those of us who write and read them

Copy-number variation in BMPR2 is not associated with the pathogenesis of pulmonary arterial hypertension

<p>Abstract</p> <p>Background</p> <p>Copy-number variations (CNVs) are structural variations in the genome involving 1 kb to 3 mb of DNA. CNV has been reported within intron 1 of the <it>BMPR2 </it>gene. We propose that CNV could affect phenotype in familial and/or sporadic pulmonary arterial hypertension (PAH) by altering gene expression.</p> <p>Methods</p> <p>97 human DNA samples were obtained which included 24 patients with familial PAH, 18 obligate carriers (<it>BMPR2 </it>mutation positive), 20 sporadic PAH patients, and 35 controls. Two sets of primers were designed within the CNV, and two sets of control primers were designed outside the CNV. Quantitative PCR was performed to quantify genomic copies of CNV and control sequences.</p> <p>Results</p> <p>A CNV in <it>BMPR2 </it>was present in one African American negative control subject.</p> <p>Conclusion</p> <p>We conclude that the CNV in intron 1 in <it>BMPR2 </it>is unlikely to play a role in the pathogenesis of either familial or sporadic PAH.</p> <p>Trial Registration</p> <p>NIH NCT00091546.</p

A high-resolution integrated map of copy number polymorphisms within and between breeds of the modern domesticated dog

<p>Abstract</p> <p>Background</p> <p>Structural variation contributes to the rich genetic and phenotypic diversity of the modern domestic dog, <it>Canis lupus familiaris</it>, although compared to other organisms, catalogs of canine copy number variants (CNVs) are poorly defined. To this end, we developed a customized high-density tiling array across the canine genome and used it to discover CNVs in nine genetically diverse dogs and a gray wolf.</p> <p>Results</p> <p>In total, we identified 403 CNVs that overlap 401 genes, which are enriched for defense/immunity, oxidoreductase, protease, receptor, signaling molecule and transporter genes. Furthermore, we performed detailed comparisons between CNVs located within versus outside of segmental duplications (SDs) and find that CNVs in SDs are enriched for gene content and complexity. Finally, we compiled all known dog CNV regions and genotyped them with a custom aCGH chip in 61 dogs from 12 diverse breeds. These data allowed us to perform the first population genetics analysis of canine structural variation and identify CNVs that potentially contribute to breed specific traits.</p> <p>Conclusions</p> <p>Our comprehensive analysis of canine CNVs will be an important resource in genetically dissecting canine phenotypic and behavioral variation.</p

Experiencing neutropenia: Quality of life interviews with adult cancer patients

BACKGROUND: Neutropenia is a common toxicity in chemotherapy but detailed information about how neutropenia is associated with changes in patients' quality of life is not readily available. This prospective study interviewed patients with grade 4 neutropenia to provide qualitative information on patients' experience of developing and coping with grade 4 neutropenia during a cycle of chemotherapy. METHODS: A sample of 34 patients who developed grade 4 neutropenia during the first cycle of chemotherapy completed a total of 100 structured clinical interviews. Interviews were transcribed, and 2 raters inductively developed 5 broad categories comprising 80 specific complaint domains nominated by patients. Thirty-five patient-nominated problems were mentioned in 5% or more of the interviews. RESULTS: Fatigue was the most common physical symptom. Interference in daily routine, negative self-evaluation, negative emotion, and social isolation were other common complaints associated with neutropenia. CONCLUSION: Neutropenia is associated with a number of negative experiences among cancer patients undergoing chemotherapy, and these negative experiences have an adverse effect on the patient's quality of life. Oncology nurses can play a key role in helping patients manage adverse effects to maintain their quality of life

Current measures of metabolic heterogeneity within cervical cancer do not predict disease outcome

<p>Abstract</p> <p>Background</p> <p>A previous study evaluated the intra-tumoral heterogeneity observed in the uptake of F-18 fluorodeoxyglucose (FDG) in pre-treatment positron emission tomography (PET) scans of cancers of the uterine cervix as an indicator of disease outcome. This was done via a novel statistic which ostensibly measured the spatial variations in intra-tumoral metabolic activity. In this work, we argue that statistic is intrinsically <it>non</it>-spatial, and that the apparent delineation between unsuccessfully- and successfully-treated patient groups via that statistic is spurious.</p> <p>Methods</p> <p>We first offer a straightforward mathematical demonstration of our argument. Next, we recapitulate an assiduous re-analysis of the originally published data which was derived from FDG-PET imagery. Finally, we present the results of a principal component analysis of FDG-PET images similar to those previously analyzed.</p> <p>Results</p> <p>We find that the previously published measure of intra-tumoral heterogeneity is intrinsically non-spatial, and actually is only a surrogate for tumor volume. We also find that an optimized linear combination of more canonical heterogeneity quantifiers does not predict disease outcome.</p> <p>Conclusions</p> <p>Current measures of intra-tumoral metabolic activity are not predictive of disease outcome as has been claimed previously. The implications of this finding are: clinical categorization of patients based upon these statistics is invalid; more sophisticated, and perhaps innately-geometric, quantifications of metabolic activity are required for predicting disease outcome.</p

Sensitivity is not an intrinsic property of a diagnostic test: empirical evidence from histological diagnosis of Helicobacter pylori infection

<p>Abstract</p> <p>Background</p> <p>We aimed to provide empirical evidence of how spectrum effects can affect the sensitivity of histological assessment of <it>Helicobacter pylori </it>infection, which may contribute to explain the heterogeneity in prevalence estimates across populations with expectedly similar prevalence.</p> <p>Methods</p> <p>Cross-sectional evaluation of dyspeptic subjects undergoing upper digestive endoscopy, including collection of biopsy specimens from the greater curvature of the antrum for assessment of <it>H. pylori </it>infection by histopathological study and polymerase chain reaction (PCR), from Portugal (n = 106) and Mozambique (n = 102) following the same standardized protocol.</p> <p>Results</p> <p>In the Portuguese sample the prevalence of infection was 95.3% by histological assessment and 98.1% by PCR. In the Mozambican sample the prevalence was 63.7% and 93.1%, respectively. Among those classified as infected by PCR, the sensitivity of histological assessment was 96.2% among the Portuguese and 66.3% among the Mozambican. Among those testing positive by both methods, 5.0% of the Portuguese and 20.6% of the Mozambican had mild density of colonization.</p> <p>Conclusions</p> <p>This study shows a lower sensitivity of histological assessment of <it>H. pylori </it>infection in Mozambican dyspeptic patients compared to the Portuguese, which may be explained by differences in the density of colonization, and may contribute to explain the heterogeneity in prevalence estimates across African settings.</p

Genome-Wide Mapping of Copy Number Variation in Humans: Comparative Analysis of High Resolution Array Platforms

Accurate and efficient genome-wide detection of copy number variants (CNVs) is essential for understanding human genomic variation, genome-wide CNV association type studies, cytogenetics research and diagnostics, and independent validation of CNVs identified from sequencing based technologies. Numerous, array-based platforms for CNV detection exist utilizing array Comparative Genome Hybridization (aCGH), Single Nucleotide Polymorphism (SNP) genotyping or both. We have quantitatively assessed the abilities of twelve leading genome-wide CNV detection platforms to accurately detect Gold Standard sets of CNVs in the genome of HapMap CEU sample NA12878, and found significant differences in performance. The technologies analyzed were the NimbleGen 4.2 M, 2.1 M and 3×720 K Whole Genome and CNV focused arrays, the Agilent 1×1 M CGH and High Resolution and 2×400 K CNV and SNP+CGH arrays, the Illumina Human Omni1Quad array and the Affymetrix SNP 6.0 array. The Gold Standards used were a 1000 Genomes Project sequencing-based set of 3997 validated CNVs and an ultra high-resolution aCGH-based set of 756 validated CNVs. We found that sensitivity, total number, size range and breakpoint resolution of CNV calls were highest for CNV focused arrays. Our results are important for cost effective CNV detection and validation for both basic and clinical applications

The Effect of Algorithms on Copy Number Variant Detection

BACKGROUND: The detection of copy number variants (CNVs) and the results of CNV-disease association studies rely on how CNVs are defined, and because array-based technologies can only infer CNVs, CNV-calling algorithms can produce vastly different findings. Several authors have noted the large-scale variability between CNV-detection methods, as well as the substantial false positive and false negative rates associated with those methods. In this study, we use variations of four common algorithms for CNV detection (PennCNV, QuantiSNP, HMMSeg, and cnvPartition) and two definitions of overlap (any overlap and an overlap of at least 40% of the smaller CNV) to illustrate the effects of varying algorithms and definitions of overlap on CNV discovery. METHODOLOGY AND PRINCIPAL FINDINGS: We used a 56 K Illumina genotyping array enriched for CNV regions to generate hybridization intensities and allele frequencies for 48 Caucasian schizophrenia cases and 48 age-, ethnicity-, and gender-matched control subjects. No algorithm found a difference in CNV burden between the two groups. However, the total number of CNVs called ranged from 102 to 3,765 across algorithms. The mean CNV size ranged from 46 kb to 787 kb, and the average number of CNVs per subject ranged from 1 to 39. The number of novel CNVs not previously reported in normal subjects ranged from 0 to 212. CONCLUSIONS AND SIGNIFICANCE: Motivated by the availability of multiple publicly available genome-wide SNP arrays, investigators are conducting numerous analyses to identify putative additional CNVs in complex genetic disorders. However, the number of CNVs identified in array-based studies, and whether these CNVs are novel or valid, will depend on the algorithm(s) used. Thus, given the variety of methods used, there will be many false positives and false negatives. Both guidelines for the identification of CNVs inferred from high-density arrays and the establishment of a gold standard for validation of CNVs are needed