Detecting Breakage Fusion Bridge cycles in tumor genomes -- an algorithmic approach

Breakage-Fusion-Bridge (BFB) is a mechanism of genomic instability characterized by the joining and subsequent tearing apart of sister chromatids. When this process is repeated during multiple rounds of cell division, it leads to patterns of copy number increases of chromosomal segments as well as fold-back inversions where duplicated segments are arranged head-to-head. These structural variations can then drive tumorigenesis. BFB can be observed in progress using cytogenetic techniques, but generally BFB must be inferred from data like microarrays or sequencing collected after BFB has ceased. Making correct inferences from this data is not straightforward, particularly given the complexity of some cancer genomes and BFB's ability to generate a wide range of rearrangement patterns. Here we present algorithms to aid the interpretation of evidence for BFB. We first pose the BFB count vector problem: given a chromosome segmentation and segment copy numbers, decide whether BFB can yield a chromosome with the given segment counts. We present the first linear-time algorithm for the problem, improving a previous exponential-time algorithm. We then combine this algorithm with fold-back inversions to develop tests for BFB. We show that, contingent on assumptions about cancer genome evolution, count vectors and fold-back inversions are sufficient evidence for detecting BFB. We apply the presented techniques to paired-end sequencing data from pancreatic tumors and confirm a previous finding of BFB as well as identify a new chromosomal region likely rearranged by BFB cycles, demonstrating the practicality of our approach

The elusive evidence for chromothripsis.

The chromothripsis hypothesis suggests an extraordinary one-step catastrophic genomic event allowing a chromosome to 'shatter into many pieces' and reassemble into a functioning chromosome. Recent efforts have aimed to detect chromothripsis by looking for a genomic signature, characterized by a large number of breakpoints (50-250), but a limited number of oscillating copy number states (2-3) confined to a few chromosomes. The chromothripsis phenomenon has become widely reported in different cancers, but using inconsistent and sometimes relaxed criteria for determining rearrangements occur simultaneously rather than progressively. We revisit the original simulation approach and show that the signature is not clearly exceptional, and can be explained using only progressive rearrangements. For example, 3.9% of progressively simulated chromosomes with 50-55 breakpoints were dominated by two or three copy number states. In addition, by adjusting the parameters of the simulation, the proposed footprint appears more frequently. Lastly, we provide an algorithm to find a sequence of progressive rearrangements that explains all observed breakpoints from a proposed chromothripsis chromosome. Thus, the proposed signature cannot be considered a sufficient proof for this extraordinary hypothesis. Great caution should be exercised when labeling complex rearrangements as chromothripsis from genome hybridization and sequencing experiments

Evolution, Perfection, and Theories of Language

In this article it is argued that evolutionary plausibility must be made an important constraining factor when building theories of language. Recent suggestions that presume that language is necessarily a perfect or optimal system are at odds with this position, evolutionary theory showing us that evolution is a meliorizing agent often producing imperfect solutions. Perfection of the linguistic system is something that must be demonstrated, rather than presumed. Empirically, examples of imperfection are found not only in nature and in human cognition, but also in language — in the form of ambiguity, redundancy, irregularity, movement, locality conditions, and extra-grammatical idioms. Here it is argued that language is neither perfect nor optimal, and shown how theories of language which place these proper-ties at their core run into both conceptual and empirical problems

A systematic review of the reporting of Data Monitoring Committees' roles, interim analysis and early termination in pediatric clinical trials

<p>Abstract</p> <p>Background</p> <p>Decisions about interim analysis and early stopping of clinical trials, as based on recommendations of Data Monitoring Committees (DMCs), have far reaching consequences for the scientific validity and clinical impact of a trial. Our aim was to evaluate the frequency and quality of the reporting on DMC composition and roles, interim analysis and early termination in pediatric trials.</p> <p>Methods</p> <p>We conducted a systematic review of randomized controlled clinical trials published from 2005 to 2007 in a sample of four general and four pediatric journals. We used full-text databases to identify trials which reported on DMCs, interim analysis or early termination, and included children or adolescents. Information was extracted on general trial characteristics, risk of bias, and a set of parameters regarding DMC composition and roles, interim analysis and early termination.</p> <p>Results</p> <p>110 of the 648 pediatric trials in this sample (17%) reported on DMC or interim analysis or early stopping, and were included; 68 from general and 42 from pediatric journals. The presence of DMCs was reported in 89 of the 110 included trials (81%); 62 papers, including 46 of the 89 that reported on DMCs (52%), also presented information about interim analysis. No paper adequately reported all DMC parameters, and nine (15%) reported all interim analysis details. Of 32 trials which terminated early, 22 (69%) did not report predefined stopping guidelines and 15 (47%) did not provide information on statistical monitoring methods.</p> <p>Conclusions</p> <p>Reporting on DMC composition and roles, on interim analysis results and on early termination of pediatric trials is incomplete and heterogeneous. We propose a minimal set of reporting parameters that will allow the reader to assess the validity of trial results.</p

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Computational Techniques to Investigate Structural Variation

The importance of structural variation as a source of phenotypic variation has become more and more apparent in recent years. At the same time, tools and techniques that detect structural variation using high-throughput data have proliferated. These trends have spurred interest in making increasingly sophisticated inferences about structural variation, including identifying complex or difficult to observe variants and elucidating the biological mechanisms that produce structural variants. Here, we identify several challenging problems in the investigation of structural variation and discuss computational techniques that solve them. First, we examine the discovery of fusion genes in the transcriptome using paired-end reads, a task complicated by reads that map to multiple locations in the genome. Earlier methods ignored these reads to control false discoveries. We demonstrate a method to resolve these ambiguous mappings and increase the sensitivity of fusion gene detection. Second, we investigate whether the breakage-fusion-bridge mechanism leaves a reliable footprint in high-throughput data, a question that had largely been addressed using ad hoc analyses. Using novel algorithms and simulation, we identify the surprisingly limited circumstances when the presence breakage-fusion-bridge can be inferred. Finally, we examine evidence for the phenomenon known as chromothripsis, the shattering and reannealing of chromosomes. We show that there are alternative hypotheses that can account for the structural variation patterns that form the currently proposed signature of chromothripsi

Computational Techniques to Investigate Structural Variation

The importance of structural variation as a source of phenotypic variation has become more and more apparent in recent years. At the same time, tools and techniques that detect structural variation using high-throughput data have proliferated. These trends have spurred interest in making increasingly sophisticated inferences about structural variation, including identifying complex or difficult to observe variants and elucidating the biological mechanisms that produce structural variants. Here, we identify several challenging problems in the investigation of structural variation and discuss computational techniques that solve them. First, we examine the discovery of fusion genes in the transcriptome using paired-end reads, a task complicated by reads that map to multiple locations in the genome. Earlier methods ignored these reads to control false discoveries. We demonstrate a method to resolve these ambiguous mappings and increase the sensitivity of fusion gene detection. Second, we investigate whether the breakage-fusion-bridge mechanism leaves a reliable footprint in high-throughput data, a question that had largely been addressed using ad hoc analyses. Using novel algorithms and simulation, we identify the surprisingly limited circumstances when the presence breakage-fusion-bridge can be inferred. Finally, we examine evidence for the phenomenon known as chromothripsis, the shattering and reannealing of chromosomes. We show that there are alternative hypotheses that can account for the structural variation patterns that form the currently proposed signature of chromothripsi