Significant Statistics: The Unwitting Policy Making of Mathematically Ignorant Judges

This article will explore several areas in which judges, hampered by their mathematical ignorance, have permitted numerical analysis to subvert the goals of our legal system. In Part II, I will examine the perversion of the presumption of innocence in paternity cases, where courts make the counter-factual assumption that regardless of the evidence, prior to DNA testing, a suspect has a 50/50 chance of being the father. In Part III, I will explore the unnecessary injection of race into trials involving the statistics of DNA matching, even when race is entirely irrelevant to the particular case. Next, in Part IV, I will discuss how courts use race- and gender-based statistics to reduce damages in tort cases for women and racial minorities, and silently assert that past racism and sexism will continue. In the final section, I will examine how judges have improperly allocated the risk of error in cases such as securities fraud, so as to reward those who have attempted to manipulate stock prices illegally

Significant Statistics: The Unwitting policy Making of Mathematically Ignorant Judges

This article will explore several areas in which judges, hampered by their mathematical ignorance, have permitted numerical analysis to subvert the goals of our legal system. In Part II, I will examine the perversion of the presumption of innocence in paternity cases, where courts make the counter-factual assumption that regardless of the evidence, prior to DNA testing, a suspect has a 50/50 chance of being the father. In Part III, I will explore the unnecessary injection of race into trials involving the statistics of DNA matching, even when race is entirely irrelevant to the particular case. Next, in Part IV, I will discuss how courts use race- and gender-based statistics to reduce damages in tort cases for women and racial minorities, and silently assert that past racism and sexism will continue. In the final section, I will examine how judges have improperly allocated the risk of error in cases such as securities fraud, so as to reward those who have attempted to manipulate stock prices illegally

Inference Of Natural Selection In Human Populations And Cancers: Testing, Extending, And Complementing Dn/ds-Like Approaches

Heritable traits tend to rise or fall in prevalence over time in accordance with their effect on survival and reproduction; this is the law of natural selection, the driving force behind speciation. Natural selection is both a consequence and (in cancer) a cause of disease. The new abundance of sequencing data has spurred the development of computational techniques to infer the strength of selection across a genome. One technique, dN/dS, compares mutation rates at mutation-tolerant synonymous sites with those at nonsynonymous sites to infer selection. This dissertation tests, extends, and complements dN/dS for inferring selection from sequencing data. First, I test whether the genomic community’s understanding of mutational processes is sufficient to use synonymous mutations to set expectations for nonsynonymous mutations. Second, I extend a dN/dS-like approach to the noncoding genome, where dN/dS is otherwise undefined, using conservation data among mammals. Third, I use evolutionary theory to co-develop a new technique for inferring selection within an individual patient’s tumor. Overall, this work advances our ability to infer selection pressure, prioritize disease-related genomic elements, and ultimately identify new therapeutic targets for patients suffering from a broad range of genetically-influenced diseases

Allele-Specific Amplification in Cancer Revealed by SNP Array Analysis

Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ

Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer.

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion

The collapse of intermediate structures?

How can we explain the rise of President Trump and the attraction of his campaign behavior before and since he took office? We argue here that the collapse of ‘intermediate structures’ has been a key factor; that the associations and groups which are building blocks of pluralistic politics have been eroded to such an extent that Trump’s personality politics have been able to take over the political stage

Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia.

The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy