TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

Fizzle Testing: An Equation Utilizing Random Surveillance to Help Reduce COVID-19 Risks

A closed-form equation, the Fizzle Equation, was derived from a mathematical model predicting Severe Acute Respiratory Virus-2 dynamics, optimized for a 4000-student university cohort. This equation sought to determine the frequency and percentage of random surveillance testing required to prevent an outbreak, enabling an institution to develop scientifically sound public health policies to bring the effective reproduction number of the virus below one, halting virus progression. Model permutations evaluated the potential spread of the virus based on the level of random surveillance testing, increased viral infectivity and implementing additional safety measures. The model outcomes included: required level of surveillance testing, the number of infected individuals, and the number of quarantined individuals. Using the derived equations, this study illustrates expected infection load and how testing policy can prevent outbreaks in an institution. Furthermore, this process is iterative, making it possible to develop responsive policies scaling the amount of surveillance testing based on prior testing results, further conserving resources