2016-2017 Research Grants

The Board of Directors approved three new research grants at the October 2016 meeting. The projects have a combined expense of $97,000.

The Effect of Demographic and Socioeconomic Factors in the Diagnosis and Treatment of Chiari I Malformation will take place at Washington University with David Limbrick, MD, PhD as Principal Investigator.

Chiari malformation with or without syringomyelia (CM+/-SM) is a common and debilitating neurological condition. While surgical treatment remains the mainstay of management, little information exists regarding barriers to diagnosis, workup, and treatment for this disease. Insurance status and race are known to have an impact on access to care in a variety of different conditions. However, these factors have not been assessed in CM+/-SM. To determine these effects, we are proposing a study that seeks to determine the relationship between geographic and demographic factors on access to surgical treatment, clinical outcomes, and quality of life (QOL) for CM+/-SM. This will be achieved using a large multi-institutional database of over 500 subjects with CM+/-SM. By analyzing these effects, we hope to understand and ultimately reduce disparities in the diagnosis and treatment of CM+/-SM.

Quality Indicators for the Surgical Management of Chiari I Malformation is a collaborative effort between the Center for Health Policy at Stanford and Stanford Health Care. Principal Investigator is Jennifer Quon, Md.

The goal of this study is to establish “quality indicators” for the surgical management of Chiari I malformation. We will use an evidence-based approach to establish Chiari quality indicators to inform clinical and surgical decision-making. A systematic literature review of Chiari I related clinical outcomes was performed to identify articles in multiple domains defined a priori as integral to reporting outcomes in patients undergoing a Chiari I decompression. We propose to identify disease-specific instruments that we could implement in the ambulatory care setting and prospectively validate these metrics to ensure they accurately reflect the range of outcomes seen in this disease. We would then integrate these metrics into epic and track our outcomes and resource utilization on a regular basis. The success of this innovative project will be measured by the 1) seamless integration of quality metrics into our daily workflow; 2) improve patient care and outcomes; and 3) lead to a national collaborative multi-institutional effort focusing on quality outcome metrics for Chiari I malformation.

The third study which will take place at Duke and further the Genetic Study.

In “Classical” CMI the cerebellar tonsillar herniation is generally thought to be caused by a volume discrepancy between the posterior cranial fossa and the residing neural tissue (cerebellum, brainstem) arising from underdevelopment of the paraxial mesoderm /occipital somites. On the basis of this assumption, Urbizu et al (2013) recently carried out a case-control genetic association study using 404 Spanish CMI patients and 524 sex-matched controls to explore the role of common genetic variation with haplotype tagging SNPs (TagSNPs) in 58 functional candidate genes involved in paraxial mesoderm, occipital somite, sclerotome and placental angiogenesis development. Although no associations met adjustment for multiple comparisons within the whole patient sample, four SNPs in three genes (CDX1, FLT1 and ALDH1A2) remained significant (at a 10% False Discovery Rate correction) when analyses were restricted to 186 patients with an underdeveloped posterior cranial fossa as defined by measures obtained from magnetic resonance imaging (MRI). We set out to replicate these genetic susceptibility alleles in an independent family-based US Caucasian dataset of CMI, as well as to test additional variants located within those genes. The relationship between the genotypes of SNPs and cranial base morphological traits was also investigated using MRI measurements as defined previously in Markunas et al (2014). When evaluating association with several posterior fossa traits, nominal association with CMI was observed for seven SNPs. The most significant of these findings was for rs11689375 ( in the MSGN1 gene), which demonstrated the highest evidence for association within a subset of families characterized by a large posterior fossa (p=0.001). Nominal genotypic associations with affection status were also identified in two ALDH1A2 SNPs, three CDX1 SNPs, and one FLT1 SNP, when subsetting families based on PF measurements. Given the consistency in evidence for association across the two independent studies (Spanish and US) in the ALDH1A2, CDX1 and FLT1 genes, we propose a targeted deep sequencing study of these three genes to identify potentially causal variants. This approach is similar to how we previously identified mutations in the GDF6 and GDF3 genes in CMI families (Markunas et al, 2013).