Cerebral Hemorrhage Risk in Hereditary Hemorrhagic Telangiectasia (RDCRN# 6203, Protocol Version Date 07Jan10)

4. Study Design and Methods In conjunction with the DMCC, we will construct a relational database and web-based data collection instrument; see Table 1 showing the sites that will contribute to this effort. Data will include demographics, symptomology, cerebral angioarchitecture, other organ involvement and HHT gene mutation results.

The database will be used to serve Aim 2 and Aim 3 but will also serve as a platform to foster further HHT research. The recruitment of HHT BAVM cases will be emphasized by use of a 3:1 ratio for enrolling non-BAVM to BAVM HHT cases, i.e., for each brain AVM recruited, 3 patients without a brain AVM will be recruited. This will provide the largest RDCRN 6203 Cerebral Hemorrhage Risk in single sample available that will also have centralized expert neuroradiological adjudication of the brain phenotype.

The study design is detailed, by aim, in Section 6. The data to be collected is detailed in Sections 4.5 and 4.5.1 and the study schedule is detailed in Section 4.6.

4.1. Study Population: The study population will include patients with HHT, with inclusion and exclusion criteria as detailed in section 4.3. Cases will be recruited from two sources: (a) the network of HHT Centers of Excellence (Table 1); and (b) patients who contact study personnel or the HHT Foundation International after learning about the study through the HHT Foundation International social networks, the RDCRN public website, friends, physicians, relatives, etc.

Inclusion and exclusion criteria are detailed in section 4.3. 4.2. Case Ascertainment and Enrollment As shown in Table 2, we estimate conservatively that 875 cases will be available for recruitment over five years. Cases will be derived from two sources. First, we will recruit from the HHT Centers of Excellence cases that are currently being followed and new cases as they pass through the individual clinics. Ascertainment and enrollment will use IRB approved, HIPAA-compliant procedures. Each center will submit cases using web-based forms. Second, we will recruit new cases through the HHT Foundation. The HHT Foundation has a mailing list of 5646 families; there is approximately 1000 new families added per year. HHT Patients who contact the HHT Foundation with an interest in participating in the study will be directed to the closest participating HHT Center of Excellence. The HHT Foundation will recruit patients who contact the HHT Foundation who are interested in participating in the BAVM arm of the study but who are not affiliated with a participating center or do not wish to visit a center to participate in the study. We will also enroll non-BAVM HHT cases to facilitate long-term involvement of the HHT community in systematic, organized rare disease research. We have structured the database to be scalable to accommodate all types of HHT. Under the supervision of the site PI, each local PI and research staff will identify and obtain informed consent from patients and their clinical information is entered into a master registry. At enrollment, arrangements for a blood specimen will also be made. Approximately 20 ml (about 4 teaspoons) of blood will be drawn (two ACD tubes of 8.5 ml each). If a blood draw is not possible, the UCSF core will provide bar-coded saliva DNA collection kits. Representative standard clinical imaging studies (MR and angiography) of enrolled cases will be provided to Dr. Karel TerBrugge at Toronto Western Hospital for adjudication and coding of angioarchitecture. We have conservatively estimated that we will be able to collect DNA from 500 of the 875 project cases that will be enrolled over the course of the study.