Cerebral Hemorrhage Risk in Hereditary Hemorrhagic Telangiectasia

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.

4.3 Patient Selection

Inclusion Criteria:

1. (a) Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis
of HHT Curacao criteria: (a) spontaneous recurrent nosebleeds; (b) mucocutaneous
telangiectasia at characteristic sites (lips, oral cavity, fingers or the nose); (c)
visceral involvement such as pulmonary, hepatic or CNS BAVM; and (d) an affected first
degree relative by same criteria.(65) OR (b) Definite clinical HHT diagnosis (at least 3
Curacao criteria) or genetic diagnosis of HHT Curacao criteria: (a) spontaneous
recurrent nosebleeds; (b) mucocutaneous telangiectasia at characteristic sites (lips,
oral cavity, fingers or the nose); (c) visceral involvement such as pulmonary, hepatic
or CNS BAVM; and (d) an affected first degree relative by same criteria.(65) AND
Presence of BAVM For the purpose of the study, we will focus on BAVM that directly
shunts blood from arterial to venous circulations without an intervening capillary bed,
including Toronto classifications(23) of A-V fistulas, "micro" BAVMs (<1 cm) and 8
"small" (1-3 cm) BAVMs, and if present, larger lesions. We will not include intracranial
telangiectasias in isolation.

2. Able to provide informed consent Exclusion Criteria: None 4.4 Recruitment and Informed
Consent The prospective HHT population will consist of patients seen for evaluation and
treatment of HHT. Health status for all patients will encompass a spectrum of
disabilities encountered with the disease processes being studied. The Human Subjects
Committee/Institutional Review Board of each clinical center will approve the informed
consent form. A copy of the letter of approval from the IRB/REB and a copy of the
consent form will be filed with the DMCC before a clinical center will be allowed to
initiate enrollment. The informed consent will include the objectives of the study, a
description of the screening process, the potential risks and benefits, the cost to the
patient, alternatives to participation and liabilities of the particular participating
center. All patients who are diagnosed with HHT, regardless of gender, race or
ethnicity, are potential candidates for the RDCRC. To the best of our knowledge, there
is no race-ethnicity predilection for HHT or sporadic BAVMs.

4.5 Data and Sample Collection Development A detailed table of relevant fields and their data
types and ranges were constructed by combining elements that are in use by the HHT community
and those fields that are collected in our ongoing study of sporadic BAVM. We used these data
tables as a departure point to work with the DMCC in constructing both the relational
database for the project as well as the data web entry forms. Database issues are also
addressed in the GSAC and AU sections.

All recruited participants will be assigned a Database study ID. The link between patient
identifying information and database study ID will only be maintained at the recruiting
center. Data will be entered through a web-based system into a central Database developed at
the DMCC. Only de-identified information will be entered in the central Database.

4.5.1 Detailed Clinical and Radiographic Information to be Collected Information collected
will include both attributes of the systemic manifestations of HHT with a focus on the brain
vascular phenotype. Detailed tables of data fields and data web entry forms are available
from the Site PI, Project Leader, and DMCC. The Clinical data elements include demographic
information as well as specific clinical information about clinical features and
complications of BAVMs, as well as other organ AVMs and complications related to HHT. The
Neuroradiological elements include information about angiographic features, clinical
presentation, complications and treatment of BAVMs. This data will be collect at baseline.
Every year after recruitment, , participants will be contacted by the recruiting Center to
collect a limited follow-up data set, regarding treatment and complications of BAVMs and
mortal status.

The diagnosis of BAVM will be made by referring centers and adjudicated by Dr. TerBrugge
based on the submitted imaging studies. All imaging studies will be abstracted under the
supervision of the consultant neuroradiologist, Dr. TerBrugge. The imaging source and date of
CT, MRI, MR angiography, and any diagnostic cerebral angiography furnish primary descriptors
including side, nidus size, anatomic location, "eloquence," feeding arteries, arterial
aneurysms, number of lesions, and venous drainage pattern. Additional factors include
location, the presence of intra- and extranidal aneurysms, and the presence of venous
stenoses, as described in the Writing Group paper. New AVM hemorrhage is bleeding into the
brain or its surrounding spaces likely to be associated with AVM (age and location of
hemorrhage are also estimated). The time from diagnosis to any new hemorrhage will be used in
the survival analyses. We will also record other potential sources of co-morbidity, including
hypertension, diabetes mellitus, smoking history, hyperlipidemia, i.e., factors that may
non-specifically increase the risk of hemorrhage. Although functional status is not part of
the primary aims, we will record Modified Rankin Score (mRS)(66-68) (adapted from the ISAT
trial patient questions(69)) coded as : 0 = no symptoms and cope well with life; 1 = few
symptoms which do not interfere with everyday life; 2 = symptoms which have changed my life
but I am still able to look after myself; 3 = symptoms which significantly changed my life,
and I need some help looking after myself; 4 = quite severe symptoms, I need help from other
people; 5 = major symptoms which severely handicap me and I need constant attention day and
night; deaths are coded as 6.

The mRS will be recorded at least for patient status at the time of BAVM discovery and the
last available date. For retrospective cases, these will be estimated using available
clinical records; for prospective cases, the last available status during the project period
will be assessed. New ICH during follow-up will also be recorded. Working with the DMCC, we
will institute a web-based system to facilitate data entry. The main follow-up will be
targeted to be completed during the fifth year of the RDCRC project and will include: (a)
date and nature of any treatment; (b) any new hemorrhagic events; and (c) modified Rankin
score.

4.5.2 Sample Collection, Processing and Banking Each site will arrange to obtain a blood
sample from BAVM cases, but we will accommodate banking of samples from HHT patients without
BAVM for exploratory analyses. Blood samples will be collected and sent directly to the
Coriell/NINDS Human Genetics DNA and Cell Line Repository using their published instructions
(http://ccr.coriell.org). Coriell with retain DNA and also release a DNA sample to the study
investigators UCSF, where it will be stored as well. The advantages of using Coriell/NINDS
are (1) 20 μg of genomic DNA will be made available to the researchers at no additional
charge, and (2) lymphocytes will be immortalized, ensuring a durable renewable supply of DNA
for future studies. The PI has worked with NINDS/Coriell before; we have sent approximately
100 sporadic brain AVM cases to the NINDS DNA bank.

For cases unable to have blood drawn, we will use commercially available saliva mailing kits
(Oragene). The kit is sent by the Study Coordinator with instructions for use, consent form,
and a return mailing box with pre-printed postage and shipping label. The specimen will be
labeled with a study ID number, and sent directly to UCSF for processing and DNA extraction.
We have used these with excellent DNA yields and genotyping results. Such samples would be
handled directly by the UCSF Genetics and Statistical Analysis Core (GSAC). The Specimen
study ID number will be assigned separately from the Database study ID number. Samples will
be retained until all DNA has been used up. If there is sample remaining when the study is
complete, the study investigators may use the sample for future research studies into genetic
factors of and brain AVMs or other aspects of HHT.

Inclusion criteria:

- Definite clinical HHT diagnosis (at least 3 Curacao criteria)or genetic diagnosis of
HHT or

- Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis of
HHT and Presence of Brain Arteriovenous Malformation

- Able to provide informed consent

Curacao criteria:

1. spontaneous recurrent nosebleeds;

2. mucocutaneous telangiectasia at characteristic sites (lips, oral cavity or the nose);

3. visceral involvement such as pulmonary, hepatic or CNS BAVM; and (d) an affected first
degree relative by same criteria.

Willingness

- Willingness to participate in the study and ability to give informed consent

Exclusion Criteria:

- Patients not complying with Inclusion criteria