- 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:
(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.
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.