Experimental Design

In collaboration with the Rare Diseases Clinical Research Network Angelman Syndrome Consortium (RDCRN-AS), GeneticaLens (GL), an information services technology company, proposes to develop a fully featured web-based interactive application (known as the SeeSystem) specifically for Angelman syndrome (AS)– (SeeSystem-AS).

SeeSystem-AS will be comprised of:

1. An existing database of over 400+ videos (The Angelman Project) An extensive video library/database documenting clinical symptoms and behaviors, tagged with keywords and descriptors according to the MESH system to help establish baseline criteria. Over 35 DVDs were produced by The Angelman Project and 4 of these DVDs have been distributed since 2002 to clinicians and families worldwide. An online version of the content of the remaining DVDs, as well as all the clips and documentaries previously made, will be offered as part of SeeSystem-AS
2. New videos to be produced to follow up on available subjects from The Angelman Project. Follow up videos will be created of subjects and families from the original Angelman Project, when this is possible, and these will be offered as well as part of SeeSystem-AS
3. A web-based interactive data/video gathering platform and analysis application will be developed to facilitate the acquisition and display of new video (photographed by GL, and to be contributed by families and researchers when appropriate) with related data as part of the ongoing RDCRN-AS natural history study
4. A Quality of Life feature to be developed in part based on the data provided by the follow up of the initial group of subjects with AS.

The interactive platform and video resources will help clinicians and researchers understand and document clinical features and their variations in their own patients, particularly regarding disease severity (sometimes associated with variations in genetic descriptions) as well as changes over time. The video resources will also have multiple uses for case managers and families, providing insights and direction into best practices in therapies and treatments, and best approaches to long-term issues such that appear over the life-span, such as adult care.

In the long term, a scale-up of SeeSystem-AS will lead to the connection of the research collection platform with the video library/database so that new videos can be created and uploaded to the library, and, using social networking tools, families can also submit videos that become part of the larger resource.

This project will be completed in two phases:

PHASE 1:

SeeSystem-AS framework will be developed using footage of 73 individuals previously videotaped for the Angelman Project between 1996 and 2002 including scenes from daily life with their families, therapy sessions, exams by clinicians and specialists – a multi-perspective view of an individual with AS. For each subject, filmed over a period on average of 3-4 days, up to 50 video projects were completed including various formats from short clips to feature documentaries, which were extensively described in texts and using keywords. The result – a comprehensive look at each individual – This library of over 400 videos will be put online as part of SeeSystem-AS.

As part of the proposed study, the families of the original Angelman Project individuals will be approached for their consent (Appendix) and families who wish to be part of the follow up will be videotaped, according to the protocols established in the original Angelman Project study and updated with Dr. Tan. Further, when possible, the follow up group will also be enrolled in the RDCRN-AS NIH study.

Systems applied to the original Angelman Project will be used. In addition, a new protocol, related to parent interview on Quality of Life (QOL) measures for their children with AS. Using the CDC guidelines, we will modify the questions so they can be used to interview the parent.

Further, we will use the concept of the Healthy Days tracking system and charts to create an interactive version, once other parameters has been assessed and tested by the RDCRN-AS researchers.

Below – see examples of how the healthy days measures will help the development of questions to be used in obtaining data from the parent.

CDC: Measuring Healthy Days: Population Assessment of Health Related Quality of Life

1. www.cdc.gov/hrqol/featured-items/healthy-days.htm
2. www.cdc.gov/hrqol/methods.htm
3. www.cdc.gov/hrqol/policy.htm

CHART provided by CDC – MONOGRAPH: “Measuring Healthy Days: Population Assessment of Health Related Quality of Life U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Center for Chronic Disease Prevention and Health Promotion Division of Adult and Community Health November 2000 page with monograph (http://www.cdc.gov/hrqol/concept.htm)

NOTE: Permission is not needed to use the Healthy Days Measures(CDC HRQOL-4 or HRQOL-14), nor is there any charge for using them. The measures have been developed and validated by the CDC and its partners to encourage their widespread use in the public domain. For maximum comparability with existing published research and public domain data, however, users are asked to retain the same wording unless there is a compelling reason for doing otherwise.

CHART PROVIDED BY THE CDC (Website: http://www.cdc.gov/hrqol/)

AMENDED CHART (FOR SeeSystem-AS QOL Parent Questionnaire)

Further, GL in collaboration with the RDCRN-AS will develop an interactive calendar-type tool set in order to track good days and bad days – especially over times when knowing emotional health and physical health status is useful on a day by day basis – for example when dealing with seizures and trying to establish a the right medication and dosage. The CDC version of the “Healthy Days” chart is below:

PZ Siegel writes (for the CDC Publication on Healthy Days):

“HRQOL is more likely than other health outcomes to reflect broad consequences of disease or injury. The Healthy Days questions may also capture health-related factors that are underreported, such as violence against women. In many cultures, a quality-of-life focus could offer a unifying theme for programs as diverse as health services and economic development. Such a focus can also help to ensure that important mental health issues, often ignored or inadequately considered in health status measures and productivity indicators, will be addressed. Asking about recent physical and mental health appears to capture a large proportion of the concerns persons have about the quality of their life related to health. This is a simple but powerful way of broadening the scope of health services to include psychosocial aspects that are now recognized as important to the health and productivity of a population (Siegel 1994). “Siegel PZ. Self-reported health status: public health surveillance and small-area analysis. In: Schechter S, ed. Proceedings of the 1993 NCHS Conference on the Cognitive Aspects of Self-Reported Health Status. Cognitive Methods Staff Working Paper Series (No. 10). Hyattsville, Maryland: US Department of Health and Human Services, Public Health Service, National Center for Health Statistics, 1994.

A primary goal -- to document on video how our original group of subjects has changed the past decade – or in some cases – more than a decade, and to show the impact of AS over the years. Such information will help to better determine the needs of individuals with AS as well as parents, caregivers and communities and provide them with the most appropriate educational and social interventions. (Currently, there are limited opportunities for adults with severe intellectual disabilities in general, and Angelman syndrome in particular.)

Analyses of video according to the protocols described, should allow us to more accurately document and analyze a wide range of issues including:

1. Impact on parents and siblings (and members of the community) of living with a “child” with Angelman syndrome.
2. The age effect – the infant child, young school-age child, the teenager, and the adult; changes in behavior over time, especially around puberty.
3. Cultural effects – How do different cultures view and cope with intellectual disabilities? Particularly important to study “closed societies / cultures”, ideally in different countries as well.
4. Documentation of specific behavioral traits (including maladaptive behaviors) to understand the precipitating factors and the impact that these behaviors have on the daily lives of the individuals and their families.
5. Analysis of gait and movement disorders.

See Clip 10: Gait Comparison, featuring Alex, (Del+), at different ages.

Further, analysis of video will also be developed to facilitate the validation of developmental outcome measures such as the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales used by the RDCRN-AS as some of the main developmental outcome measures in the clinical studies used at each visit. The Bayley score is based on a series of “objective” observations made by the evaluating psychologist but parents often report that their child can do a lot more when they are at home than what the Bayley score would suggest. The Vineland score is based largely on parental report of their child’s abilities, but there is no way of verifying the accuracy of their responses independently.

In addition, video clips can be used to Increase accuracy of parent report via video enhanced questionnaires to give parents better guidance on the question asked. GL has developed the iM-CHAT (Interactive Modified Checklist for Autism in Toddlers) based on the validated and widely used assessment by Robins, et. al. The interface for the iM-CHAT: the Question with a video showing the behavior asked about included (see Screen capture below – child’s name is included in online version: “If you point at something across the room, does Amy look at it?”) (SeeAutism iM-CHAT test site).

It is important that the outcome measures used are valid and accurate – by analyzing non-intrusive video recordings of these individuals going about their daily lives, there is the opportunity to evaluate more objectively the outcome measures. This has important implications for development of future clinical trials because the FDA is increasingly relying on patient-reported outcome measures in their drug-approval decisions.

Another aspect – to Identify novel behavioral characteristics – via informant testimony and observation videos -- that may not have been previously documented and hence unknown to the medical community, for example behaviors that might not easily be easily observable or able to be documented in the time frame and setting of a patient appointment. (…and may be known to the parent or caregiver).

PHASE 2:

Development of the software for use by the RDCRN. Comprising 6 study sites across the country (San Diego, Houston, Nashville, Cincinnati, Greenwood, Boston), the Consortium has enrolled a total of around 270 children and adults with Angelman syndrome across a wide age range since March 2006. In Phase 2, during the development period, the prototype platform will be scaled up and new features added. and trialed by the RDCRN-AS team.

At the beginning of Phase 2, after the beta software package is launched and has been put through several rounds of feasibility and usability testing, the SeeSystem-AS platform and resources will be used on an on-going basis by the RDCRN-AS as they collect data and videos over time to document the lives of enrolled individuals with AS. The platform will be evolved and modified as researchers put it to the test. The data collected as well as the new videos will also become part of the library. With feedback from the RECRN-AS and Dr. Tan, we will create a fully featured platform offering an extensive, multi-featured video database of individuals with AS, a description of their symptoms as well as extensive observations of their behaviors, and multiple interviews with experts and families. Feedback and development will facilitate the development of useful data entry features so that as new video is added, it is easily integrated into the larger system.

The web-based platform will allow the results to be shared with all concerned- researchers, clinicians and families.

The long-term goal: to create a software platform for natural history studies to use in order to track data and video, and to be able to update and document new data and new video using secure cloud technology. We will offer the results of specific Angelman syndrome study as well as the resulting technologies to families and researchers worldwide

Next: About the Participants