Not What We Went Looking For

1
Not What We Went Looking For

• Ethical, Legal, and Social Issues in
  Identification of Sex Chromosome Variations

Arlene M. Davis, JD
Assistant Professor Department of Social
Medicine Investigator Center for Genomics and
Society University of North Carolina, Chapel Hill
2
Fellow CGS Researchers

• Nancy M.P. King, JD
• Department of Social Sciences and Health Policy
• Wake Forest University School of Medicine
• Cynthia M. Powell, MD
• Department of Pediatrics
• University of North Carolina, Chapel Hill
• Ian Whitmarsh, PhD
• Department of Anthropology
• University of Iowa

3
Overview of Presentation

• Technologic and societal changes regarding
  screening and genetics
• Intended or incidental
• Identification of sex chromosome variations
  (SCVs) in genetic screening
• Data from two interview studies
• Implications

4
Changing Landscape

• 2006 Supplement to Pediatrics A Look at Newborn
  Screening Today and Tomorrow

5
Genetic Screening SCVs

• Genotype vs. phenotype wide variation in
  presentations
• People may do well, whether or not the SCV is
  ever identified
• Some struggle with life-long medical, learning,
  behavioral issues

• Detected incidentally during prenatal screening
  or when symptoms are identified
• Proposed NBS methodologies detecting X-linked
  conditions may also detect SCVs
• Early intervention detection of medical
  problems may be beneficial

6
Screening May Identify SCVs

• Klinefelter (47,XXY)

• Turner (45,X)

• 1/1000 boys
• Symptoms vary and may include
• Tall stature
• Low testosterone/puberty
• Infertility
• Behavioral problems learning disabilities
• 60-70 never diagnosed

• 1/4000-1/5000 girls
• Symptoms vary and may include
• Short stature (47)
• Delayed puberty
• Infertility
• Hearing impairment, lymphedema, cardiac kidney
  problems, learning disabilities
• Some never diagnosed

7
Our Two Interview Studies

• Family Study

• New Mothers Study

• 14 families of children with 45,X and 47,XXY
• Parents ages 30s-50s
• Children 1-16 years
• Families with KS 6
• Families with TS 8
• Questions diagnosis care for children and
  interest/concerns about NBS to identify SCVs

• 28 mothers of infants
• Mothers ages19-45 years
• Infants 8-12 weeks
• Questions views on expanding NBS to include
  specific SCVs

8
Family Study Results Inform Mothers Study
Questions

• Family Study

• New Mothers Study

• Parents embrace uncertainty about condition,
  focus on
• Individuality of child
• Her accomplishments
• Argue w/o symptoms, syndrome doesnt exist
• Whitmarsh, I. et al. (2007). A place for
  genetic uncertainty. SSM, 65 1082-1093.

• Should SCV screening be offered? Would you
  accept?
• Would it matter that
• Often no medical treatment until symptoms
  develop?
• Some show few symptoms while others have many?
• Some may live entire lives without diagnosis?

9
Perceived BenefitsIdentifying SCVs with NBS

• Family Study

• New Mothers Study

• Early intervention
• Gives an opportunity to
• prepare financially
• prepare emotionally
• research resources before symptoms arise
• learn more about child
• Peace of mind if results are negative

• Early intervention
• Have an explanation
• Might not be detected otherwise

10
Perceived Concerns Identifying SCVs with NBS

• New Mothers Study

• Family Study

• Increase worry
• Increase sense of guilt
• Diagnosing all behaviors
• Some families offer testing when symptoms arise
• Chromosomal diagnosissyndrome

• Parents might jump to conclusions about childs
  prognosis
• Symptoms may never present
• Offer screening for older babies, not newborns
• Confidentiality breaches
• Accuracy and expense of screening

11
Views

• New Mothers Study

• Family Study

• New mothers regarding some have few symptoms
  while others have many
• I am interested in knowing if she has it, not
  in how severe it may be.
• Thats the one where it makes me wish that we
  just wait and get him screened if he had any
  symptoms.

• Mother of son with KS on getting diagnosis
• Well, you find out and then you dont know any
  more than you did before you found out. Its
  just, you just know that he has an extra
  chromosome and thats as far as it goes.

12
Views

• Family Study

• New Mothers Study

• New mothers regarding some live their entire
  lives without a diagnosis
• If he does not have symptoms, and I do not have
  a reason to think he has it, there is no reason
  to do this test.
• The possibility that she would have severe
  symptoms is enough to make me want to know.

• Grandmother of a teenager with Klinefelter
• Hes really not a full blown Klinefelter, hes
  just a borderline.You know, hes just a little
  Klinefelters, hes not a lot Klinefelters.
• Father of girl with Turner
• I dont think Turners exists without some of
  the physical aspects of it.

13
ConclusionsNew Mothers Study

• Most said they would want screening for SCVs.
• If its there, you would want to know about it.
  Even if its mild or asymptomatic. I mean, I
  would still want to know about it.
• They believed diagnosis would provide access to
  early intervention services they thought would be
  beneficial.
• Some viewed screening as peace of mind, assuming
  the results would be negative.

14
Implications

• Our Views of Screening and Genetic Variation
• Who Controls Meaning of Genetic Information?

15
One Presentation of Our Future
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
Thank You

• davisam_at_med.unc.edu

21
(No Transcript)
22
Enrollment of Children in a Study of Huntington's
Disease
Leon S. Dure, MD
Bew White Professor of Pediatrics and
Neurology The University of Alabama at Birmingham
23
Clinical Features of HD

• Prevalence 4 10/100,000
• Inheritance Dominant
• High penetrance
• Expansion of htt gene
• Age of onset 35 45 yrs
• (range 2 80)
• lt10 under 18 yrs
• Duration 15 30 yrs

24
HD Genetics

• Expansion of translated CAGn, chromosome 4p
• Polyglutamate motif (similar to MCD, SCA-1, etc.)
• CAG gt 39 correlated with clinical disease
• Age of onset inversely related to CAG expansion
• Testing easily done not highly accessed

25
Clinical Presentation of HD

• Initial signs and symptoms
• Chorea, incoordination, personality changes
• Psychiatric diagnoses common
• Later signs and symptoms
• Progressive chorea, dystonia
• Dysarthria
• Dementia, ongoing psychiatric disturbances
• Early death

26
HSG - COHORTFramingham study for HD

• Scientific rationale
• Innovations
• Inclusion of spouses and 1º relatives
• Inclusion of minors
• Biobank repository
• Comprehensive environmental history

27
Concerns for COHORT

• HD family attitudes
• Clinical research in general
• Research involving minors
• Logistics of assent and consent
• Departure for HSG
• Age and development specific process
• Practical question what and how are children to
  be approached?
• When do they know about HD?
• What do they know?
• What would be the effect of participation on
  children?

28
Dataset Development

• Pilot Internet survey targeting HD families
• HDSA website
• HSG website
• Advantages
• Inexpensive
• Anonymous
• Disadvantages
• How representative are responses?
• Limited information

29
HD Parent Survey

• 6 months duration
• 249 respondents
• Survey design
• Basic demographics
• Gene status
• Family information children, risk,
  understanding
• Attitudes regarding research for adults and
  children

30
Respondent Characteristics

• Gender 81 female
• Mean Age 42 yrs (F 40y, M 48y)
• Gene status
• 42 not at risk/gene negative
• 37 at risk
• 18 gene positive
• Clinical research
• 84 never participated in HD clinical research
• Children of respondents
• 225 reported from 75 of respondents
• Mean age 11yrs

31
Informing Children

• 62 had provided information of some type
• Average age of respondent 47y
• lt 50 of AR parents had informed
• Age of children
• Current average 14y
• Age informed 12y

32
Uninformed Children

• Average age 7y
• Gene status of parents
• AR 47
• NEG 35
• POS 18
• Reasons for not informing
• Age
• Sparing distress
• Appropriate age to inform
• Wait until adulthood 8
• 15-18y 44
• 10-14y 26
• 5-9y 16

33
Attitudes Towards Research

• Adults regarding themselves
• 88 Agree/Strongly agree that symptomatic and
  at-risk persons should participate
• No major differences regarding gene status
• Adults regarding children
• 55 agree that children should participate
• 35 neutral
• 10 disagree with participation
• Age for participation
• 51 greater than 14yrs
• 29 10-14yrs
• 20 less than 10yrs

34
Adult/Parental Concerns

• Adult participation
• Insurance
• Confidentiality
• Child participation
• Childs understanding of the study
• Most commonly cited psychological effect of
  participation

35
Clinical Activities in COHORT

• Yearly neurologic examination
• 63 supportive
• Age 47 15-18y
• Blood specimen for research and DNA testing
• 49 supportive
• Age 45 15-18y
• Statistically, AR group was least likely to be
  supportive of examination/blood specimen

36
Summary/Conclusions

• Parental support for inclusion of children in
  COHORT
• Older children
• Informed children
• Importance of family composition/gene
  status/symptom presence
• Not all families inform children at the same time
• Clinical activities of COHORT will need to be
  tailored to parental concerns
• Need to develop strategies to assess childhood
  understanding of HD

37
(No Transcript)
38
Genetic Screening in CVID

• What are we looking for?

Kristen Hayward, MD
Fellow, Pediatric Rheumatology Seattle Childrens
Hospital
39
the Case

• 16 m.o. F presents for immune work-up
• Past Medical History
• term, healthy
• 2 infections treated with oral antibiotics
• mild eczema
• Family History
• Dad immunodeficiency syndrome (CVID)
• sepsis, anemia, thrombocytopenia
• splenectomy, steroids, IV immunoglobulin

40
the Case(continued)

• Physical Exam
• normal growth development
• normal exam
• Labs
• mild anemia
• normal vaccine responses
• normal antibody levels
• Moms concern
• Should we send a genetic test for CVID?

41
What is CVID?

• Common Variable Immunodeficiency
• Incidence 1/10,000 50,000 in U.S.
• Presents in 2nd 3rd decade of life
• recurrent bacterial infections
• chronic lung disease
• autoimmune phenomena
• malignancies
• Inheritance
• 90 sporadic

42
What is CVID?

• Treatment
• replacement immunoglobulins (IVIG)
• timely antibiotics
• Prognosis
• mortality 20-30 over 30 years
• Diagnosis
• clinical and laboratory criteria
• So what about genetic testing?

43
Genetic Testing in CVID?

• TACI gene
• mutation in 7-10 of CVID cases
• good biologic plausibility
• same change found in
• asymptomatic family members
• Fathers TACI gene analysis
• single amino acid substitution
• described on OMIM, not validated
• mutation or variation?

44
Back to the CASE

• Should we
• test our patient
• for a TACI mutation?

45
How do we decide?

• Burke, Pinsky Press framework

Effective treatment available?
Clinical Validity?
No
Yes
High
CVID
Low
Burke, Pinsky, Press, American Journal of Medical
Genetics 106 (2001), pp. 233240
46
Clinical Validity? Genetic test for CVID

• Negative result
• - Unclear if causative
• - Baseline risk based
• on family history

• Positive result
• - Unclear if causative
• - Unclear penetrance
• - Unclear age of onset

Indeterminant clinical validity
47
Effective Treatmentfor CVID?

• No preventative therapies
• No cure
• Supportive care
• - Timely antibiotics can be life saving
• - IVIg may improve outcomes

48
What are the issues?
Health Outcomes
Labeling Effects
Closer follow-up? Earlier detection?
Vulnerable child?
Future insurability?
49
What would YOU do?
?
50
the Case What happened?

• Patient underwent genetic testing
• same TACI sequence as her father
• 26 months
• developed arthritis in multiple joints
• started treatment within 8 weeks
• 36 months
• low WBC, low antibodies
• started replacement IVIG

51
What was the familys perspective?

• Testing was a good thing
• Altered perception of child
• - Convinced that child had disease
• Value of information
• - Empowered to seek appropriate care

52
Providers perspective?

• More questions than answers
• Test may be more valuable in time
• Treatment dilemmas
• - Usual medications?
• Increased risk of malignancy, infection?
• test most appropriate for research setting

53
Summary

• Become familiar applying the
• Burke, Pinsky, Press model to evaluate genetic
  tests for pediatric diseases
• Identify dilemmas arising from genetic tests with
  low or indeterminate clinical validity
• Recognize differences between provider
• and family perceptions of genetic testing

54
Thank you

• Truman Katz Center
• for Pediatric Bioethics
• -Doug Diekema
• -Doug Opal
• UW Public Health Genetics
• -Kelly Fryer-Edwards
• Pediatric Rheumatology
• and Immunology Departments

55
(No Transcript)
56
Attitudes toward carrier testing of minors

• A study of families with X-linked autosomal
  recessive diseases

Cynthia A. James, ScM, PhD
Genetic Counselor Johns Hopkins ARVD Program
57
Purpose of the study

• To investigate the desirability of and rationale
  for/against carrier testing of minors among
  members of families affected by X-linked (XL) and
  autosomal recessive (AR) conditions
• Attitudes of adolescent and adult siblings
• Influence of mode of inheritance of the disease
  on attitudes

58
Chronic granulomatous disease

• Primary immunodeficiency disorder characterized
  by recurrent fungal and catalase positive
  bacterial infections
• Incidence 1/200,000
• Mortality 2- 5 per year
• 2/3 XL, 1/3 AR

59
Duchenne Becker muscular dystrophy

• X-linked
• Duchenne
• Diagnosis age 3-5
• Loss of ambulation age 9-12
• Death in 20s - early 30s
• Becker
• Diagnosis around age 12 (varied)
• Loss of ambulation in 20s
• Survival well into adulthood

60
Spinal muscular atrophy (II III)

• Autosomal recessive
• Type II
• Onset lt 18 months
• Children learn to sit unaided /- walk
• Death late adolescence / young adulthood
• Type III
• Onset gt age 2
• Loss of ambulation variable - adolescence /
  adulthood
• Normal lifespan

61
Recruitment

• CGD
• Registry of U.S. Residents Affected by CGD of the
  Immune Deficiency Foundation
• NIH Clinical Center intramural studies on CGD
• Neuromuscular conditions
• Maryland/Southern Delaware and Washington DC
  Chapters of the Muscular Dystrophy Association
• Mailed invitations to participate

62
Methodology overview

• Interview phase
• Semi-structured telephone interviews with 14
  parents and 9 adolescent sisters (age 12-15) from
  10 families with CGD
• Qualitative analysis (template analysis)
• Questionnaire phase
• Mailed questionnaires completed by 206 (54
  response rate) parents, adult siblings, and
  adults with CGD, muscular dystrophy and SMA
• Quantitative analysis

63
Interviews

• Semistructured telephone interviews
• 20 - 90 minutes
• Topics
• Family and medical history of CGD
• Impact of CGD on the family
• Perceptions of genetics of CGD
• Perceptions of reproductive risks
• Family communication
• Attitudes toward carrier testing of minors

64
Perceptions of the best age for carrier testing
65
Risks and benefits of carrier testing - parents

• Test prior to adolescence
• Parental role both in caring for child both
  medically
• a good parent knows as much health information
  as possible (mother, AR)
• emotionally
• I would want to cultivate a positive attitude
  about the news as early as possible (mother, AR)

66
Risks and benefits of carrier testing - parents

• Test at adolescence
• It is vital to know carrier status before
  becoming sexually active and may affect choices
  re. sexual activity
• If a girl knows at 14 hey, I could get mixed
  up with the wrong guy and end up with a child of
  my own, like my brother maybe she would think
  twice (mother, AR)
• Girls are ready to understand both intellectually
  and emotionally the meaning of test results
• Adolescents have the right to know their carrier
  status
• They grow up with CGD in the family, its their
  right to know whether they are carriers (mother,
  XL)

67
Risks benefits of testing - adolescents

• Girls believed it important to have access to
  carrier testing for reproductive decision-making
• Girls were more cognizant of psychological risks
• Around 18, because when youre younger its
  probably harder to take the news and youd be
  worried about ever having a husband because youd
  be like oh what would we think if we had a child
  like that? Would he still like me? (XL age
  12)
• I dont think they should do it when they are
  real young, I think about my age (15) is good
  if they are young and they found out about it
  then they will worry about it a whole lot (XL
  age 15)

68
Desirability of hypothetical test

• 5/6 untested girls had clear ideas on whether
  they would want testing were it hypothetically
  offered tomorrow
• Among the 9 parents, 4 had discordant views from
  their daughters on the desirability of the girl
  having the test tomorrow

69
Parental Predictions

• 5/11 predictions (4 from fathers) of whether
  their children would say they wanted testing were
  incorrect
• I would think she would (want carrier testing)
  Shes an extrovert and shes not bashful about
  those things. And I think shed want to know
  once she understood the magnitude of. what it
  could mean to her in the long run (father, XL)
• I want to know for myself but I dont think I
  want to know now. I dont want it to overpower
  my life. I dont want to stay up nights
  thinking, OK from this point on Im not going to
  have kids (age 12, XL)

70
Questionnaires

• Mail questionnaires
• Administered to parents, adult siblings, and
  adults with CGD, MD, SMA. (9 versions)
• 30 minutes
• Topics
• Family history
• Clinical severity perceived severity
• Understanding of inheritance reproductive risks
• Parental guilt and blame
• Stigma
• Attitudes toward carrier testing of minors

71
Imagine you had a 3/13 year-old daughter who had
a chance of being a carrier. Also imagine the
carrier test is a blood test and is 100
accurate. Would you have her tested at age 3/13?
72
Logistic regression - carrier testing for a minor
daughter
73
Reasons for/against testing

• How important would each of the following
  reasons be in your decision of whether or not to
  have her tested at age 3/13?

74
Rationale for Testing

Parental Role 3yo () 13yo()
I could make plans to tell her about her genetic risk 98 94
As a parent, testing would give me peace of mind 94 83
A good parent knows as much as possible about anything related to the health of their child 94 98
She could be raised (go through her teens) knowing her carrier status. I could help her adjust to her genetic risk 91 100
I would be able to answer questions about whether or not she is a carrier when she asks them 90 99
75
Rationale for testing
Psychosocial Risks 3yo () 13yo()
She might experience insurance, educational, or job discrimination someday if she is a carrier 44 35
Learning she is a carrier too early could scare her 39 37
Other people might treat her differently if they find out she is a carrier 31 20
Testing might damage her self-image and self-esteem 32 27
I might treat her differently if she is a carrier 23 18
76
Rationale for testing
Reproductive issues 3yo () 13yo()
She would be certain to know and understand her genetic risk before she becomes sexually active 96 98
She would be able to start a romantic relationship knowing whether she is a carrier 86 90
Finding out whether or not someone is a carrier is only important when they could have/are planning children. The test results wouldnt be important at her age. 30 43
77
Rationale for testing
Informed consent 3yo () 13yo()
A person should have a say in making a decision about whether to know their carrier status and a 3 year-old is too young to provide an opinion / at 13 she would be old enough to help make the decision 26 66
She would be too young / old enough to understand what the results mean 33 85
A person has the right to decide as an adult whether to find out if they are a carrier. If I tested her I would take away that right. 13 21
A blood test is painful. 10 7
78
Rationale for NOT Testing
Informed consent 3yo () 13yo()
A person should have a say in making a decision about whether to know their carrier status and a 3 year-old is too young to provide an opinion / at 13 she would be old enough to help make the decision 78 46
She would be too young / old enough to understand what the results mean 80 65
A person has the right to decide as an adult whether to find out if they are a carrier. If I tested her I would take away that right. 56 47
A blood test is painful. 33 7
79
Rationale for NOT testing
Psychosocial Risks 3yo () 13yo()
She might experience insurance, educational, or job discrimination someday if she is a carrier 53 43
Learning she is a carrier too early could scare her 83 60
Other people might treat her differently if they find out she is a carrier 44 50
Testing might damage her self-image and self-esteem 50 58
I might treat her differently if she is a carrier 13 14
80
Conclusions

• There is widespread support of carrier testing of
  minors among adult members of families affected
  by XL and AR genetic conditions
• Fulfilling parental role
• Protection from uninformed reproductive
  decision-making
• Adolescent and adult family members perceive the
  risks and benefits of carrier testing differently
• Adolescents perceive more psychosocial risks

81
Recommendations

• Maintain current policies regarding deferring
  carrier testing of minors
• Genetic counseling and other medical sessions
  should attend to perceived benefits of carrier
  testing of minors.
• Further research into the experiences of
  adolescent family members

82
Acknowledgements

• Johns Hopkins
• Neil A. Holtzman, MD MPH
• Jerry A. Winkelstein, MD
• Karl Broman, PhD
• Kathy DeVet, PhD
• Dave Valle, MD
• Crystal Tichnell, MS
• Hugh Calkins, MD

• NIH
• Don Hadley, MS (NHGRI)
• Harry Malech, MD (NIAID)
• Steve Holland, MD (NIAID)
• John Gallin, MD (NIAID)
• Muscular Dystrophy Association
• Immune Deficiency Foundation

83
(No Transcript)
84
The Public Health Value of Prenatal Screening
Victoria Seavilleklein, PhD
Clinical and Organizational Ethics Fellow Joint
Centre for Bioethics University of Toronto, Canada
85
Prenatal Screening (PNS)

• Multiple marker screening (maternal serum
  screening and nuchal translucency screening)
• Used to detect likelihood of conditions
• Positive screen ? CVS/amniocentesis ? abortion
• Traditionally
• Down syndrome, open neural tube defects, Trisomy
  18
• Offered to high-risk women

86
Overview

• Prenatal screening is expanding
• Autonomy and public health relied upon to justify
  PNS and its expansion
• Argue that PNS isnt justified on the basis of
  public health

87
Public Health

• Multiple definitions, no single field, discipline
  or methodology
• The science and art of promoting health,
  preventing disease, prolonging life and improving
  quality of life through the organized efforts of
  society. (Health Canada 2003)

88
PNS as a Public Health Initiative

• Offered population-wide
• Coordinated by health clinics and hospitals,
  often provincially funded
• Intended to reduce the incidence of illness and
  disability, thereby improving population health
• Broadly recognized by PH agencies, clinicians, in
  conferences literature

89
Challenges to PNS as a Public Health Strategy

1. Morally problematic definition of prevention
2. Contested benefit/burden ratio
3. Limited effectiveness
4. Negative consequences for people with
   disabilities and society

90
1) Definition of prevention

• Preventing the person, not the condition
• No treatments or cures, just abortion
• Morally problematic because it devalues people
  with disabilities
• Poor track record of discrimination, past and
  present

91
2) Burdens and Benefits

• Ideally, those who suffer the burdens of PH
  initiatives will benefit from them
• Not always the case with women and fetuses
• To justify a population screen, the disease or
  condition should be an important public health
  burden to the target population in terms of
  illness, disability, and death (Khoury et al.,
  2003, 55).
• The burden of people with disabilities is debated

92
3) Limited Effectiveness

• 5 of disability due to genetics
• Most common causes Low birth weight and
  prematurity
• Cost-effectiveness
• Based on the abortion of fetuses with projected
  disabilities
• Challenges with cost-benefit analyses

93
4) Negative Consequences

• For people with disabilities
• Reinforces a medical model of disability
• Focus on avoidance, less on integration
• For mothers and families
• Increased care responsibilities
• For society
• Discrimination, social justice
• Public policy message of devaluation
• Socioeconomic disparities

94
Conclusion

• Public health resources would be better spent
  elsewhere
• Morally problematic definition of prevention
• Contested benefit/burden ratio
• Limited effectiveness
• Negative consequences
• Routinely offering PNS isnt justified according
  to the value of public health

95
Thank you!Questions?