Not What We Went Looking For

Treuman Katz Center for Pediatric Bioethics - 2008 Conference

Not What We Went Looking ForNot What We Went Looking ForEthical, Legal, and Social Issues in Identification

of Sex Chromosome VariationsEthical, Legal, and Social Issues in Identification

of Sex Chromosome Variations

Arlene M. Davis, JDArlene M. Davis, JD

Assistant ProfessorDepartment of Social Medicine

InvestigatorCenter for Genomics and Society

University of North Carolina, Chapel Hill

Assistant ProfessorDepartment of Social Medicine

InvestigatorCenter for Genomics and Society



Fellow CGS ResearchersFellow CGS ResearchersNancy M.P. King, JD

Department of Social Sciences and Health Policy

Wake Forest University School of Medicine

Cynthia M. Powell, MD

Department of Pediatrics


Ian Whitmarsh, PhD

Department of Anthropology

University of Iowa

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


Ian Whitmarsh, PhD

Department of Anthropology

University of Iowa


Overview of PresentationOverview 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

• 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


Changing LandscapeChanging Landscape

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

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


Genetic Screening & SCVsGenetic Screening & SCVs• 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

• 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

• 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

• 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


Turner (45,X)Turner (45,X)• 1/4000-1/5000 girls • Symptoms vary and

may include:– Short stature* (4’7”)– Delayed puberty*– Infertility*– Hearing impairment,

lymphedema, cardiac & kidney problems, learning disabilities

• Some never diagnosed

• 1/4000-1/5000 girls • Symptoms vary and

may include:– Short stature* (4’7”)– Delayed puberty*– Infertility*– Hearing impairment,

lymphedema, cardiac & kidney problems, learning disabilities

• Some never diagnosed

Klinefelter (47,XXY)Klinefelter (47,XXY)• 1/1000 boys• Symptoms vary and

may include:– Tall stature– Low testosterone/

puberty*– Infertility– Behavioral problems

& learning disabilities*• 60-70% never diagnosed

• 1/1000 boys• Symptoms vary and

may include:– Tall stature– Low testosterone/

puberty*– Infertility– Behavioral problems

& learning disabilities*• 60-70% never diagnosed

Screening May Identify SCVsScreening May Identify SCVs


Family StudyFamily 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

• 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

New Mothers’ StudyNew Mothers’ Study

• 28 mothers of infants– Mothers’ ages:19-45

years– Infants: 8-12 weeks

• Questions: views on expanding NBS to include specific SCVs

• 28 mothers of infants– Mothers’ ages:19-45

years– Infants: 8-12 weeks

• Questions: views on expanding NBS to include specific SCVs

Our Two Interview StudiesOur Two Interview Studies


Family StudyFamily Study

• Parents embrace uncertainty about condition, focus on:–Individuality of child–Her accomplishments

• Argue: w/o symptoms, syndrome doesn’t exist

Whitmarsh, I. et al. (2007). A Whitmarsh, I. et al. (2007). A

place for genetic uncertainty. place for genetic uncertainty. SS&M, 65: 1082-1093SS&M, 65: 1082-1093.

• Parents embrace uncertainty about condition, focus on:–Individuality of child–Her accomplishments

• Argue: w/o symptoms, syndrome doesn’t exist

Whitmarsh, I. et al. (2007). A Whitmarsh, I. et al. (2007). A

place for genetic uncertainty. place for genetic uncertainty. SS&M, 65: 1082-1093SS&M, 65: 1082-1093.

New Mothers’ StudyNew Mothers’ Study• 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?

• 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?

Family Study Results Inform Mothers’ Study Questions

Family Study Results Inform Mothers’ Study Questions


Perceived BenefitsIdentifying SCVs with NBS

Perceived BenefitsIdentifying SCVs with NBSFamily StudyFamily Study

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

otherwise

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

otherwise

New Mothers’ StudyNew 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• Gives an opportunity to:

– prepare financially– prepare emotionally– research resources

before symptoms arise– learn more about child

• Peace of mind if results are negative


Perceived Concerns Identifying SCVs with NBS

Perceived Concerns Identifying SCVs with NBSFamily StudyFamily Study

• Increase worry• Increase sense of guilt • Diagnosing all

behaviors• Some families: offer

testing when symptoms arise

• Chromosomal diagnosis=“syndrome”

• Increase worry• Increase sense of guilt • Diagnosing all

behaviors• Some families: offer

testing when symptoms arise

• Chromosomal diagnosis=“syndrome”

New Mothers’ StudyNew Mothers’ Study• Parents might jump to

conclusions about child’s prognosis

• Symptoms may never present

• Offer screening for older babies, not newborns

• Confidentiality breaches• Accuracy and expense

of screening

• Parents might jump to conclusions about child’s prognosis

• Symptoms may never present

• Offer screening for older babies, not newborns

• Confidentiality breaches• Accuracy and expense

of screening


ViewsViewsFamily StudyFamily StudyMother of son with KS on getting diagnosis: •“Well, you find out and then you don’t know any more than you did before you found out.… It’s just, you just know that he has an extra chromosome and that’s as far as it goes.”

Mother of son with KS on getting diagnosis: •“Well, you find out and then you don’t know any more than you did before you found out.… It’s just, you just know that he has an extra chromosome and that’s as far as it goes.”

New Mothers’ StudyNew Mothers’ StudyNew 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.”•“That’s the one where it makes me wish that we just wait and get him screened if he had any symptoms.”

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.”•“That’s the one where it makes me wish that we just wait and get him screened if he had any symptoms.”


ViewsViewsFamily StudyFamily StudyGrandmother of a teenager with Klinefelter:•“He’s really not a full blown Klinefelter, he’s just a borderline….You know, he’s just a little Klinefelter’s, he’s not a lot Klinefelter’s.”

Father of girl with Turner:•“I don’t think Turner’s exists without some of the physical aspects of it.”

Grandmother of a teenager with Klinefelter:•“He’s really not a full blown Klinefelter, he’s just a borderline….You know, he’s just a little Klinefelter’s, he’s not a lot Klinefelter’s.”

Father of girl with Turner:•“I don’t think Turner’s exists without some of the physical aspects of it.”

New Mothers’ StudyNew Mothers’ StudyNew 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.”

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.”


ConclusionsNew Mothers’ Study

ConclusionsNew Mothers’ Study

• Most said they would want screening for SCVs.

• “If it’s there, you would want to know about it. Even if it’s 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.

• Most said they would want screening for SCVs.

• “If it’s there, you would want to know about it. Even if it’s 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.


ImplicationsImplicationsOur Views of Screening and Genetic Variation

Who Controls Meaning of Genetic Information?

Our Views of Screening and Genetic Variation

Who Controls Meaning of Genetic Information?


One Presentation of Our Future

One Presentation of Our Future






Thank YouThank You

[email protected]@med.unc.edu



Enrollment of Children in a Study of Huntington's

Disease

Enrollment of Children in a Study of Huntington's

Disease

Leon S. Dure, MDLeon S. Dure, MD

Bew White Professor of Pediatrics and NeurologyThe University of Alabama at Birmingham

Bew White Professor of Pediatrics and NeurologyThe University of Alabama at Birmingham


Clinical Features of HD 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)

<10% under 18 yrs

• Duration 15 – 30 yrs

• Prevalence 4 – 10/100,000• Inheritance Dominant

High penetrance

Expansion of htt gene

• Age of onset 35 – 45 yrs (range 2 – 80)

<10% under 18 yrs

• Duration 15 – 30 yrs


HD GeneticsHD Genetics

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

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


Clinical Presentation of HDClinical 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

• 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


HSG - COHORT“Framingham study for HD”

HSG - COHORT“Framingham study for HD”

• Scientific rationale

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

• Scientific rationale

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


Concerns for COHORTConcerns 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?

• 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?


Dataset DevelopmentDataset Development• Pilot Internet survey targeting HD families

– HDSA website– HSG website

• Advantages– Inexpensive– Anonymous

• Disadvantages– How representative are responses?– Limited information

• Pilot Internet survey targeting HD families– HDSA website– HSG website

• Advantages– Inexpensive– Anonymous

• Disadvantages– How representative are responses?– Limited information


HD Parent SurveyHD 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

• 6 months duration• 249 respondents• Survey design

– Basic demographics– Gene status– Family information – children, risk,

understanding– Attitudes regarding research for adults

and children


Respondent CharacteristicsRespondent 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

• 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


Informing ChildrenInforming Children

• 62% had provided information of some type– Average age of respondent = 47y– < 50% of AR parents had informed

• Age of children– Current average = 14y– Age informed = 12y

• 62% had provided information of some type– Average age of respondent = 47y– < 50% of AR parents had informed

• Age of children– Current average = 14y– Age informed = 12y


Uninformed ChildrenUninformed 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%

• 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%


Attitudes Towards ResearchAttitudes 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

• 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


Adult/Parental ConcernsAdult/Parental Concerns

• Adult participation– Insurance– Confidentiality

• Child participation– Child’s understanding of the study– Most commonly cited – “psychological

effect of participation”

• Adult participation– Insurance– Confidentiality

• Child participation– Child’s understanding of the study– Most commonly cited – “psychological

effect of participation”


Clinical Activities in COHORTClinical 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

• 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


Summary/ConclusionsSummary/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

• 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



Genetic Screening in CVID:

Genetic Screening in CVID:

What are we looking for?What are we looking for?

Kristen Hayward, MDKristen Hayward, MD

Fellow, Pediatric RheumatologySeattle Children’s Hospital

Fellow, Pediatric RheumatologySeattle Children’s Hospital


the Casethe Case16 m.o. F presents for immune work-up

Past Medical History:term, healthy2 infections treated with oral antibiotics mild eczema

Family History:Dad: immunodeficiency syndrome (CVID)

•sepsis, anemia, thrombocytopenia•splenectomy, steroids, IV immunoglobulin

16 m.o. F presents for immune work-up

Past Medical History:term, healthy2 infections treated with oral antibiotics mild eczema

Family History:Dad: immunodeficiency syndrome (CVID)

•sepsis, anemia, thrombocytopenia•splenectomy, steroids, IV immunoglobulin


the Case(continued)

the Case(continued)

Physical Exam:normal growth & developmentnormal exam

Labs:mild anemianormal vaccine responsesnormal antibody levels

Mom’s concern:Should we send a genetic test for CVID?

Physical Exam:normal growth & developmentnormal exam

Labs:mild anemianormal vaccine responsesnormal antibody levels

Mom’s concern:Should we send a genetic test for CVID?


What is CVID?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

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


What is CVID?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?

Treatment:• replacement immunoglobulins (IVIG)• timely antibiotics

Prognosis:• mortality 20-30% over 30 years

Diagnosis:• clinical and laboratory criteria

So what about genetic testing?


Genetic Testing in CVID?Genetic Testing in CVID?TACI gene:

mutation in 7-10% of CVID casesgood biologic plausibilitysame change found in

asymptomatic family members

Father’s TACI gene analysis:single amino acid substitutiondescribed on OMIM, not validated

mutation or variation?

TACI gene: mutation in 7-10% of CVID casesgood biologic plausibilitysame change found in

asymptomatic family members

Father’s TACI gene analysis:single amino acid substitutiondescribed on OMIM, not validated

mutation or variation?


Back to the CASE…Back to the CASE…

Should we

test our patient

for a TACI mutation?

Should we

test our patient

for a TACI mutation?


How do we decide?How do we decide?Burke, Pinsky & Press frameworkBurke, Pinsky & Press framework

Yes No

High

Low

Burke, Pinsky, Press, American Journal of Medical Genetics 106 (2001), pp. 233–240


Clinical Validity? Genetic test for CVIDClinical Validity? Genetic test for CVID

“Positive” result

- Unclear if causative

- Unclear penetrance

- Unclear age of onset

“Positive” result


- Unclear penetrance

- Unclear age of onset

“Negative” result


- Baseline risk based

on family history

“Negative” result


- Baseline risk based

on family history

Indeterminant clinical validity


Effective Treatmentfor CVID?

Effective Treatmentfor CVID?

No preventative therapiesNo cure

Supportive care:- Timely antibiotics can be life saving

- IVIg may improve outcomes

No preventative therapiesNo cure

Supportive care:- Timely antibiotics can be life saving

- IVIg may improve outcomes


What are the issues?What are the issues?

Labeling Effects

Health Outcomes

Vulnerable child?Future insurability?

Closer follow-up?Earlier detection?


What would YOU do?What would YOU do?


the Case What happened?

the Case What happened?

Patient underwent genetic testing:same TACI sequence as her father

26 months: developed arthritis in multiple jointsstarted treatment within 8 weeks

36 months: low WBC, low antibodiesstarted replacement IVIG

Patient underwent genetic testing:same TACI sequence as her father

26 months: developed arthritis in multiple jointsstarted treatment within 8 weeks

36 months: low WBC, low antibodiesstarted replacement IVIG


What was the family’s perspective?

What was the family’s perspective?

Testing was a good thing

Altered perception of child- Convinced that child had disease

Value of information- Empowered to seek appropriate care

Testing was a good thing

Altered perception of child- Convinced that child had disease

Value of information- Empowered to seek appropriate care


Provider’s perspective?Provider’s perspective?

More questions than answersTest may be more valuable in timeTreatment dilemmas:

- Usual medications?- Increased risk of malignancy, infection?

test most appropriate for research setting

More questions than answersTest may be more valuable in timeTreatment dilemmas:

- Usual medications?- Increased risk of malignancy, infection?

test most appropriate for research setting


SummarySummary 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

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


Thank youThank youTruman Katz Center

for Pediatric Bioethics-Doug Diekema-Doug Opal

UW Public Health Genetics -Kelly Fryer-Edwards

Pediatric Rheumatology and Immunology Departments

Truman Katz Center for Pediatric Bioethics

-Doug Diekema-Doug Opal

UW Public Health Genetics -Kelly Fryer-Edwards

Pediatric Rheumatology and Immunology Departments



Attitudes toward carrier testing of minors

Attitudes toward carrier testing of minors

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

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

Cynthia A. James, ScM, PhDCynthia A. James, ScM, PhD

Genetic CounselorJohns Hopkins ARVD Program

Genetic CounselorJohns Hopkins ARVD Program


Purpose of the studyPurpose 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

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


Chronic granulomatous diseaseChronic 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


Duchenne & Becker muscular dystrophyDuchenne & Becker muscular dystrophy• X-linked• Duchenne

– Diagnosis age 3-5– Loss of ambulation age 9-12– Death in 20’s - early 30’s

• Becker– Diagnosis around age 12 (varied)– Loss of ambulation in 20’s– Survival well into adulthood


Spinal muscular atrophy (II & III)Spinal muscular atrophy (II & III)• Autosomal recessive• Type II

– Onset < 18 months– Children learn to sit unaided +/- walk – Death late adolescence / young adulthood

• Type III– Onset > age 2– Loss of ambulation variable - adolescence /

adulthood– Normal lifespan

• Autosomal recessive• Type II

– Onset < 18 months– Children learn to sit unaided +/- walk – Death late adolescence / young adulthood

• Type III– Onset > age 2– Loss of ambulation variable - adolescence /

adulthood– Normal lifespan


RecruitmentRecruitment• 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

• 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


Methodology overviewMethodology 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


InterviewsInterviews• 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


Perceptions of the “best” age for carrier testing

Perceptions of the “best” age for carrier testing

Age Parents Sisters**(n =14) (n = 9)

Young as possible 4 0Puberty 8 3Mid-teens 1 1

18 or older* 1 4

* Parents were significantly more likely than girls tofavor carrier testing before age 18 (p<0.05)

**One girl thought there was no ideal age for carrier testing


• 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)

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, it’s their right to know whether they are carriers” (mother, XL)

• 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, it’s their right to know whether they are carriers” (mother, XL)

Risks and benefits of carrier testing - parents


• 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 you’re younger it’s probably

harder to take the news and you’d be worried about ever having a husband because you’d be like ‘oh what would we think if we had a child like that? Would he still like me?’” (XL – age 12)

– “ I don’t 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)

Risks & benefits of testing - adolescents


Desirability of hypothetical testDesirability 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”

• 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”


Parental PredictionsParental 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)… She’s an

extrovert… and she’s not bashful about those things. And I think she’d 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 don’t think I want to know now. I don’t want it to overpower my life. I don’t want to stay up nights thinking,… OK from this point on I’m not going to have kids…” (age 12, XL)

• 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)… She’s an

extrovert… and she’s not bashful about those things. And I think she’d 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 don’t think I want to know now. I don’t want it to overpower my life. I don’t want to stay up nights thinking,… OK from this point on I’m not going to have kids…” (age 12, XL)


QuestionnairesQuestionnaires• 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


100

80

60

40

20

0

% w

ho w

ould

test

dau

ghte

r

3 year-old 13 year-old

XL CGD AR CGD XL neuro (MD) AR neuro (SMA)

“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?”


Logistic regression - carrier testing for a minor daughter

Three-year oldVariable Coefficient Odds ratio p-value

(SE) (95% CI) (<)Mode of inheritance 0.96 (0.38) 2.6 (1.2-5.5) 0.05(0=XL)Condition 1.5 (0.39) 4.6 (2.1-9.9) 0.001(0=CGD)

Thirteen-year old

Variable Coefficient Odds ratio p-value(SE) (95% CI) (<)

Mode of inheritance 1.5 (0.51) 4.6 (1.7-12.4) 0.01(0=XL)Condition 0.99 (0.53) 2.7 (0.96-7.6) 0.1(0=CGD)


Reasons for/against testingReasons 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?”

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


Rationale for TestingRationale for Testing

Parental Role3yo (%)

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


Rationale for testingRationale for testing

Psychosocial Risks3yo (%)

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



Reproductive issues3yo (%)

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 wouldn’t be important at her age.

30 43



Informed consent3yo (%)

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


Rationale for NOT TestingRationale for NOT Testing

Informed consent3yo (%)

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


Rationale for NOT testingRationale for NOT testing

Psychosocial Risks3yo (%)

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


ConclusionsConclusions• 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

• 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


RecommendationsRecommendations

• 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

• 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


AcknowledgementsAcknowledgementsJohns HopkinsNeil A. Holtzman, MD MPHJerry A. Winkelstein, MDKarl Broman, PhDKathy DeVet, PhDDave Valle, MDCrystal Tichnell, MSHugh Calkins, MD

NIHDon Hadley, MS (NHGRI)Harry Malech, MD (NIAID)Steve Holland, MD (NIAID)John Gallin, MD (NIAID)

Muscular Dystrophy Association

Immune Deficiency Foundation



The Public Health Value of Prenatal Screening

The Public Health Value of Prenatal Screening

Victoria Seavilleklein, PhDVictoria Seavilleklein, PhD

Clinical and Organizational Ethics FellowJoint Centre for Bioethics

University of Toronto, Canada

Clinical and Organizational Ethics FellowJoint Centre for Bioethics

University of Toronto, Canada


Prenatal Screening (PNS)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

• 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


OverviewOverview

• Prenatal screening is expanding

• Autonomy and public health relied upon to justify PNS and its expansion

• Argue that PNS isn’t justified on the basis of public health

• Prenatal screening is expanding

• Autonomy and public health relied upon to justify PNS and its expansion

• Argue that PNS isn’t justified on the basis of public health


Public HealthPublic 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)

• 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)


PNS as a Public Health Initiative

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

• 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


Challenges to PNS as a Public Health Strategy

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

1) Morally problematic definition of ‘prevention’

2) Contested benefit/burden ratio

3) Limited effectiveness

4) Negative consequences for people with disabilities and society


1) Definition of ‘prevention’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

• 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


2) Burdens and Benefits2) 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

• 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


3) Limited Effectiveness3) 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

• ~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


4) Negative Consequences4) 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

• 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


ConclusionConclusion

• Public health resources would be better spent elsewhere– Morally problematic definition of ‘prevention’– Contested benefit/burden ratio– Limited effectiveness– Negative consequences

• Routinely offering PNS isn’t justified according to the value of public health

• Public health resources would be better spent elsewhere– Morally problematic definition of ‘prevention’– Contested benefit/burden ratio– Limited effectiveness– Negative consequences

• Routinely offering PNS isn’t justified according to the value of public health


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