- Email: [email protected]
The Relative Accuracy of a Questionnaire Compared With Pedigree Analysis in Genetic Risk Assessment for Infertility
The Relative Accuracy of a Questionnaire Compared With Pedigree Analysis in Genetic Risk Assessment for Infertility Kari Danziger Kaplan, Monica Brown, Mary S. Croughan and Paul J. Turek* From the Departments of Urology (KDK, MB, PJT), Obstetrics, Gynecology and Reproductive Sciences (MSC, PJT), Epidemiology and Biostatistics (MSC), and the Program in Genetics of Infertility (KLD, PJT), University of California San Francisco, San Francisco, California
Purpose: For infertile couples family history assessment can add valuable information about genetic infertility and possible risks for offspring. We created a genetic questionnaire for eliciting family history and asked whether it could capture information similar to a pedigree. Materials and Methods: Infertile male patients completed a genetic questionnaire and had a pedigree obtained by a genetic counselor. We assessed the accuracy of the questionnaire to elicit family history information compared to the gold standard pedigree. Results: Of 93 patients 76 (82%) patients indicated relevant genetic information. A comparison of the 2 methods revealed that 61 (80%) patients failed to report key genetic information on the questionnaire that was ascertained by the pedigree. Assessment of 5 relevant family history elements revealed that the questionnaire missed 75% or more of stillbirths, birth defects, developmental delay/learning disabilities/mental retardation, recurrent miscarriages and congenital heart defects. The positive predictive value and the negative predictive value of the questionnaire ranged from 67% to 100% and 74% to 87%, respectively. The sensitivity and specificity of the questionnaire ranged from 12% to 30% and 98% to 100%, respectively. Conclusions: A comprehensive family history questionnaire is not as reliable for capturing relevant, genetic information as a pedigree. The optimal method will become more important as our knowledge of genetic infertility and its implications expands. Key Words: infertility, male; genetics; genetic counseling; reproductive medicine
en with oligospermia (low sperm count) and nonobstructive azoospermia (zero sperm count) have an increased risk for chromosome abnormalities and deletions on the Y chromosome.1,2 The combined risk of detecting these anomalies approaches 10% in oligospermic men and 30% in azoospermic men. For men with congenital absence of the vas deferens there is up to an 80% risk of cystic fibrosis genetic mutations.3– 6 Given that a significant proportion of male infertility, characterized by low or no sperm counts, may have an underlying genetic etiology, a thorough medical and family history is a critical component of the infertility evaluation. In particular, a comprehensive family history can identify genetic etiologies of infertility and also delineate possible inherited risks for offspring.2 This is particularly important as our knowledge of how variations in genetic haplotypes and single gene mutations that can affect infertility increases in the future.7 The pedigree analysis is the standard evaluation tool for family history assessment in genetic counseling. Studies using pedigree analysis in unselected primary care and prenatal patients have observed that additional, previously unidentified genetic risk factors can be revealed in as many as 40% of
M
Submitted for publication July 13, 2007. * Correspondence: Department of Urology, University of California, San Francisco, 1600 Divisadero St, Rm. A633, San Francisco, California 94143-1695 (telephone: 415-353-7352; FAX: 415-8857443; e-mail: [email protected]).
See Editorial on page 1225.
0022-5347/08/1794-1499/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
patients.8 –10 Furthermore, in many instances relevant diagnostic testing is available to further evaluate the genetic risk identified from the pedigree analysis.9,10 Overall, the literature supports the conclusion that personal and family medical history is valuable for genetic risk assessment among infertility patients.11,12 However, the best method of ascertaining this information is controversial, particularly given the costs associated with pedigree analyses by a qualified genetic counselor. This study was performed to ascertain the quality and accuracy of information obtained through patient questionnaire when compared to pedigree analysis. We developed a family history questionnaire based on critical information that would be accrued with a pedigree analysis for use in conjunction with the standard male infertility evaluation.13 The concept of the family history questionnaire was based, in part, on recent national public health initiatives that seek to improve the collection of family history information in the risk assessment, detection and prevention of common diseases.14 The objective of this study was to compare the findings from the family history obtained on the questionnaire with that ascertained by a formal pedigree analysis by a genetic counselor in a cohort of consecutive, male infertility patients. MATERIALS AND METHODS Consecutive adult male patients were referred for infertility evaluation to the University of California, San Francisco Program in the Genetics of Infertility because of oligosper-
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mia (less than 10 million sperm per ml) or azoospermia (zero sperm count). All patients underwent an evaluation with a single urologist (PJT) for male factor infertility. Immediately before this appointment patients were asked to complete a family history questionnaire integrated into a general health history intake form. All patients also underwent a 4-generation pedigree constructed by a board certified genetic counselor (KDK) during a genetic counseling session. Because patient data were decoded of all protected health information, a waiver was obtained from the UCSF Committee on Human Research for this study. The questionnaire is based on questions from a standard American College of Obstetrics and Gynecology prenatal genetic screening tool13 and is represented in Appendix 1. The yes-no format includes questions about personal and family history, ethnicity and racial background, as well as genetic reproductive risks. Included in this last section are inquiries regarding family history of chromosomal abnormality, mental retardation, genetic disorders, birth defects, recurrent miscarriages/stillbirths and infant death (less than 1 year), among others. Partially completed questionnaires were included in this analysis and the questions that were unanswered were also recorded. Also, the genetic counselor did have access to the questionnaire during the pedigree analysis. To structure the comparative analysis of questionnaire and pedigree 14 family history elements were created that represented a broad spectrum of conditions that have significant clinical implications for either diagnosis or management of genetic infertility (Appendix 2). Using the pedigree as the gold standard, patient responses to each of the 14 categories on the questionnaire were scored as concordant or discordant. If a patient indicated relevant information on both questionnaire and pedigree, then the response was considered concordant. If a patient failed to indicate relevant family history information on the questionnaire that was reported on the pedigree, then the response was scored as discordant. An unanswered question on the questionnaire that was reported on the pedigree was also graded as discordant. If a condition occurred more than once in the family history, then concordance with each occurrence was scored individually. For example, if a patient failed to indicate on the questionnaire that a family member had 4 stillbirths but this was noted on the pedigree, then this was recorded as 4 discordant responses. Questionnaire responses and pedigree for a single patient are presented in figure 1. Subset analysis was performed to compare data regarding 5 family history elements that have particular relevance to infertility and reproductive risk assessment, namely recurrent miscarriages, congenital heart defects, stillbirth, developmental delay/learning disability and birth defects (table 1). For these outcomes the PPV, NPV, sensitivity and specificity of the questionnaire were ascertained relative to the pedigree. Finally, an additional subset analysis assessed the accuracy of family history reporting on the questionnaire according to the degree of relationship (ie 1st, 2nd, 3rd, 4th, 5th degree relative). RESULTS Family history questionnaires from 105 consecutive male factor infertility cases were retrospectively compared to the pedigree analysis and constitute the study population. Among this
group 93 patients (fully or partially) completed the questionnaire and 12 patients left the questionnaire blank and were excluded from further analysis. Overall 80% of patients failed to report significant family history information on the questionnaire that was obtained by the genetic counselor constructed pedigree. Discordant responses were broadly observed in 10 of 14 family history categories, including recurrent miscarriages (3 or more), stillbirth, baby died less than 1 year old, cystic fibrosis, bone/skeletal disorder, birth defect, developmental delay/learning disability/mental retardation, congenital heart defect, Down syndrome, bleeding disorder and congenital deafness or blindness. In the subset analysis of 5 family history elements with particular relevance to infertility and reproduction, these elements were missed most often on the questionnaire. In particular, questionnaires ascertained less than 25% of recurrent miscarriages, stillborn births, heart defects, birth defects and developmental delay/learning disability/mental retardation issues. The categories of early menopause, sex chromosome abnormality and sickle cell anemia/thalassemia revealed no difference in reporting frequency, although each of these elements was only rarely reported. In the degree of relatedness subset analysis, patients were found to be most accurate when reporting information that pertained to their personal history, with a concordance rate of 85% (fig. 2). However, beyond this the pedigree revealed significantly more information about the couples’ relatives than did the questionnaire. Responses regarding family history on questionnaire matched less than 27% of pedigree information for 1st, 2nd, 3rd and 4th degree relatives. The PPV of the questionnaire for ascertaining family history of stillbirth, developmental delay/mental retardation and birth defect was 100% (table 2). The PPV of the questionnaire for ascertaining family history of recurrent miscarriage and heart defect was calculated to be 67% and 75%, respectively. However, it was noted that the pedigree failed to account for 1 report of recurrent miscarriage and 1 report of heart defect, so the PPV for these family history elements may have been 100%. The range of NPVs for the 5 family history elements was 74% to 87%. Analysis of these 5 family history elements revealed that the questionnaire had a sensitivity of 12% to 30% and a specificity of 98% to 100% (given that the pedigree missed 2 outcomes, specificity is likely 100%). Positive PV, NPV, sensitivity and specificity are summarized in table 2.
DISCUSSION The importance of genetic risk in disease assessment has become increasingly clear. To address this issue the U.S. Department of Health and Human Services, including the Office of the Surgeon General, the National Institutes of Health, the Centers for Disease Control and Prevention as well as other organizations, embarked on a public health initiative in 2004 to generate awareness of the importance of family history information in assessing risk of common diseases and strategies for integrating this information into prevention programs.14 Although the most appropriate method of ascertaining family history information is not known, the initiative explored how this should be investigated and what the results might demonstrate.15
ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY
A
Do you, your partner or blood relatives have one of the following disorders? You Partner Family
Who?
Never began menstruation
yes no
yes no
yes
no _________
Early menopause
yes no
yes no
yes
no _________
no
yes no
yes
no _________
yes
no
yes no
yes
no _________
Cystic fibrosis
yes
no
yes no
yes
no _________
Tay-Sachs or Canavan disease
yes
no
yes no
yes
no _________
Muscular disorders
yes
no
yes no
yes
no _________
Neurological disorders
yes
no
yes no
yes
no _________
Bone/skeletal disorder (e.g.dwarfism) yes
no
yes no
yes
no _________
Birth defect
no
yes no
yes
no _________
Recurrent miscarriages (3 or more) yes
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Stillborn baby or baby died < 1year old
yes
(e.g. cleft palate, hip dislocation) Developmental delay, learning
yes
no
yes no
yes
no _________
Polycystic Kidney disease
yes
no yes no
yes
no _________
Heart defect from birth
yes
no yes no
yes
no _________
Down Syndrome
yes
no
yes
no _________
disability or mental retardation
yes no
Sex chromosome abnormality (e.g. Klinefelter/Turner syndrome)
yes
no yes
no
yes
no _________
Other chromosomal abnormalities
yes
no
yes
no
yes
no _________
Marfan Syndrome
yes
no
yes
no
yes
no _________
Bleeding disorders (e.g.Hemophilia)
yes
no
yes no
yes
no _________
Sickle cell anemia, Thalassemia
yes
no
yes no
yes
no __Aunt___
Deafness /blindness
yes
no
yes no
yes
no _________
(at birth or early onset)
B d. 45 MI
d.71 thyroid Ca
62 club foot
d. newborn
59 Sickle cell anemia
30 Oligospermia
34
d. 67 MI
All 3 stillborn
Trying to conceive for ~ 2yrs
FIG. 1. Representative set responses by patient to questionnaire (A) and genetic counselor constructed pedigree (B). Red arrows in questionnaire and circles in pedigree indicate family history information that was discordant (missed) by questionnaire.
ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY
TABLE 1. Summary of significant family history identified No. Questionnaire
No. Pedigree
2 3 7
12 21 16
10 18 9
3 3
13 22
10 18
18
84
65 (77)
Recurrent SAB Stillborn Developmental delay/learning disabilities/MR Heart defect Birth defect Total pos responses (%)
TABLE 2. PPV, NPV, sensitivity and specificity for 5 key family history elements
No. Missed by Questionnaire
Recurrent SAB Stillbirth Developmental delay/MR Heart defect Birth defect
The setting for the collection of family history information will also affect analytic validity. A take-home questionnaire that will allow individuals to confer with relatives or review family records will likely be more accurate than an interview that occurs on the spot. The evaluation of the analytic validity of a family history instrument should involve comparisons with some gold standard, such as can be done with medical records or direct interviews with living relatives. It should also include an assessment of the specific diseases included in the tool, the relationship of the relatives included (first and second-degree) and the settings in which the tool is administered. In our study population of infertile patients 80% of subjects reported significant family history information on a genetic counselor-constructed pedigree that was not captured on a self-reported family history questionnaire. In 5 family history categories with particular relevance to infertility and reproductive risks, the questionnaire missed most (75%) of the information ascertained on the pedigree. Not surprisingly subjects were much more likely to be consistent (85% concordance) in reporting health information that pertained to themselves, rather than to relatives (less than 27% concordance) on the questionnaire. The sensitivity of the questionnaire for eliciting relevant family history information in 5 categories was low, which suggests that the questionnaire failed to capture the vast majority of significant family history information elicited on the pedigree. For patients who indicated on the questionnaire that they do not have a family history of any of the 5 elements, this was
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
NPV (%)
Sensitivity (%)
Specificity (%)
66.7* 100 100
87.2 74.7 81.8
14.3 10.7 30.4
98.8* 100 100
75.0* 100
86.0 77.3
18.8 12.0
98.8* 100
correct most (74% to 87%) of the time, depending on the condition. The questionnaire faired better with respect to positive predictive value suggesting that when subjects report significant information on the questionnaire, this information is likely to be correct compared to the pedigree. Similarly, specificity was found to be high indicating that for patients who have no significant family history in any of the 5 categories, their responses on the questionnaire were accurate. Thus, this study indicates that most significant family history information is not captured on a patient-reported family history questionnaire. Moreover, without accurate family history information, opportunities may be missed for accurate risk assessment, diagnosis and medical management. The importance of thorough family history assessment has been recognized by the American Society for Reproductive Medicine. The Practice Committee recommends that the infertility evaluation begin with thorough medical, social, reproductive and genetic histories on both partners.11 In addition, a thorough pedigree analysis can identify genetic etiologies associated with infertility, inherited disorders and possible modes of inheritance (autosomal dominant, recessive or X-linked dominant, recessive), and forms the basis for recommending appropriate diagnostic testing.2 Thus, information obtained from the pedigree assessment can alter medical management of infertility and influence reproductive decisions. This study represents the first attempt to examine how well this information is being gathered in the
85%
27%
18%
14%
18%
4)
)
n e( de gr ee
5t h
de gr ee 4t h
re la tiv
e(
re la tiv e( n
n
=
=
=
11
22 )
) 83 = n 3r d
de gr ee
re la tiv de gr ee 2n d
1s t
de gr ee
re la tiv
e(
e(
(n
n
=
=
13
44
)
)
0%
/P ar tn er nt Pa tie
PPV (%)
* The pedigree missed 1 report of recurrent SAB and heart defect. Therefore, PPV and specificity for these family history elements are likely to be 100%.
re la tiv
1502
FIG. 2. Degree of relatedness subset analysis comparing questionnaire accuracy with respect to degree of relatedness. Patients are much more accurate when reporting personal history information than information about relatives.
ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY setting of infertility care. It suggests that a carefully devised family history questionnaire is not as effective as a formal pedigree analysis for collecting information related to genetic risk in infertility. Our findings are consistent with previous studies in other medical disciplines that have also identified deficiencies in the use of family history questionnaires. French et al found that significant pedigree obtained information was not identified in 61.5% of questionnaires completed before prenatal genetic counseling.16 Another study found that a questionnaire had a 40% sensitivity for identify genetic risks in a prenatal population, and that a pedigree analysis following administration of the questionnaire identified 50.6% at-risk pedigrees compared to 20% identified by the questionnaire alone.17 Thus, the inability of family history questionnaires to elicit critical information about genetic risk with disease is not specific to infertility. Studies have also identified deficiencies when family history is obtained by physicians rather than genetic counselors and emphasize the need for creative alternatives.18 –20 In primary care and family practice settings, care providers are less likely to elicit, record, discuss or revisit the family history than genetic counselors. In 1 study the average duration of family history discussion was less than 2.5 minutes and in only 11% of patient records was a family tree of some format included in the record.19 Additionally, a study that compared genetic risk assessment by an obstetrician with that of a genetic counselor found that the genetic counselor’s risk assessment identified additional risks for genetic disorders in 38% of prenatal genetic patients.20 Preliminary data from our own institution corroborate these findings. In a previous retrospective study we compared the family history information collected by a urologist during a standard male infertility evaluation with that ascertained through a 4 generation pedigree constructed and assessed by a genetic counselor on 215 patients. We sought to determine what unique information could be garnered through the formal family history that was missed by the standard medical evaluation. The study revealed that the formal pedigree analysis provided unique and informative
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information that could alter medical management in 6.5% of cases. Examples of family history that the pedigree analysis uncovered included autosomal dominant polycystic kidney disease, consanguineous matings, Fragile X syndrome and recurrent spontaneous abortions or neonatal deaths. Thus, in several practice settings physicians themselves routinely miss important genetic risk associated with disease. Although unique to the field of infertility care, this study has limitations. We did not study the effect of order of the 2 methods for collecting family history. In all cases completion of the questionnaire occurred first, followed by pedigree construction, a sequence that could have enhanced recall and information for the pedigree. Another issue is that patients may not understand all of the questions on a questionnaire and may need, but do not necessarily receive, an explanation of what is being asked to understand and comfortably answer questions. Moreover, using a questionnaire in the couple-oriented, infertility setting can be complex, especially if the partner fills out portions of the form for the patient. The relative contribution of the patient’s partner to the ascertainment of patient family history is not well defined, but could represent a significant confounding variable affecting accuracy. Lastly, while a pedigree is considered the gold standard, there were 2 instances in which information was recorded on the questionnaire, but missed on the pedigree. In such instances neither the accuracy of the information nor the source of the error is verifiable. Despite these limitations, these findings ably corroborate those reported in other medical disciplines.
CONCLUSIONS Family history assessment is an important component of the infertility evaluation. Based on a comparison of a self-administered written questionnaire and a formal pedigree analysis, the questionnaire was observed to be much less effective at capturing important information that may effect the reproductive decision of couples with male infertility. As a compromise one could consider offering patients a family history questionnaire that is then verified with a thorough patient interview.
APPENDIX 1 Self-administered family history questionnaire emphasizing infertility and reproductive risk assessment. These questions are a component of a larger general health questionnaire routinely used in practice. GENETIC INFERTILITY SCREENING Do you or your partner have any of the following ancestry? You Asian/Asian American Caucasian Southern European Northern European African/African American Ashkenazi Jewish Cajun/French Canadian Hispanic/Caribbean
yes yes yes yes yes yes yes yes
Partner no no no no no no no no
yes yes yes yes yes yes yes yes
no no no no no no no no
24. If you have children: 24a. Are they healthy? Together A previous partner Your partner/a previous partner yes no yes no yes no 24b. Do they have birth defects, genetic condition or severe medical problems? Together A previous partner Your partner/a previous partner yes no yes no yes no If yes, please describe: _______________________________________________________________________________________________________________________ (appendix continued)
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ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY
APPENDIX 1 continued 24c. Do they have developmental delay, learning disabilities or mental retardation? Together A previous partner Your partner/a previous partner yes no yes no yes no If yes, please describe: _______________________________________________________________________________________________________________________ 25. Do you, your partner or blood relatives have one of the following disorders? You Never began menstruation Early menopause Recurrent miscarriages (3 or more) Stillborn baby or Baby died at less than 1 year old Cystic fibrosis Tay-Sachs or Canavan disease Muscular disorders Neurological disorders
yes yes yes yes yes yes yes yes
Bone/skeletal disorder (e.g. dwarfism) Birth defect (e.g. cleft palate, hip dislocation) Developmental delay, learning disability or mental retardation Polycystic kidney disease Heart defect from birth Down syndrome Sex chromosome abnormality (e.g. Klinefelter/Turner syndrome) Other chromosomal abnormalities Marfan syndrome Bleeding disorders (e.g. hemophilia) Sickle cell anemia, thalassemia Deafness/blindness (at birth or early onset)
Partner no no no no no no no no
yes yes yes yes yes yes yes yes
yes yes yes yes yes yes yes
no no no no no no no
yes yes yes yes yes yes yes
no no no no no no no
Who? _____ _____ _____ _____ _____ _____ _____ _____ Who? _____ _____ _____ _____ _____ _____ _____
yes yes yes yes yes
no no no no no
yes yes yes yes yes
no no no no no
_____ _____ _____ _____ _____
no no no no no no no no
yes yes yes yes yes yes yes yes
yes yes yes yes yes yes yes
no no no no no no no
yes yes yes yes yes
no no no no no
You
Family
Partner
no no no no no no no no Family
26. Are you concerned someone in your or your partners’ family has a genetic condition that puts you or your offspring at risk? _________________________ _________________________________________________________________________________________________________________________________________________
APPENDIX 2 Family History Elements Early menopause Recurrent miscarriages* Stillborn baby* Cystic fibrosis Bones/skeletal disorder Birth defect* Heart defect (congenital)*
6. Bleeding disorder Sex chromosome abnormality Other chromosome abnormality Developmental delay/learning disability/mental retardation* Sickle cell/thalassemia Deafness/blindness (congenital or early onset) Down syndrome
7.
* Family history elements included in subset analysis
8.
Abbreviations and Acronyms MR NPV PPV SAB
⫽ ⫽ ⫽ ⫽
mental retardation negative predictive value positive predictive value spontaneous abortion
REFERENCES Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z and Schlegel PN: Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003; 18: 1660. 2. Turek PJ and Reijo Pera RA: Current and future genetic screening for male infertility. Urol Clin North Am 2002; 29: 767. 3. Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C et al: Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. JAMA 1992; 267: 1794. 4. Costes B, Girodon E, Ghanem N, Flori E, Jardin A, Soufir JC et al: Frequent occurrences of the CFTR intron 8 (TG)n 5T allele in men with congenital bilateral absences of the vas deferens. Eur J Hum Genet 1995; 3: 285. 5. Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S et al: Mutations in the cystic fibrosis gene in patients with
9.
10.
11.
1.
12. 13.
14.
15.
congenital absence of the vas deferens. N Engl J Med 1995; 332: 1475. Dumur V, Gervias R, Rigot JM, Delomel-Vinner E, Decaestecker B, Lafitte JJ et al: Congenital bilateral absence of the vas deferens (CBAVD) and cystic fibrosis transmembrane regulator (CFTR): correlation between genotype and phenotype. Hum Genet 1996; 97: 7. Tung J, Rosen MP, Nelson LM, Turek PJ, Witte JS, Cramer DW et al: Novel missense mutations of the Deleted-inAZoospermia-Like (DAZL) gene in infertile women and men. Reprod Biol Endocrinol 2001; 2: 40. Scheuner MT, Wang SJ, Raffel LJ, Larabell SK and Rotter JI: Family history: a comprehensive genetic risk assessment for the chronic conditions of adulthood. Am J Med Genet 1997; 71: 315. Rose P, Humm E, Hey K, Jones L and Huson SM: Family history taking and genetic counselling in primary care. Fam Pract 1999; 16: 78. Meschede D, Albersmann S and Horst J: The practical importance of pedigree analysis in women considering invasive prenatal diagnosis for advanced maternal age or abnormal serum screening tests. Prenat Diagn 2000; 20: 865. Practice Committee of the American Society for Reproductive Medicine: Information on commonly asked questions about genetic evaluation and counseling for infertile couples. Fertil Steril 2004; 82: S97. Tulandi T and Platt R: The art of taking a history. Fertil Steril 2004; 81: 11. American College of Obstetricians and Gynecologists: Antenatal Diagnosis of Genetic Disorders. Washington, D. C.: ACOG Technical Bulletin No. 188; 1987. United States Department of Health and Human Services: US Surgeon General’s Family Health History Initiative. Available at http://www.hhs.gov/familyhistory/. Accessed April 20, 2006. Yoon PW, Scheuner MT, Peterson-Oehlke KL, Gwinn M, Faucett A and Khoury MJ: Can a family history be used as a tool for public health and preventative medicine? Genetics in Medicine 2002 4: 304.
ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY 16.
French B, Casperson S, Lenke R and Kurczynski T: Questionnaire vs pedigree. Birth Defects 1990; 26: 176. 17. Cohen GM, Cimaroli T, Gould M, Macr CJ, Habecker-Green J and Miller RC: The usefulness of a prenatal genetic questionnaire in genetic risk assessment. Obstet Gynecol 1996; 88: 806. 18. Hayflick SJ, Eiff MP, Carpenter L and Steinberger J: Primary care physician’s utilization and perceptions of genetic services. Genet Med 1998; 1: 13.
19.
20.
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Acheson LS, Wiesner GL, Zyzanski SJ, Goodwin MA and Stange KC: Family history-taking in community family practice: implications for genetic screening. Genet Med 2000; 2: 180. Koscica KL, Canterino JC, Harrigan JT, Dalaya T, Ananth CV and Vintzileos AM: Assessing genetic risk: comparison between the referring obstetrician and genetic counselor. Am J Obstet Gynecol 2001; 185: 1032.
Purpose: For infertile couples family history assessment can add valuable information about genetic infertility and possible risks for offspring. We created a genetic questionnaire for eliciting family history and asked whether it could capture information similar to a pedigree. Materials and Methods: Infertile male patients completed a genetic questionnaire and had a pedigree obtained by a genetic counselor. We assessed the accuracy of the questionnaire to elicit family history information compared to the gold standard pedigree. Results: Of 93 patients 76 (82%) patients indicated relevant genetic information. A comparison of the 2 methods revealed that 61 (80%) patients failed to report key genetic information on the questionnaire that was ascertained by the pedigree. Assessment of 5 relevant family history elements revealed that the questionnaire missed 75% or more of stillbirths, birth defects, developmental delay/learning disabilities/mental retardation, recurrent miscarriages and congenital heart defects. The positive predictive value and the negative predictive value of the questionnaire ranged from 67% to 100% and 74% to 87%, respectively. The sensitivity and specificity of the questionnaire ranged from 12% to 30% and 98% to 100%, respectively. Conclusions: A comprehensive family history questionnaire is not as reliable for capturing relevant, genetic information as a pedigree. The optimal method will become more important as our knowledge of genetic infertility and its implications expands. Key Words: infertility, male; genetics; genetic counseling; reproductive medicine
en with oligospermia (low sperm count) and nonobstructive azoospermia (zero sperm count) have an increased risk for chromosome abnormalities and deletions on the Y chromosome.1,2 The combined risk of detecting these anomalies approaches 10% in oligospermic men and 30% in azoospermic men. For men with congenital absence of the vas deferens there is up to an 80% risk of cystic fibrosis genetic mutations.3– 6 Given that a significant proportion of male infertility, characterized by low or no sperm counts, may have an underlying genetic etiology, a thorough medical and family history is a critical component of the infertility evaluation. In particular, a comprehensive family history can identify genetic etiologies of infertility and also delineate possible inherited risks for offspring.2 This is particularly important as our knowledge of how variations in genetic haplotypes and single gene mutations that can affect infertility increases in the future.7 The pedigree analysis is the standard evaluation tool for family history assessment in genetic counseling. Studies using pedigree analysis in unselected primary care and prenatal patients have observed that additional, previously unidentified genetic risk factors can be revealed in as many as 40% of
M
Submitted for publication July 13, 2007. * Correspondence: Department of Urology, University of California, San Francisco, 1600 Divisadero St, Rm. A633, San Francisco, California 94143-1695 (telephone: 415-353-7352; FAX: 415-8857443; e-mail: [email protected]).
See Editorial on page 1225.
0022-5347/08/1794-1499/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
patients.8 –10 Furthermore, in many instances relevant diagnostic testing is available to further evaluate the genetic risk identified from the pedigree analysis.9,10 Overall, the literature supports the conclusion that personal and family medical history is valuable for genetic risk assessment among infertility patients.11,12 However, the best method of ascertaining this information is controversial, particularly given the costs associated with pedigree analyses by a qualified genetic counselor. This study was performed to ascertain the quality and accuracy of information obtained through patient questionnaire when compared to pedigree analysis. We developed a family history questionnaire based on critical information that would be accrued with a pedigree analysis for use in conjunction with the standard male infertility evaluation.13 The concept of the family history questionnaire was based, in part, on recent national public health initiatives that seek to improve the collection of family history information in the risk assessment, detection and prevention of common diseases.14 The objective of this study was to compare the findings from the family history obtained on the questionnaire with that ascertained by a formal pedigree analysis by a genetic counselor in a cohort of consecutive, male infertility patients. MATERIALS AND METHODS Consecutive adult male patients were referred for infertility evaluation to the University of California, San Francisco Program in the Genetics of Infertility because of oligosper-
1499
Vol. 179, 1499-1505, April 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.11.056
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ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY
mia (less than 10 million sperm per ml) or azoospermia (zero sperm count). All patients underwent an evaluation with a single urologist (PJT) for male factor infertility. Immediately before this appointment patients were asked to complete a family history questionnaire integrated into a general health history intake form. All patients also underwent a 4-generation pedigree constructed by a board certified genetic counselor (KDK) during a genetic counseling session. Because patient data were decoded of all protected health information, a waiver was obtained from the UCSF Committee on Human Research for this study. The questionnaire is based on questions from a standard American College of Obstetrics and Gynecology prenatal genetic screening tool13 and is represented in Appendix 1. The yes-no format includes questions about personal and family history, ethnicity and racial background, as well as genetic reproductive risks. Included in this last section are inquiries regarding family history of chromosomal abnormality, mental retardation, genetic disorders, birth defects, recurrent miscarriages/stillbirths and infant death (less than 1 year), among others. Partially completed questionnaires were included in this analysis and the questions that were unanswered were also recorded. Also, the genetic counselor did have access to the questionnaire during the pedigree analysis. To structure the comparative analysis of questionnaire and pedigree 14 family history elements were created that represented a broad spectrum of conditions that have significant clinical implications for either diagnosis or management of genetic infertility (Appendix 2). Using the pedigree as the gold standard, patient responses to each of the 14 categories on the questionnaire were scored as concordant or discordant. If a patient indicated relevant information on both questionnaire and pedigree, then the response was considered concordant. If a patient failed to indicate relevant family history information on the questionnaire that was reported on the pedigree, then the response was scored as discordant. An unanswered question on the questionnaire that was reported on the pedigree was also graded as discordant. If a condition occurred more than once in the family history, then concordance with each occurrence was scored individually. For example, if a patient failed to indicate on the questionnaire that a family member had 4 stillbirths but this was noted on the pedigree, then this was recorded as 4 discordant responses. Questionnaire responses and pedigree for a single patient are presented in figure 1. Subset analysis was performed to compare data regarding 5 family history elements that have particular relevance to infertility and reproductive risk assessment, namely recurrent miscarriages, congenital heart defects, stillbirth, developmental delay/learning disability and birth defects (table 1). For these outcomes the PPV, NPV, sensitivity and specificity of the questionnaire were ascertained relative to the pedigree. Finally, an additional subset analysis assessed the accuracy of family history reporting on the questionnaire according to the degree of relationship (ie 1st, 2nd, 3rd, 4th, 5th degree relative). RESULTS Family history questionnaires from 105 consecutive male factor infertility cases were retrospectively compared to the pedigree analysis and constitute the study population. Among this
group 93 patients (fully or partially) completed the questionnaire and 12 patients left the questionnaire blank and were excluded from further analysis. Overall 80% of patients failed to report significant family history information on the questionnaire that was obtained by the genetic counselor constructed pedigree. Discordant responses were broadly observed in 10 of 14 family history categories, including recurrent miscarriages (3 or more), stillbirth, baby died less than 1 year old, cystic fibrosis, bone/skeletal disorder, birth defect, developmental delay/learning disability/mental retardation, congenital heart defect, Down syndrome, bleeding disorder and congenital deafness or blindness. In the subset analysis of 5 family history elements with particular relevance to infertility and reproduction, these elements were missed most often on the questionnaire. In particular, questionnaires ascertained less than 25% of recurrent miscarriages, stillborn births, heart defects, birth defects and developmental delay/learning disability/mental retardation issues. The categories of early menopause, sex chromosome abnormality and sickle cell anemia/thalassemia revealed no difference in reporting frequency, although each of these elements was only rarely reported. In the degree of relatedness subset analysis, patients were found to be most accurate when reporting information that pertained to their personal history, with a concordance rate of 85% (fig. 2). However, beyond this the pedigree revealed significantly more information about the couples’ relatives than did the questionnaire. Responses regarding family history on questionnaire matched less than 27% of pedigree information for 1st, 2nd, 3rd and 4th degree relatives. The PPV of the questionnaire for ascertaining family history of stillbirth, developmental delay/mental retardation and birth defect was 100% (table 2). The PPV of the questionnaire for ascertaining family history of recurrent miscarriage and heart defect was calculated to be 67% and 75%, respectively. However, it was noted that the pedigree failed to account for 1 report of recurrent miscarriage and 1 report of heart defect, so the PPV for these family history elements may have been 100%. The range of NPVs for the 5 family history elements was 74% to 87%. Analysis of these 5 family history elements revealed that the questionnaire had a sensitivity of 12% to 30% and a specificity of 98% to 100% (given that the pedigree missed 2 outcomes, specificity is likely 100%). Positive PV, NPV, sensitivity and specificity are summarized in table 2.
DISCUSSION The importance of genetic risk in disease assessment has become increasingly clear. To address this issue the U.S. Department of Health and Human Services, including the Office of the Surgeon General, the National Institutes of Health, the Centers for Disease Control and Prevention as well as other organizations, embarked on a public health initiative in 2004 to generate awareness of the importance of family history information in assessing risk of common diseases and strategies for integrating this information into prevention programs.14 Although the most appropriate method of ascertaining family history information is not known, the initiative explored how this should be investigated and what the results might demonstrate.15
ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY
A
Do you, your partner or blood relatives have one of the following disorders? You Partner Family
Who?
Never began menstruation
yes no
yes no
yes
no _________
Early menopause
yes no
yes no
yes
no _________
no
yes no
yes
no _________
yes
no
yes no
yes
no _________
Cystic fibrosis
yes
no
yes no
yes
no _________
Tay-Sachs or Canavan disease
yes
no
yes no
yes
no _________
Muscular disorders
yes
no
yes no
yes
no _________
Neurological disorders
yes
no
yes no
yes
no _________
Bone/skeletal disorder (e.g.dwarfism) yes
no
yes no
yes
no _________
Birth defect
no
yes no
yes
no _________
Recurrent miscarriages (3 or more) yes
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Stillborn baby or baby died < 1year old
yes
(e.g. cleft palate, hip dislocation) Developmental delay, learning
yes
no
yes no
yes
no _________
Polycystic Kidney disease
yes
no yes no
yes
no _________
Heart defect from birth
yes
no yes no
yes
no _________
Down Syndrome
yes
no
yes
no _________
disability or mental retardation
yes no
Sex chromosome abnormality (e.g. Klinefelter/Turner syndrome)
yes
no yes
no
yes
no _________
Other chromosomal abnormalities
yes
no
yes
no
yes
no _________
Marfan Syndrome
yes
no
yes
no
yes
no _________
Bleeding disorders (e.g.Hemophilia)
yes
no
yes no
yes
no _________
Sickle cell anemia, Thalassemia
yes
no
yes no
yes
no __Aunt___
Deafness /blindness
yes
no
yes no
yes
no _________
(at birth or early onset)
B d. 45 MI
d.71 thyroid Ca
62 club foot
d. newborn
59 Sickle cell anemia
30 Oligospermia
34
d. 67 MI
All 3 stillborn
Trying to conceive for ~ 2yrs
FIG. 1. Representative set responses by patient to questionnaire (A) and genetic counselor constructed pedigree (B). Red arrows in questionnaire and circles in pedigree indicate family history information that was discordant (missed) by questionnaire.
ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY
TABLE 1. Summary of significant family history identified No. Questionnaire
No. Pedigree
2 3 7
12 21 16
10 18 9
3 3
13 22
10 18
18
84
65 (77)
Recurrent SAB Stillborn Developmental delay/learning disabilities/MR Heart defect Birth defect Total pos responses (%)
TABLE 2. PPV, NPV, sensitivity and specificity for 5 key family history elements
No. Missed by Questionnaire
Recurrent SAB Stillbirth Developmental delay/MR Heart defect Birth defect
The setting for the collection of family history information will also affect analytic validity. A take-home questionnaire that will allow individuals to confer with relatives or review family records will likely be more accurate than an interview that occurs on the spot. The evaluation of the analytic validity of a family history instrument should involve comparisons with some gold standard, such as can be done with medical records or direct interviews with living relatives. It should also include an assessment of the specific diseases included in the tool, the relationship of the relatives included (first and second-degree) and the settings in which the tool is administered. In our study population of infertile patients 80% of subjects reported significant family history information on a genetic counselor-constructed pedigree that was not captured on a self-reported family history questionnaire. In 5 family history categories with particular relevance to infertility and reproductive risks, the questionnaire missed most (75%) of the information ascertained on the pedigree. Not surprisingly subjects were much more likely to be consistent (85% concordance) in reporting health information that pertained to themselves, rather than to relatives (less than 27% concordance) on the questionnaire. The sensitivity of the questionnaire for eliciting relevant family history information in 5 categories was low, which suggests that the questionnaire failed to capture the vast majority of significant family history information elicited on the pedigree. For patients who indicated on the questionnaire that they do not have a family history of any of the 5 elements, this was
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
NPV (%)
Sensitivity (%)
Specificity (%)
66.7* 100 100
87.2 74.7 81.8
14.3 10.7 30.4
98.8* 100 100
75.0* 100
86.0 77.3
18.8 12.0
98.8* 100
correct most (74% to 87%) of the time, depending on the condition. The questionnaire faired better with respect to positive predictive value suggesting that when subjects report significant information on the questionnaire, this information is likely to be correct compared to the pedigree. Similarly, specificity was found to be high indicating that for patients who have no significant family history in any of the 5 categories, their responses on the questionnaire were accurate. Thus, this study indicates that most significant family history information is not captured on a patient-reported family history questionnaire. Moreover, without accurate family history information, opportunities may be missed for accurate risk assessment, diagnosis and medical management. The importance of thorough family history assessment has been recognized by the American Society for Reproductive Medicine. The Practice Committee recommends that the infertility evaluation begin with thorough medical, social, reproductive and genetic histories on both partners.11 In addition, a thorough pedigree analysis can identify genetic etiologies associated with infertility, inherited disorders and possible modes of inheritance (autosomal dominant, recessive or X-linked dominant, recessive), and forms the basis for recommending appropriate diagnostic testing.2 Thus, information obtained from the pedigree assessment can alter medical management of infertility and influence reproductive decisions. This study represents the first attempt to examine how well this information is being gathered in the
85%
27%
18%
14%
18%
4)
)
n e( de gr ee
5t h
de gr ee 4t h
re la tiv
e(
re la tiv e( n
n
=
=
=
11
22 )
) 83 = n 3r d
de gr ee
re la tiv de gr ee 2n d
1s t
de gr ee
re la tiv
e(
e(
(n
n
=
=
13
44
)
)
0%
/P ar tn er nt Pa tie
PPV (%)
* The pedigree missed 1 report of recurrent SAB and heart defect. Therefore, PPV and specificity for these family history elements are likely to be 100%.
re la tiv
1502
FIG. 2. Degree of relatedness subset analysis comparing questionnaire accuracy with respect to degree of relatedness. Patients are much more accurate when reporting personal history information than information about relatives.
ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY setting of infertility care. It suggests that a carefully devised family history questionnaire is not as effective as a formal pedigree analysis for collecting information related to genetic risk in infertility. Our findings are consistent with previous studies in other medical disciplines that have also identified deficiencies in the use of family history questionnaires. French et al found that significant pedigree obtained information was not identified in 61.5% of questionnaires completed before prenatal genetic counseling.16 Another study found that a questionnaire had a 40% sensitivity for identify genetic risks in a prenatal population, and that a pedigree analysis following administration of the questionnaire identified 50.6% at-risk pedigrees compared to 20% identified by the questionnaire alone.17 Thus, the inability of family history questionnaires to elicit critical information about genetic risk with disease is not specific to infertility. Studies have also identified deficiencies when family history is obtained by physicians rather than genetic counselors and emphasize the need for creative alternatives.18 –20 In primary care and family practice settings, care providers are less likely to elicit, record, discuss or revisit the family history than genetic counselors. In 1 study the average duration of family history discussion was less than 2.5 minutes and in only 11% of patient records was a family tree of some format included in the record.19 Additionally, a study that compared genetic risk assessment by an obstetrician with that of a genetic counselor found that the genetic counselor’s risk assessment identified additional risks for genetic disorders in 38% of prenatal genetic patients.20 Preliminary data from our own institution corroborate these findings. In a previous retrospective study we compared the family history information collected by a urologist during a standard male infertility evaluation with that ascertained through a 4 generation pedigree constructed and assessed by a genetic counselor on 215 patients. We sought to determine what unique information could be garnered through the formal family history that was missed by the standard medical evaluation. The study revealed that the formal pedigree analysis provided unique and informative
1503
information that could alter medical management in 6.5% of cases. Examples of family history that the pedigree analysis uncovered included autosomal dominant polycystic kidney disease, consanguineous matings, Fragile X syndrome and recurrent spontaneous abortions or neonatal deaths. Thus, in several practice settings physicians themselves routinely miss important genetic risk associated with disease. Although unique to the field of infertility care, this study has limitations. We did not study the effect of order of the 2 methods for collecting family history. In all cases completion of the questionnaire occurred first, followed by pedigree construction, a sequence that could have enhanced recall and information for the pedigree. Another issue is that patients may not understand all of the questions on a questionnaire and may need, but do not necessarily receive, an explanation of what is being asked to understand and comfortably answer questions. Moreover, using a questionnaire in the couple-oriented, infertility setting can be complex, especially if the partner fills out portions of the form for the patient. The relative contribution of the patient’s partner to the ascertainment of patient family history is not well defined, but could represent a significant confounding variable affecting accuracy. Lastly, while a pedigree is considered the gold standard, there were 2 instances in which information was recorded on the questionnaire, but missed on the pedigree. In such instances neither the accuracy of the information nor the source of the error is verifiable. Despite these limitations, these findings ably corroborate those reported in other medical disciplines.
CONCLUSIONS Family history assessment is an important component of the infertility evaluation. Based on a comparison of a self-administered written questionnaire and a formal pedigree analysis, the questionnaire was observed to be much less effective at capturing important information that may effect the reproductive decision of couples with male infertility. As a compromise one could consider offering patients a family history questionnaire that is then verified with a thorough patient interview.
APPENDIX 1 Self-administered family history questionnaire emphasizing infertility and reproductive risk assessment. These questions are a component of a larger general health questionnaire routinely used in practice. GENETIC INFERTILITY SCREENING Do you or your partner have any of the following ancestry? You Asian/Asian American Caucasian Southern European Northern European African/African American Ashkenazi Jewish Cajun/French Canadian Hispanic/Caribbean
yes yes yes yes yes yes yes yes
Partner no no no no no no no no
yes yes yes yes yes yes yes yes
no no no no no no no no
24. If you have children: 24a. Are they healthy? Together A previous partner Your partner/a previous partner yes no yes no yes no 24b. Do they have birth defects, genetic condition or severe medical problems? Together A previous partner Your partner/a previous partner yes no yes no yes no If yes, please describe: _______________________________________________________________________________________________________________________ (appendix continued)
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ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY
APPENDIX 1 continued 24c. Do they have developmental delay, learning disabilities or mental retardation? Together A previous partner Your partner/a previous partner yes no yes no yes no If yes, please describe: _______________________________________________________________________________________________________________________ 25. Do you, your partner or blood relatives have one of the following disorders? You Never began menstruation Early menopause Recurrent miscarriages (3 or more) Stillborn baby or Baby died at less than 1 year old Cystic fibrosis Tay-Sachs or Canavan disease Muscular disorders Neurological disorders
yes yes yes yes yes yes yes yes
Bone/skeletal disorder (e.g. dwarfism) Birth defect (e.g. cleft palate, hip dislocation) Developmental delay, learning disability or mental retardation Polycystic kidney disease Heart defect from birth Down syndrome Sex chromosome abnormality (e.g. Klinefelter/Turner syndrome) Other chromosomal abnormalities Marfan syndrome Bleeding disorders (e.g. hemophilia) Sickle cell anemia, thalassemia Deafness/blindness (at birth or early onset)
Partner no no no no no no no no
yes yes yes yes yes yes yes yes
yes yes yes yes yes yes yes
no no no no no no no
yes yes yes yes yes yes yes
no no no no no no no
Who? _____ _____ _____ _____ _____ _____ _____ _____ Who? _____ _____ _____ _____ _____ _____ _____
yes yes yes yes yes
no no no no no
yes yes yes yes yes
no no no no no
_____ _____ _____ _____ _____
no no no no no no no no
yes yes yes yes yes yes yes yes
yes yes yes yes yes yes yes
no no no no no no no
yes yes yes yes yes
no no no no no
You
Family
Partner
no no no no no no no no Family
26. Are you concerned someone in your or your partners’ family has a genetic condition that puts you or your offspring at risk? _________________________ _________________________________________________________________________________________________________________________________________________
APPENDIX 2 Family History Elements Early menopause Recurrent miscarriages* Stillborn baby* Cystic fibrosis Bones/skeletal disorder Birth defect* Heart defect (congenital)*
6. Bleeding disorder Sex chromosome abnormality Other chromosome abnormality Developmental delay/learning disability/mental retardation* Sickle cell/thalassemia Deafness/blindness (congenital or early onset) Down syndrome
7.
* Family history elements included in subset analysis
8.
Abbreviations and Acronyms MR NPV PPV SAB
⫽ ⫽ ⫽ ⫽
mental retardation negative predictive value positive predictive value spontaneous abortion
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ACCURACY OF GENETIC QUESTIONNAIRE FOR MALE INFERTILITY 16.
French B, Casperson S, Lenke R and Kurczynski T: Questionnaire vs pedigree. Birth Defects 1990; 26: 176. 17. Cohen GM, Cimaroli T, Gould M, Macr CJ, Habecker-Green J and Miller RC: The usefulness of a prenatal genetic questionnaire in genetic risk assessment. Obstet Gynecol 1996; 88: 806. 18. Hayflick SJ, Eiff MP, Carpenter L and Steinberger J: Primary care physician’s utilization and perceptions of genetic services. Genet Med 1998; 1: 13.
19.
20.
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Acheson LS, Wiesner GL, Zyzanski SJ, Goodwin MA and Stange KC: Family history-taking in community family practice: implications for genetic screening. Genet Med 2000; 2: 180. Koscica KL, Canterino JC, Harrigan JT, Dalaya T, Ananth CV and Vintzileos AM: Assessing genetic risk: comparison between the referring obstetrician and genetic counselor. Am J Obstet Gynecol 2001; 185: 1032.