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(Stroke. 2000;31:1076.)
© 2000 American Heart Association, Inc.

Original Contributions

Verifying the Stroke-Free Phenotype by Structured Telephone Interview

James F. Meschia, MD; Thomas G. Brott, MD; Felix E. Chukwudelunzu, MD; John Hardy, PhD; Robert D. Brown, Jr, MD; Irene Meissner, MD; Linda J. Hall, CCRC; Elizabeth J. Atkinson, MS Peter C. O’Brien, PhD

From the Department of Neurology (J.F.M., T.G.B., F.E.C.), the Section of Pharmacology (J.H.), and the Clinical Studies Unit (L.J.H.), Mayo Clinic Jacksonville, Jacksonville, Fla; and the Department of Neurology (R.D.B., I.M.) and the Section of Biostatistics (E.J.A., P.C.O.), Mayo Clinic and Mayo Foundation, Rochester, Minn.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—Case-control, cohort, and twin studies support a genetic contribution to ischemic stroke risk. Sibling pair linkage methods require identification of concordant or discordant siblings or both. We designed and tested a structured telephone interview to verify the stroke-free phenotype.

Methods—A coordinator unaware of medical record data used an 8-item questionnaire to conduct a structured telephone interview of 70 outpatients aged >60 years. The questionnaire inquired about the sudden onset of deficits in strength, sensation, vision, and language. A subject was defined as stroke free by interview if responses to all items on the questionnaire were negative. Results of the telephone interview were compared with data obtained from a systematic medical record review (benchmark).

Results—Interview time was 5 minutes or less for all subjects. All subjects who began the interview completed it. Records were reviewed in all subjects. Medical record review detected ischemic stroke or transient ischemic attack (TIA), or both, in 5 patients (7%). There were no significant differences in sex distribution or risk factor rates in patients who were designated stroke free or not stroke free by interview. Having 1 or more positive items on the questionnaire was significantly associated with finding stroke (P<0.001), TIA (P<0.001), or either stroke or TIA (P<0.001), on medical record review. The telephone interview had a sensitivity of 1.0 (95% CI 0.48 to 1.0), specificity of 0.86 (95% CI 0.75 to 0.93), positive predictive value of 0.36 (95% CI 0.13 to 0.65), and negative predictive value of 1.0 (95% CI 0.94 to 1.0).

Conclusions—Our instrument can identify the stroke-free individual with a high degree of confidence in a very efficient manner. It may be particularly suited for centralized verification of stroke discordancy in multicentered sib-pair genetic studies.

Key Words: cerebral ischemia, transient • linkage (genetics) • questionnaires • stroke, ischemic

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Observational studies support a genetic component to the risk of development of an ischemic stroke. A Finnish cohort study¹ of 14 371 middle-aged men and women demonstrated a significant association of stroke with a positive parental history. The Family Heart Study assessed personal and family histories of stroke in 3168 probands and 29 325 first-degree relatives, and associations were found between risk of stroke and positive maternal, paternal, and familial histories.² Many observational studies do not distinguish between ischemic and hemorrhagic stroke. In the Framingham Heart Study, however, the distinction was made, and a strong association was found between ischemic stroke in siblings and ischemic stroke in cohort members (relative risk 3.4; 95% CI 1.4 to 8.2; P<0.01).³ Twin studies also support a genetic susceptibility to ischemic stroke. In a study of >9 000 twins, proband concordance rates for stroke were 17.7% for monozygotic pairs and 3.6% for dizygotic pairs (relative risk 4.3; P<0.05).⁴ Ischemic stroke is most likely a complex genetic disorder in which environmental factors interact with host genetics to produce an overall host risk. Risk for the development of ischemic stroke may be influenced by several genes and elements that regulate gene expression.

Sibling pair linkage studies can screen for chromosomal regions of interest that correlate with risk of acquiring a complex disorder.^{5 6 7 8} The method is being applied to diverse neurological and nonneurological disorders.^{9 10 11 12} Linkage studies can be done with concordant or discordant sibling pairs or a combination of the two. Methods have been developed for the use of discordant sibling pairs for linkage studies of both qualitative¹³ and quantitative¹⁴ traits. For quantitative traits, extreme discordant sibling pairs are often the preferred study subjects.¹⁵ It may not always be possible to know the most statistically powerful sibling pair collection strategy at the onset of a study.¹⁶ Regardless of the strategy of sibling pair collection, the success of a linkage study depends on accurate phenotyping of all siblings. No standard method currently exists for verifying the stroke-free phenotype. We developed a structured telephone interview as a practical means of verifying the stroke-free phenotype and tested the validity of our method by comparing findings on the interview with a review of medical records.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The subjects were male and female outpatients aged >60 years who contacted the clinical studies unit at our institution and stated that they would be willing to participate in the study. The study was advertised in the volunteers office and in a periodical that lists trials in progress. Nursing home residents, nonclinic patients, and historians deemed potentially unreliable by the clinical coordinator were excluded from the study. All physician investigators who helped design the questionnaire for verifying stroke-free status (QVSFS) were neurologists with subspecialty interest in cerebrovascular diseases. The final version is shown in Table 1. Items 1 and 2 of the QVSFS review medical history, and items 3 through 8 review previous symptoms. The review of previous symptoms was written to emphasize that cerebrovascular symptoms are typically sudden, focal, and painless. Potential synonyms were used in items 2 and 4 to promote inclusion of patients who might describe their symptoms in nonstandard ways. A subject was defined as having the stroke-free phenotype if all 8 items on the questionnaire were answered negatively. A clinical coordinator who was unaware of the medical record data conducted a structured telephone interview using the QVSFS. The interviewer was a Certified Clinical Research Coordinator with 5 years of experience in clinical investigations both within and outside the neurosciences. QVSFS items were read aloud exactly as written and in numerical order. Clarification of the meaning of questionnaire items was permitted.

View this table: [in this window] [in a new window]   Table 1. The Questionnaire for Verifying Stroke-Free Status

General history and physical examination notes, neurology consultation notes, and radiology reports of CT scans and MRI of the head were obtained by a computerized medical record retrieval system and were reviewed without prior knowledge of the results of the structured telephone interview. The same physician reviewed all of the medical records. We did not include review of secondary reports of radiographic findings, such as entries at the end of admission notes, because of concerns that result reporting is likely to be partial and directed at the presenting complaint. Data obtained from the telephone interview and medical record review were recorded on standardized case report forms. Confidence intervals were calculated by the exact method, which relates binomial probabilities to tail areas of the beta distribution.¹⁷ Characteristics of subjects who were stroke free (all QVSFS items negative) and not stroke free (at least 1 QVSFS item positive) were compared by use of the ² test. Age was compared with the t test. The governing Institutional Review Board approved the protocol before the study began.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The structured telephone interview was held with 70 subjects. Medical records were reviewed in every case. The telephone interview took 5 minutes or less to administer in every instance. No subject was deemed unreliable or had the interview terminated prematurely. Negative response rates for questionnaire items ranged from 91.4% to 100%. The item most frequently answered positively was item 8, which inquired about loss of ability to express oneself orally or in writing. Items required clarification from the clinical coordinator in 0% to 7.2% of the interviews. Item 8 required clarification most commonly, but the differences in rates at which items required clarifications were not significant.

The average age of the subjects was 72.6±6.7 years, and 39 (56%) were female. One, 2, and 3 risk factors were present in 32.9%, 12.9%, and 10.0% of subjects, respectively. Hypertension was the most common risk factor (present in 47.1%). Four subjects (5.7%) had ischemic strokes, 3 (4.3%) had a transient ischemic attack (TIA), and 5 (7.1%) had either an ischemic stroke or a TIA. At least 1 noncerebrovascular neurological diagnosis was identified in 16 subjects (23%). These diagnoses included both peripheral and central nervous system conditions. There were 5 false-positive results overall (ie, neither stroke nor TIA was found on record review, but the subjects had 1 or more positive items on the QVSFS). Each of the 5 subjects had an alternative diagnosis on record review: simple partial seizures and ulnar neuropathy, optic neuritis, lumbar radiculopathy, complex partial seizures, or essential tremor and carpal tunnel. Radiological reports of head imaging were available and reviewed for 14 subjects (20%), MRI reports for 12 (17%), and CT reports for 3 (4.3%). The interval from performance of the imaging study to administration of the structured telephone interview was 935±657 days (median 855; range 82 to 2289). The average age of the subjects at the time of imaging was 72.1±7.3 years. Evidence of previous cerebral infarction was seen in none of the CT scans and in 1 of 13 MRI scans (8%). Nonspecific white matter hyperintensities were noted in 7 of 13 MRI scans (54%).

Every patient who had a TIA or stroke by record review reported at least 1 positive item on the QVSFS (Table 2). None of 56 subjects responding negatively to all QVSFS items had stroke or TIA by record review, and 5 of 14 (36%) responding positively to 1 or more items had stroke or TIA by record review. Having 1 or more positive items on the QVSFS was significantly associated with finding stroke (P<0.001), TIA (P<0.001), or either stroke or TIA (P<0.001) on medical record review. There was a nonsignificant trend toward greater age in subjects with a positive QVSFS (P=0.062). There were no significant differences in sex distribution or risk factor rates in the 2 groups. When data abstracted from medical records were accepted as definitive, the telephone interview had a sensitivity of 1.0 (95% CI 0.48 to 1.0). Sensitivity in this context refers to the conditional probability that a subject with a positive medical history of stroke or TIA will answer positively on 1 or more questionnaire items. The instrument had a specificity of 0.86 (0.75 to 0.93), positive predictive value of 0.36 (0.13 to 0.65), and negative predictive value of 1.0 (0.94 to 1.00; Table 3). If only the 2 medical history items in the QVSFS were used, the telephone interview had a sensitivity of 1.0 (95% CI 0.48 to 1.0), specificity of 0.97 (0.89 to 1.0), positive predictive value of 0.71 (0.29 to 0.96), and negative predictive value of 1.0 (0.94 to 1.0). If only the 6 review-of-symptoms items in the QVSFS were used, the telephone interview had a sensitivity of 1.0 (95% CI 0.48 to 1.0), specificity of 0.88 (0.77 to 0.95), positive predictive value of 0.38 (0.14 to 0.68), and negative predictive value of 1.0 (0.94 to 1.0).

View this table: [in this window] [in a new window]   Table 2. Characteristics Found by Medical Record Review of Subjects Who Were Stroke Free (All QVSFS Items Negative) or Not Stroke Free (1 Item Positive) by Telephone Interview

View this table: [in this window] [in a new window]   Table 3. Comparison of All Items of the QVSFS With Record Review

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our pilot study demonstrates that a structured telephone interview using the QVSFS may be a practical and reliable means of verifying that a subject has not had a stroke or TIA. The QVSFS was designed to be sensitive in detecting stroke or TIA, so that the telephone interview has a high probability of properly classifying stroke-free subjects. When the subjects responded negatively to all items, the QVSFS also had a high negative predictive value, but this result may reflect the low prevalence of stroke in the study population. One cannot conclude with a high degree of certainty that a subject had a stroke or TIA because 1 or more items were positive. The QVSFS should not be used to determine which study subjects had a stroke. The review-of-symptoms items on the QVSFS were not designed to differentiate stroke from TIA. To do so would have demanded that the interviewee recall the duration of symptoms. We emphasized in the review-of-symptoms items that a stroke deficit is typically sudden, focal, and painless. Many patients in our study who had non–stroke-related neurological conditions and did not have a cerebrovascular history answered negatively to all the review-of-symptoms items. Our data suggest that the review-of-symptoms items were not able to differentiate stroke from noncerebrovascular sudden, focal conditions such as postictal paralysis and optic neuritis. To keep the questionnaire efficient to administer, many stroke symptoms were intentionally omitted. We emphasized visual and motor symptoms to efficiently screen for a wide variety of stroke syndromes. The primary visual pathway and the corticospinal pathway are roughly orthogonal; therefore, anatomically diverse stroke lesions are screened effectively by questionnaire items that inquire about weakness and visual deficit. It is not necessary for a questionnaire defining the stroke-free phenotype to capture all stroke symptoms so long as at least 1 symptom is found in each subject. For example, a patient with the Weber syndrome will have a symptom not covered by our questionnaire (diplopia) but would probably not be classified as stroke-free because of coexistent hemiparesis.

We looked at the performance characteristics of the QVSFS as a whole and also at the performance characteristics of the medical history and review-of-symptoms items separately. Our pilot study was not able to demonstrate that the review-of-symptoms items added to the ability of the medical history items to verify the stroke-free phenotype. Were the interview to be conducted in a population with less access to health care, we suspect that the review-of-symptoms questions would be able to detect patients with stroke who would otherwise not be detected by the medical history questions. Follow-up studies should be done in a population with a wide range of socioeconomic statuses.

We used medical record review as a benchmark for determining whether a patient ever had a stroke or TIA. However, use of the QVSFS might surpass medical record review as the standard means for verifying the absence of stroke or TIA in different clinical circumstances. Potentially discordant siblings might not have seen a physician for years, or the outside medical records available for review might be incomplete. For example, the general practice record review system used in the British Regional Heart Study tended to underreport events rather than overreport them (false-positive rate, 5%; false-negative rate, 23%).¹⁸ In our study, we needed to use a convenience sample of patients who regularly seek care at our institution to increase the validity of record review as a definitive measurement. Our pilot study, which used systematic medical record review as a benchmark, suggests that our instrument may be a valid and practical means of verifying the stroke-free phenotype. However, a protocol-mandated history and physical examination may be a better clinical benchmark of whether a study subject had a stroke than systematic medical review. We believe that there would be value in conducting a larger confirmatory study of the QVSFS in a separate population using as a benchmark a history and physical examination done contemporaneously with, but independent of, a structured interview.

An alternative approach to verifying the stroke-free phenotype would be to define the stroke-free phenotype by the lack of findings on brain imaging. However, an imaging approach has several potential limitations. Although MRI is typically more sensitive for detecting ischemic stroke than CT, neither modality is 100% sensitive.¹⁹ Requiring a subject to have normal MRI findings to be classified as stroke-free may be placing an unnecessarily stringent enrollment criterion on potential study subjects and may introduce bias. Our data show that subjects who respond negatively to all items on the QVSFS can have nonspecific signal abnormalities on MRI. Other investigators have also found that white matter hyperintensities on MRI can have no clinical correlation.^{20 21} Mandating normal findings on brain MRI in all discordant siblings would also greatly increase the study cost per sibling pair and the logistic complexity of verifying stroke discordancy.

A potentially efficient method for collecting sibling pairs concordant and discordant for ischemic stroke would be to have multiple clinical centers screening probands. We anticipate that discordant siblings of probands collected at multiple clinical centers would be geographically dispersed. Such discordant siblings may not live near a study center, and face-to-face examination of potentially discordant siblings may not be practical. The structured telephone interview using the QVSFS described here allows for rapid centralized verification of discordancy by a clinical coordinator. When the instrument is administered, there will be patients in the diagnostic gray zone who are not stroke free but who do not have a definite stroke. Such persons should not be included in a sibling pair linkage study. We recommend that a positive diagnosis of stroke be made either by examination or by record review. The rate-limiting step in recruitment of subjects in a sibling pair study in ischemic stroke is recruitment of concordant sibling pairs rather than recruitment of discordant sibling pairs. Therefore, our instrument is not expected to curtail recruitment of subjects despite the high false-positive rate.

Our instrument was tested in a convenience sample of older adults who receive routine medical care in our system. The instrument was not tested in a population of siblings of probands with stroke. Siblings of stroke patients may be biased for or against reporting symptoms. We suspect, however, that siblings of stroke patients would be more likely to recognize and report stroke symptoms than siblings who lack a family history of stroke. Therefore, if such a bias exists, it would tend to underestimate the sensitivity of the QVSFS.

An alternative way to verify the stroke-free phenotype would be to use the TIA/stroke questionnaire developed for the Asymptomatic Carotid Atherosclerosis Study (ACAS).²² It has measured sensitivity, specificity, positive predictive value, and negative predictive values of 0.88, 0.72, 0.77, and 0.85, respectively. Among items addressing 6 main symptoms, the TIA/stroke questionnaire’s most sensitive item inquires about speech and most specific item about numbness. The QVSFS also inquires about these items but with slightly modified wording. The TIA/stroke questionnaire and the QVSFS have a comparable specificity, but the 2 instruments have very different structures because they were designed for different purposes. The TIA/stroke questionnaire uses confirmatory questions when symptoms are first reported as present.²³ The TIA/stroke questionnaire also provides localizing information, something the QVSFS was not designed to do. We anticipate that genetic risk factors are independent of stroke location, either by cerebrovascular territory or by laterality. The added information obtained from the TIA/stroke questionnaire comes at the expense of ease of administration. Interviewers who administered the TIA/stroke questionnaire in both the ACAS and the Atherosclerosis Risk in Communities Study required extensive training and certification.^{22 23} The interviewer who administered the QVSFS in this study did not undergo formal certification. The average administration time for the TIA/stroke questionnaire has not been reported, but the QVSFS took 5 minutes or less to administer in all cases. This brief time is not likely to be regarded by study subjects as intrusive. By minimizing the burden of verifying stroke-free status, we hope to maximize the chance that verified subjects will consent to providing material for genetic analysis.

	Acknowledgments

 
Supported by the Mayo Foundation for Medical Education and Research. Dr Meschia was supported in part by the Robert and Clarice Smith Fellowship. We thank Mr Kenneth Offord for suggestions regarding the questionnaire for verifying stroke-free status.

	Footnotes

 
Reprint requests to James F. Meschia, MD, Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224.

Received January 12, 2000; revision received January 12, 2000; accepted February 16, 2000.

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