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INTERPRETING MEDICAL TESTS AND OUTCOMES

INTERPRETING MEDICAL TESTS AND OUTCOMES. SESSION 8: FEBRUARY 27, 2006 SESSION PRODUCER: Denise Liston, Vice-President Underwriting Products & Services LifePlans, Inc. Our Panelists. Dr. Robert Watson, Allianz Life Dr. Bruce Margolis, Genworth Financial. White Matter Lesions.

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INTERPRETING MEDICAL TESTS AND OUTCOMES

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  1. INTERPRETING MEDICAL TESTS AND OUTCOMES SESSION 8: FEBRUARY 27, 2006 SESSION PRODUCER: Denise Liston, Vice-President Underwriting Products & Services LifePlans, Inc.

  2. Our Panelists • Dr. Robert Watson, Allianz Life • Dr. Bruce Margolis, Genworth Financial

  3. White Matter Lesions Robert Watson, MD, FLMI Vice President & Chief Medical Director Allianz Life

  4. A 58 yo F with an MRI report in her APS Reason for MRI: “Change in headaches” MRI sequences performed: Sagittal T1-weighted, axial T-2 weighted, axial FLAIR, axial DWI, sagittal FLAIR. The radiologist’s interpretation: “There are a few small areas of hyperintense T2 signals in the periventricular and subcortical white matters (sic) bilaterally. They are nonspecific in etiology. Differential dx includes demyelinating disease, vasculitis, chronic small vessel ischemic disease, inflammatory or infectious disease such as Lyme disease, or post-traumatic changes. Correlation with the patient’s clinical history is suggested.”

  5. Those things in the brain…. • White matter lesions (WML) • White matter hyperintensities (WMH) • White matter changes (WMC) • Small vessel disease • Small vessel ischemic changes • Chronic small vessel ischemic disease • Subcortical atherosclerotic changes • Unidentified bright objects (UBOs) • Leukoaraiosis (CT scan)

  6. THE FEMALE BRAIN

  7. WML Talk Objectives • What they are & what causes them • Importance of grading & location • Associated stroke risk • Associated dementia risk • Combination with infarcts and/or cerebral atrophy • Migraines & WML • Underwriting the risk

  8. What they are & what causes them • Pathology • Demyelination & glial rarefaction … as opposed to the scar tissue (gliosis) & cavitation seen with strokes. • Causation • ischemic demyelination • “hyaline arteriosclerosis” (hyaline wall thickening of the small arterioles)

  9. What they are & what causes them (cont.) 2 major risk factors • Hypertension • Increasing age

  10. What they are & what causes them(cont.) The variables of blood pressure strongly associated with WML risk • Hypertension presence • Hypertension duration • Adequacy of control with Rx de Leeuw FE et al. The Rotterdam Study. Brain. 2002;125:765-72.

  11. What they are & what causes them(cont.) A random sample of 1920 participants aged 55 72. Prevalence & grade according to hypertension present or not. BP statusmild WMLmod WMLsevere WML Normotensives 53% 24% 7.6% Hypertensives - Rx, goodcontrol 49% 22% 14% - Rx, w/o control 39% 23% 24% Liao D et al. Atherosclerosis Risk in Communities Study (ARIC). Stroke. 1996;27:2262-2270.

  12. What they are & what causes them(cont.) Subjects with a negative hx of hypertension Age severe WML 60-70 7.4% 70-80 16.7% 80-90 47.4% de Leeuw FE et al. The Rotterdam Scan Study. Brain. 2002;125:765-72.

  13. What they are & what causes them(cont.) Other causes • ApoE e4 (subcortical WML) • Other as yet unidentified genetic factors • Severe COPD with hypoxemia de Leeuw FE et al. The Rotterdam Scan Study. Brain. 2002;125:765-72.

  14. What they are & what causes them(cont.) • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) • Binswanger’s disease (syndrome of WML & dementia)

  15. What they are & what causes them(cont.) Other cardiac risk factors? • DM: • No. • Lipids: • No. • Smoking: • Yes, but only in African Americans. (ARIC study) • No. Worsens it if already present, doesn’t cause it. (Cardiovascular Health Study) • Nope. (Rotterdam Scan Study)

  16. A Simple Desultory Philippic High quality (at least somewhat credible) WML studies: The Rotterdam Scan Study The Cardiovascular Health Study The Atherosclerosis Risk in Communities (ARIC) Study Large, community-based populations, prospective, multivariate-controlled, longitudinal with medium to long-term follow-up, published in journals with documented high journalistic quality standards.

  17. A Simple Desultory Philippic (cont.) • Regarding the interpretation of findings in the • medical literature: • Most medical studies published in the world • literature are flawed in numerous ways -- • due to major study design problems such as • selection bias and ascertainment bias -- and • their findings are unreliable. • Most “new” medical findings published in • the medical literature will eventually be • proven to be false.

  18. A Simple Desultory Philippic (cont.) When a medical study shows a dramatic “new” result that was unknown and unexpected prior to the publication of that new study…. ….the likelihood of this finding representing a true fact more often than not goes from being “highly improbable” up to “improbable.”

  19. A Simple Desultory Philippic (cont.) Regarding the interpretation of a medical test, a general rule of thumb applicable to most: When the “pretest” probability of a certain condition being present is low, a positive test result does not usually raise that level of probability to the range of “high.”

  20. Carbohydrate Deficient Transferrin (CDT) Test Interpretation: An Example of Truth vs. Illusion - 99 - 90 - 80 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 5 - 2 - 1 - 0.5 - 0.2 - 0.1 0.1 - 0.2 - 0.5 - 1 - 2 - 5 - 10 - 20 - 30 - 40 - 50 - 60 - 70 - 80 - 90 - 99 - % % 1000 - 500 - 200 - 100 - 50 - 20 - 10 - 5 - 1- illusory +test line - 0.5 - 0.2 - 0.1 - 0.05 - 0 .02 - 0 .01 - 0 005 - 0.002 - 0.001 true +test line Post-test probability Pre-test probability Likelihood ratio

  21. WML Severity & Location

  22. WML grading 1-9 (ARIC Study) grade 0: no white matter findings grade 1: discontinuous periventricular rim with minimal dots of subcortical disease grade 2: thin, continuous periventricular rim with a few patches of subcortical disease grade 3: thicker, continuous periventricular rim with scattered patches of subcortical disease grade 4: thicker, shaggier periventricular rim with mild subcortical disease, may have minimal confluent periventricular lesions

  23. WML grading 1-9 (cont.) grade 5: mild periventricular confluence surrounding the frontal and occipital horns grade 6: moderate periventricular confluence surrounding the frontal and occipital horns grade 7: periventricular confluence with moderate involvement of the centrum semiovale grade 8: periventricular confluence involving most of the centrum semiovale grade 9: findings more remarkable than grade 8

  24. WML grading (cont.) 1 2 3 4 1 5 6 7 8 Liao D et al. Atherosclerosis Risk in Communities Study, Stroke. 1996;27:2262-70.

  25. WML grading (cont.) ARIC Study grade 1 = mild grade 2 = moderate grade 3-9 = severe Rotterdam Scan Study Subcortical: graded in tertiles by volume Periventricular: grade 0-1 = mild grade 1.5-3.0 = moderate grade 3.5-9.0 = severe

  26. 2 main WML risks • Stroke risk • Cognitive decline risk

  27. WML & Stroke Risk

  28. WML & stroke RR in the elderly 3973 CHS participants, mean age 75, mean 7-yr. FU. Controlled for age, gender, race, SBP, DM, CVD, AF, infarct(s) on MRI, LVH, creat., carotid wall thickness. WML gradeStroke RRIncidence 0 or 1 1.0 0.6%/yr. 2 1.4 0.9%/yr. 3 2.4 1.7%/yr. 4 3.7 2.8%/yr. > 5 2.7 2.6%/yr. Kuller LH et al. Cardiovascular Health Study. Stroke. 2004;35(8):1821-5.

  29. WML & symptomatic stroke risk Mean age 72; multivariate controlled; mean 4.2-yr. follow-up LocationStroke RR Subcortical tertile 1 1.0 tertile 2 1.4 tertile 3 1.4 Periventricular grade 0-1 1.0 grade 1.5-3.0 2.0 grade 3.5-9.0 2.8 (Silent infarct3.3) (Subcortical & periventricular risks are additive.) Vermeer SE et al. Rotterdam Scan Study. Stroke. 2003;34:1126-9.

  30. Risk of WML/silent stroke combined WML gradeWML onlyWML & silent stroke 0 or 1 1.0 1.1 2 1.4 2.1 3 2.4 4.2 4 3.7 4.4 > 5 2.6 3.7 Kuller LH et al. Cardiovascular Health Study. Stroke. 2004;35(8):1821-5.

  31. WML & stroke RR in the very old 1433 subjects aged >75 yrs. with no stroke on initial MRI. FU MRI done 5 yrs. later, showing 17.7% had 1 or more new strokes. Severe WML was the single strongest predictor of having a stroke out of68 variables, including all potential cardiovascular risk factors. Longstreth WT et al. Cardiovascular Health Study. Stroke. 2002;33:2376-82.

  32. WML & Dementia Risk • Small vessel disease • is implicated in vascular dementia • amplifies the effects of the • pathologic changes of Alzheimer’s

  33. WML & dementia risk Mean age 72; mean 5.2-yr. FU. Adjusted for age, sex, education, BP, DM, smoking & APOE genotype. LocationDementia RR Subcortical tertile 1 1.0 tertile 2 0.8 (NS) tertile 3 2.0 (NS) Periventricular grade 0-3 1.0 grade >3-6 2.0 grade >6-9 4.5 (Dementia: 76% AD, 13% VD, 11% other) Prins ND et al. Rotterdam Scan Study. Arch Neurol. 2004;1531-4.

  34. WML & dementia risk (cont.) 563 nondemented subjects aged 60-90, mean 7.3-yr FU.Adjusted for age, sex, education, depression, cerebral atrophy, cerebral infarcts. Subjects with severe periventricular WML experience cognitive decline nearly 3 times as fast as the group average. (0.28 MMSE points lost per yr. vs. 0.10 points lost per yr.) De Groot J et al. Rotterdam Scan Study. Ann Neurol. 2002;52:335-341.

  35. WML worsening & dementia Subjects with worsening white matter grade experience greater cognitive decline. WML progression by 2 grades correlates with a 2-fold average rate of cognitive score drop (i.e., average cognitive scores reach by 5 yrs. the level reached by nonprogressors at 10 yrs.) Longstreth WT et al. Cardiovascular Health Study, Stroke. 2005;36:56-61.

  36. WML, cerebral atrophy, & post-stroke dementia 323 stroke pts. who underwent MRIs 3 mos. post-stroke • The severity of WML is independently related to post-stroke cognitive decline. • General cortical atrophy also predicts a range of cognitive deficits • Infarct volume had less relevance. Jokinen H et al. . Helsinki Stroke Aging Memory Study. J Neurol Neurosurg Psychiatry. 2005;76:1229-33.

  37. WML & Migraines

  38. Migraines & WML 295 migraineurs, mean age 48.5, half previously undiagnosed from a community population (40% with hypertension); cross-sectional study. Controlled for age, sex, BP, smoking, BMI, BCP, chol, EtOH, education, hx ergotamineuse. • 38% of both migraineurs and controls had at least 1 WML.So, no difference in overall WML incidence. • Also no difference according to sex, migraine frequency, or migraine type (with aura vs. without). • Also no difference for periventricular WML. • 1.9 OR for top quintile subcortical WML for women with migraines • 2.4 OR for top quintile subcortical WML for women with high-frequency migraines (> 1/mo.). Kruit MC et al. MRI CAMERA Study. JAMA. 2004; 291:427.

  39. Migraines & silent strokes Small “subclinical” posterior circulation strokes much more common in migraineurs, esp. in migraine with aura: -- 0.7% in controls -- 2.2% in migraine without aura -- 7.5% of migraine with aura Kruit MC et al. MRI CAMERA Study. Brain. 2005; 128:2068-77.

  40. Migraines & WML summary The Jury is still out. Need a medium to long-term prospective community-based study of a larger number of migraineurs to find the truth. Tentative working inferences • WMLs somewhat more common in migraineurs than in the general population. • Nature of association uncertain. • No good evidence to date that WMLs in migraineurs increase risk of future symptomatic stroke or other adverse outcome long-term.

  41. Underwriting WML • Optimal rating system for WML considers: • WML severity • Associated symptomatology • Age • Hypertension presence & control • Grade (especially for the periventricular WML) • Coexistent silent infarct(s) • Coexistent cerebral atrophy (& its severity) • Stability on sequential MRIs (if done) • Hx of migraine (+ modestly favorable if mild/mod subcortical WML present at a younger age)

  42. Underwriting WML: Generalizations Mild: • Common finding, not much of a concern. Moderate: • Not a concern if isolated problem in older ages, especially if subcortical only. • More of a concern at younger ages, especially if periventricular, and/or if progressive or combined with BP not under excellent control; and/or combined with mod-severe atrophy; and/or with stroke(s).

  43. Underwriting WML: Generalizations(cont.) Severe: • Major concern in younger age. • Major concern in older age, especially if periventricular, and/or if progressive or combined with BP not under excellent control; and/or combined with mod-severe atrophy; and/or with stroke(s). • .

  44. Back to our 58 yo F with an MRI report in her APS…. Has grade 1 periventricular & grade 1 subcortical WML – like approx. 50% of people her age. This MRI finding = no increased risk per se.

  45. The End

  46. Liver Function Tests Evaluating Abnormal Values Bruce Margolis, DO, MBA Genworth Financial

  47. Agenda • Liver function tests (LFT) • Causes of abnormal LFTs • Non-alcoholic steatosis/steatohepatitis (NASH) • Hepatitis A,B,C • Gilbert’s Syndrome • Primary Biliary Cirrhosis • Underwriting Considerations

  48. Liver Anatomy http://www.cincinnatichildrens.org/NR/rdonlyres/32143992-B411-43F4-8B25-AB3A460A3478/0/LiverFINALweb.jpg

  49. Liver Function Tests • Misnomer • Proteins • High Concentration in Liver Cells • Present in Other Bodily Tissues • Released with Liver Injury

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