作66醫學系b101099101-神經科學專題討論-連立明-High Titer of Anticardiolipin Antibody Is Associated with

Reporters: B101099139 李佳駺 B101099047 黃冠閔 B101099101 曾士剛 Cerebrovasc Dis 2006; 22-225-230 IF:2.723 1

 Antiphospholipid antibodies  Autoantibodies

 Thrombo-occlusive events (IgG isotype)

◦ _{Cerebrovascular system (most)}

 aCL↑, stroke patients under 40 years old  aCL↑, future stoke↑

 Not yet established as an independent risk

factor for ischemic strokes

 Case-control study was set up to determine

the association between aCL and ischemic stroke among Taiwanese

Ischemic stroke patients First-ever ischemic stroke < 48 hr onset > 40 years old No cancer No connective tissue disease 1996-1999, Shin Kong WHS Memorial Hospital, Neurological wards

 Response rate = 96.5% (n=273)

Pregnancy，systemic lupus erythematosus, transient ischemic attack, venous thrombosis and peripheral vessel thrombosis

 Control: outpatients (n=181)

◦ _{Other than stroke (nonspecific symptoms)}

 Headache

 Musculoskeletal pain

 Peripheral vestibulopathy  Parkinson’s disease

◦ _{No cancer or connective tissue disease}

Serum specimens centrifuged and frozen ELISA

IgG aCL (GPL) and IgM aCL (MPL) levels:

• Negative(<10GPL <7.5MPL), low positive(10-20GPL 7.5-15MPL), high positive(>20GPL >15MPL)

 Demographics and vascular risk factor

◦ _X2 _{test: categorical variables}

◦ _{Two sample t test: continuous variables}

 Odds ratios:

◦ _{Stroke risk: high positive aCL vs normal/low}

positive aCL

 Adjustment (logistic regression):

◦ _{Model I : not adjusted} ◦ _{Model II : age, sex}

◦ _{Model III : age, sex, smoking, history of deseases}

 Table 1. Characteristics of the study

participants

T test

 There are significant differences in the

proportion of gender, cigarette smoking, hypertension, DM, LVH, A-fib, and

hyperlipidemia between the control group and ischemic stroke patient

* * * * * * * 15

 No significant difference between mean

aCL-IgG aCL-IgM is observed applying two sample t test

 After stratifying mean aCL-Igs into three

groups, no significant difference is observed applying the Chi square test

Table 2. Distribution of aCL

 Determine whether or not subject with high

level of aCL-Igs is more likely to develop ischemic stroke

 Blood aCL-IgG>20GPL and aCL-IgM>15MPL

is the cut off point

Ischemic

Stroke

Control

IgG>20

12

2

IgG 20

261

179

_OR=

 Calculation of 95% CI, taking aCL-IgG as an

example

 CI of OR is between 0.091 to 18.595, which

includes 1

 Unable to justified that high blood aCL-IgG is

a risk factor for ischemic stroke

 Method for calculation for 95% CI is the same

for aCL-IgM

 95% CI of aCL-IgM also contains 1, therefore

high aCL-IgM present in blood is not a significant risk factor of ischemic stroke

 As previously mentioned, there is significant

different the ratio of gender, smoking status…between the two group

 Even age is not significantly different between

two group, it’s widely accepted that advanced age is a risk factor for ischemic stroke

 In order to avoid interference, two model is

constructed in order to eliminate these factors

 Model 1: Unadjusted

 Model 2: Adjusted by age and sex

 Model 3:adjusted by age, sex, smoking, and

history of hypertension, DM, A-fib, LVH, and hyperlipidemia

 Method for adjustment: Adjusted Logistic

Regression

Framingha m Study

 Unadjusted OR can be expressed as:

ln(OR)=β₀+β_aCL

 In the formula above, β_aCL represent the effect

of high blood aCL on the risk of developing ischemic stroke

 If the CI of β_aCL contains 0，calculated OR

( β0+βaCL)is statistically insignificant compare

to the OR ( β0) that did not consider aCL as a

risk factor



In the form of null hypothesis:

H

: β

= β

+ β

β

= 0

H

: β

β

+β

β

0



When the CI of β

contains 0，H

 In the case of considering smoking status as

a risk factor

 Unadjusted formula of OR:

ln(OR)=β₀+β_aCL

 After considering smoking status, formula is

transformed into :

ln(OR)=β’₀+β’_aCL+β’_smoke

 The β’_aCL in the second formula is the effect

of high blood aCL on the risk of developing ischemic stroke under identical smoking

status

 β’_aCL and β’_smoke have their own CI

 If the CI of β’_aCL contain 0，no significant

effect of high blood aCL is associate with the risk of developing ischemic stroke under

identical smoking status

 OR formula for Model 1:

ln(OR)=β₀+β_aCL

 OR formula for Model 2:

ln(OR)=β’

0+β’aCL+β’age+β’sex

 OR formula for Model 3:

ln(OR)=β’’₀+β’’_aCL+β’’_age+β’’_sex+…+β’’_{hyperlipidemi}

a

Note: aCL-IgM and aCL-IgG is calculated separately

 From Model 2, the 95% CI of β’_aCL contains 0

(CI of β’

age and β’sex is unknown)

 95% CI of β’’_aCL derived from Model 3 (only for

gG) doesn’t contain 0, which imply under identical status (age, sex, smoking status), subject with high aCL-IgG present in blood have a higher odds ratio for developing

 The definition above is based on the reviews

of past research (as the following table), and the further Discussions will also compare with this table.

 Model I: Unadjusted

 Model II: Adjusted by age and sex

 Model III: Adjusted by age, sex, smoking,

hypertension, diabetes, atrial fibrillation, left ventricular hypertrophy and hyperlipidemia

 Studies of stroke victims under 40 years of

age have found that the studied antibodies are associated with incident ischemic stroke.

 Several investigations have provided

conflicting Results with respect to the

significance of elevated aCL levels in older patients.



Table 4. Prevalence of a higher titer of aCL IgG

in non-Asians and Asians

 The Framingham study reported that high

aCL levels predict the occurrence of an incident of ischemic stoke.

 The Framingham study adjusted for age, prior

 Given the fact that multivariate analysis is a

more precise estimation that univariate analysis.

 After adjustment for age, sex, smoking,

hypertension, diabetes, atrial fibrillation, left ventricular hypertrophy and hyperlipidemia, ischemic stroke patients aged over 40 years compared to controls. A fivefold increase in stroke risk was also observed.

 The Results of this study suggest that

elevated titer of aCL IgG (>20 GPL) is

associated with first-ever ischemic stroke in Taiwanese patients aged over 40 years.

 High positive aCL titer is related to ischemic

stroke after adjustment for conventional

cerebrovascular risk factors, indicating that it is probably an independent risk factor for

 A separate analysis has demonstrated that

aCL is associated with cerebral stroke and

myocardial infarction, but not with deep vein thrombosis.

 37 李碩堯

 Q:本篇只有在model III才看到各組間的顯著差異，

model I和model II都沒有看到，那為什麼還要把 model II放進來呢？

 A:那是一開始作者的研究順序，原本是想要探討性

別之間的影響，調整之後發現還是沒有顯著差異， 故才進行了第三個model來排除更多risk factor

 69謝蓁  Q:為什麼一開始有提到aCL IgM，可是之後的討論 卻只在討論aCL IgG了？  A:會把aCL IgM放進來是因為之前別人的實驗都有 個別在探討IgM和IgG的isotype，只是本篇文章最 後都只發現到aCL IgG比較和疾病有相關性所以到 最後就只在探討這部分。其實也和前人的結果符合， 就是aCl IgG 的level對於疾病的影響比較aCL IgM 來的明顯

 132李易軒  Q:請問第27頁，238是指人數，旁邊為什麼會有百 分比呢？  A:那個並不是百分比，而是標準差，下面的項目才 是百分比。 43

 118劉郁欣

 Q:為什麼cancer 和connective tissue diseases不

像其他risk factor一樣等到最後再用logistic regression去掉？

 A:Cancer 和 connective tissue diseases和其他

risk factor 不一樣，他們是直接影響了aCL的濃度， 所以既然已經知道他們的直接相關性了就直接排除。

 老師：覺得本篇論文有什麼可以改進？  士剛：我覺得控制組選得很有爭議，因為沒辦法完 全說有這些疾病的患者，並不會引響此次統計的結 果，而實驗組，若是能一開始就排除心血管因子， 雖然可能有些難度，但是這樣討論就更具意義。  佳駺+冠閔：本篇的IgM和IgG的level是個別探討 的，可以深入探討IgM和IgG的level在同一個病人 上的不同的組合和疾病的相關性（考慮到IgM 和 IgG之間是有可能會有一些相互關係，也可以探討） 45

 135劉冠宏

 Q:有沒有可能這樣的做法在調整之後，實際上沒有

相關的risk factor也變成有相關？

 A:任何的實驗都有可能出現偽陽性的情況，唯有加