#402 ‒ 核磁共振血液分析：如何通过单一血液样本评估心脏病风险、胰岛素抵抗、炎症和死亡风险 | Jim Otvos 博士

我有大的、蓬松的、浮力大的。

I have large, fluffy, buoyant.

是的，所以我的LDL粒子数超过每升2000纳摩尔，这大概让我处于第八十个百分位左右，但我不需要担心，因为它们都是大的。

Yes, So my LDL particle number is over 2,000 nanomole per liter, which probably places me at the eightieth percentile or so, but I don't need to worry about it because they're all big.

我没有那种B模式。

I don't have that pattern B.

我没有那些。

I don't have those.

你会对那个人说什么？

What would you say to that person?

我会说那是个错误的想法，而且我提到的数据完全支持这一点。

I would say that's a fallacious idea, and the data that I've mentioned supports it completely.

然后你还必须考虑到，心血管风险最著名或最被接受的遗传原因之一是FH，即家族性高胆固醇血症。

And then you also have to think about the fact that one of the best known or best accepted genetic reasons for cardiovascular risk is FH, familiar hypercholesterolemia.

患有FH的人有非常高的LDL胆固醇水平。

People with FH have very high LDL cholesterol levels.

他们的LDL粒子数量也非常高，但这些粒子都是大的。

They also have very high LDL particle levels, but those particles are large.

它们不是小的。

They're not small.

而且，这些人是当他们有同型FH时，在30或35岁就去世了。

And there's, you know, these are people that die when they're 30 or 35 years old when they're homozygous FH.

所以，那种认为蓬松的大LDL粒子不用担心或无害的想法是完全错误的。

So this idea that somehow fluffy large LDL particles are not to worry about or benign is completely fallacious.

在我们转向其他话题之前，让我们再讨论一下这个问题，你之前简要提到过，但我们后来跑偏了，那就是LDL胆固醇和LDL粒子数量之间可能存在的不一致。

Let's talk about one more thing on this before we pivot away from this, which you alluded to very briefly, but we went off on a different path, which is the potential discordance that exists between LDL cholesterol and LDL particle number.

事实上，吉姆，当我第一次了解你的工作时，这实际上是我读你的第一篇论文，差不多是十五年前，几乎就是在这个月。

In fact, when I first came to learn about your work, Jim, this was actually one of the first papers I read of yours literally fifteen years ago, almost to the month.

那是在Mesa人群中，展示了四条Kaplan-Meier曲线。

And it was in the Mesa population, and it was showing four Kaplan Meier curves.

所以我会让你解释什么是Kaplan-Meier曲线，但基本上就是四种情况，即LDL P和LDL C之间的不一致，每次一个高于另一个，以及它们之间的一致。

So I'll let you explain what a Kaplan Meier curve is, but it was basically the four scenarios, which was discordance between LDL P and LDL C when one is higher than the other each time and then concordance between them.

那可能里面有三条曲线。

So maybe there were three curves then in that.

对，就是那三条曲线。

That's exactly the three curves.

好的。

Okay.

所以LDL C和LDL P一致，以及偏向LDL P的不一致，偏向……的不一致。

So concordance between LDL C and LDL P, and discordance in favor of LDL P, discordance in favor of...

好的。

Okay.

那篇论文对我来说真的非常非常有启发。

So that was a very, very eye opening paper to me.

我希望你能解释一下那个发现及其意义，因为直到今天，这对临床医生和患者来说仍然非常重要。

And I'd love you to just kind of explain that finding and what the significance are, because to this day, it's still a very important thing for clinicians and patients to understand.

是的，确实如此。

No, it is.

而且在2011年那篇Mesa论文之前，2007年还有一篇论文。

And prior to that Mesa paper in 2011 was a 2007 paper.

所以那是第一篇我们引入这种想法的论文，就是通过看LDL P和LDL C是否一致来评估情况。

So it was the first one that we sort of introduced This idea of assessing the situation by whether the LDL P and the LDL C agreed or not.

那篇用的是Framingham研究的数据。

And in that case is a Framingham study.

在这种情况下，经常出现的一个问题是，什么算不一致，其实这并不重要，每个人定义不一致的方式都不同，而且这没关系，因为我们并不是说不一致是一个风险因素，对吧？

And in that case, one question that always comes up is what defines discordance and and basically it doesn't matter and everybody defines it differently and it doesn't matter because we're not saying discordance is a risk factor, right?

我们只是想。

We're simply trying to.

理清一个情况，就是大多数人的LDL C和LDL P之间并没有差异。

Disentangle a situation where most people don't have a discrepancy between LDL C and LDL P.

所以如果你想了解LDL P是否是衡量LDL相关心血管风险的更好指标，而你在整个研究人群中，有百分之八十的人LDL C和LDL P是一致的，或者说是相符的。

So if you're trying to understand whether LDL P is a better measure of LDL associated cardiovascular risk and you do a whole study population and eighty percent of those people have concordant or in agreement LDL C and LDL P.

那请解释一下这是什么意思，因为人们会说，数字不一样啊。

And just explain what that means, cause people will say, well, the numbers are different.

那他们怎么能

How can they

好的。

Okay.

所以一种方法，我们在Mesa论文中用的，就是把每分升毫克数的胆固醇数值转换成百分位数。

Be in So one way to do it, which we did in the Mesa paper, is transform the milligram per deciliter cholesterol number into a percentile.

这样就根据排名来定义人们，低、高、中等。

So that defines people according to their rank, low, high, intermediate.

如果你对LDL P也做同样的处理，那现在就是苹果对苹果的比较了，一个百分位数对另一个百分位数。

And if you do the same thing to the LDL P, now you're comparing apples to apples, percentile of one percentile of the other.

然后你把它画出来，你会看到数据点分布在各处，那些沿着对角线附近的点，就是LDL P的50百分位数接近LDL C的50百分位数的情况。

And you plot that and then you see the data points all over the place and the ones that track on the diagonal, the ones that are close to the diagonal are the ones for which a 50 percentile LDL P is close to a 50 percentile LDL C.

这就是我们所说的“一致性”。

So that's what we call concordance.

在那个案例中，我们选了一个奇怪的数字，正负12个百分位数的差异作为我们的分界点。

And in that case, we picked this weird number of 12 percentile difference was our cut point plus or minus.

所以，彼此之间在12个百分点以内的，都算是一致的。

So everybody within 12 percentile units of each other, called concordant.

为什么是12？

Why 12?

为什么不用一个整数？

Why not a round number?

那是因为我们想让一致的人群数量，大致等于两个方向不一致的人群数量。

And it was because we were trying to make the concordant population about equal in number to the discordant in one direction and the discordant in other direction population.

你是说50%在一致组，另外50%分在两个不一致组里。

You have 50% in one hundred twenty five and fifty percent in the two discordant groups.

不，其实我们是想要一个大概的

No, it's actually we're trying to make a sort

30、30，还有30，差不多是这样。

of 30, 30, you know, Got 130 it.

好的。

Okay.

所以这就是我们所做的。

And so that's what what we did.

然后我们简单地把这三组人拿来，你提到卡普兰-迈耶，这基本上就是心血管事件的累积发生率。

And then we simply took these three groups of people and you talk about Kaplan Meier, all this is basically cumulative incidence of cardiovascular events.

所以在X轴上，你可以看到数字在增加。

So on the X axis, you can see the number increasing.

如果增加很多，这就是一个比风险曲线平缓、随浓度增加不明显的人群风险更高的子群体。

If it increases a lot, this is a higher risk subpopulation than somebody whose risk is much shallower and doesn't increase very much as a function of concentration.

所以这清楚地表明，对于LDL P和LDL C一致的人来说，你无法论证为什么LDL P比LDL C更好测量。

So that very clearly showed that for people whose LDL P and LDL C agree, you can make no argument about why LDL P is a better thing to measure than LDL C.

那么问题就变成了，从基本原理出发，我们预期胆固醇还是粒子数量更能衡量风险？

Then it's a matter of well, from first principles, what would we expect the cholesterol to be a better measure of risk or the particle number?

而且说实话，如果你诚实面对，并没有一个机制上的解释让你对其中一个比另一个更放心。

And really, if you're honest about it, there is no mechanistic explanation that you should really be too comfortable with for one versus the other.

我们在那篇论文中解释了，当Ron Krause表明小而密的LDL更具致动脉粥样性时，发生了什么。

And we explained that in that paper that what has happened with when Ron Krause showed that small dense LDL was more atherogenic.

而且这是基于流行病学的人群研究得出的。

And that this was based on epidemiologic population studies.

问题是，为什么会这样呢？

The question was, well, why is that?

然后基本上，这个推测最终被各种证据所支持，确实，较小的LDL颗粒比大的颗粒更容易进入动脉壁。

And then basically the speculation was ultimately supported by various lines of evidence that yes, smaller LDL particles are likely to get into the arterial wall easier than a bigger particle.

而且颗粒表面物质的形状差异，使得它们更容易与动脉壁中的分子结合，从而被更牢固地保留，也更容易被氧化。

And then the difference in the shape of the stuff on the surface of the particles combine more avidly to molecules that are in the arterial wall and retain it more, and then it's more readily oxidized.

所以，这些事我无法告诉你我读过多少篇论文，在讨论部分都有这段必写的段落，关于为什么小而密的LDL更具致动脉粥样硬化性。

So, of these things I can't tell you how many papers I've read were in the discussion section is this obligatory paragraph about why small dense LDL is so much more atherogenic.

反过来的论点是，好吧，大的LDL颗粒也能进入动脉壁，而且当它们被氧化时，它们被保留得更多。

The flip side argument is that, okay, large LDL particles also get into the artery wall, and when they get oxidized, they're more retained.

不，不，它们并没有被保留得更多。

They're no, no, they're not more retained.

我只是说你可以提出那个论点，对吧？

I mean, I'm just saying you could make that argument, right?

那我们就说，它们到达了终点，然后被巨噬细胞吞噬，把胆固醇内容物沉积在动脉壁上。

Well, let's just say that they get to the end of the trail and they get taken up by macrophages and deposit their cholesterol contents into the arterial wall.

嗯，更大的颗粒含有更多的胆固醇。

Well, bigger particles have more cholesterol.

更多的胆固醇，

More cholesterol,

更多的氧化损伤。

more oxidative damage.

所以，你认为富含胆固醇的颗粒应该更容易导致动脉粥样硬化。

So, you think the more cholesterol rich particles should be more atherogenic.

但如果这被小颗粒不那么频繁到达终点所抵消，也许就抵消了。

But if that's counterbalanced by not getting to the end of the party as often as the small particles, maybe it's a wash.

你怎么回答这个问题？

How do you answer the question?

你进行研究，这就是不一致性分析让我们能够做到的。

You do the study, and so that's what the discordance analysis allowed us to do.

每当出现这种方向上的不一致时，心血管风险跟的是颗粒数量，而不是胆固醇。

Whenever there's a discrepancy in one direction or another, the cardiovascular risk tracks with the particle number, not the cholesterol.

对，所以那条曲线确实把这三组数据分得很清楚。

Yeah, so the curve really had a beautiful separation of those three figures.

中间是一致的情况，然后在这条线上方，意味着这些人死亡速度更快。

You had the concordance in the middle and then above that line, which means these are people that are dying quicker.

那就是当LDL颗粒数高于LDL胆固醇的时候。

That's when LDL P was above LDL C.

而在这条线下方，这些人死亡速度比预期的要慢得多。

And below the line, these people died much slower than you would expect.

正好相反。

It was the flip.

胆固醇高，但颗粒数低。

Cholesterol was high, but their particles were low.

没错。

Exactly.

所以，是的，那个，我的意思是，我无法告诉你我不得不和多少人进行过多少次辩论。

So, yeah, that and so I mean, and I can't tell you how many debates I had to have with people.

通常都是非常受尊敬的心脏病专家。

I mean, usually very well regarded cardiologists.

跟我讲讲吧。

Tell me about it.

他们就是拒绝承认有任何必要去看LDL胆固醇以外的任何东西。

Who just refused to acknowledge there was ever a need to look at anything beyond LDL cholesterol.

好吧，现在让我稍微谈谈这个的临床实用性，因为人们从说了所有这些之后会想象的是，LDL P应该是评估心血管风险的更好的工具。

Well, now let me let me sort of go somewhere about the clinical utility of this because what people would imagine from having said all this is that LDL P should be a much better thing to use to assess cardiovascular risk.

而现实是，心血管风险的评估方式，

And the reality is that the way cardiovascular risk is.

今天和过去几乎一样，都是通过考虑总胆固醇、HDL胆固醇、糖尿病有无、吸烟有无、高血压的方程来进行的。

Assess today is the same pretty much the same way it's always been assessed by by equations that take into account total cholesterol, HDL cholesterol, diabetes present absent, smoking present absent, hypertension.

所以这些是风险方程，而且最近刚刚更新了新的风险方程。

So these these are risk equations and there's updated risk equations just fairly recently a new one.

这些公式里都有总胆固醇和高密度脂蛋白胆固醇。

They all have total and HDL cholesterol in it.

如果你问，用LDL P或者把LDL P加到包含这些指标的模型里，风险评估会不会更准？

When you ask the question, if I use LDL P or I add LDL P to a model that has that those things in it, is my risk assessment better?

答案是不会，不会更准。

And the answer is no, it's not better.

这基本上就让你没法从商业角度说，风险评估应该用LDL P而不是LDL C。

And this sort of kills you if you're trying to make a commercial argument that you should be testing LDL P instead of LDL C for risk assessment.

我觉得之所以这样，是因为模型里有高密度脂蛋白胆固醇，而且我们还不完全清楚，高密度脂蛋白是不是在低密度脂蛋白和总胆固醇之外，能带来额外的风险评估价值。

The reason I think that that is true is because the HDL cholesterol is in the model, and we still don't really understand whether it's HDL is bringing extra risk assessment to the table above and beyond what the LDL and the total cholesterol brings.

还是说，是富含甘油三酯的颗粒？现在人们已经不太相信高密度脂蛋白胆固醇很重要了，因为提高高密度脂蛋白胆固醇的试验结果都是阴性的，或者说没有阳性结果。

Or is it the triglyceride rich particles now people have swung away from the idea that HDL cholesterol is important because the HDL cholesterol raising trials were negative or weren't positive.

然后，因为甘油三酯和高密度脂蛋白胆固醇呈负相关，高密度脂蛋白胆固醇低的时候，甘油三酯就高。

And then they because there's an inverse correlation between triglyceride and HDL cholesterol When HDL cholesterol is low triglycerides are high.

哦，那可能问题出在甘油三酯上。

Oh, maybe it's the triglycerides.

嗯，说甘油三酯分子本身会导致动脉粥样硬化，这说不通，但携带它们的那些富含甘油三酯的颗粒很可能有这种作用，因为它们也能进入动脉壁，并输送大量胆固醇。

Well, it doesn't make sense that the triglycerides per se, the molecules triglyceride are atherogenic, but the triglyceride rich particles that carry them could well be because they also get into the arterial wall and deliver a lot of cholesterol.

吉姆，我不知道这是不是你的一篇论文，但我觉得应该是。

Now, Jim, I don't know if this was one of your papers, but I think it was.

那大概是在2012年、2013年前后。

And it was around that time, probably twenty twelve, twenty thirteen.

如果我没记错的话，那篇论文里的图，具体来说，是个柱状图，对吧？

And if I recall the paper, the figure specifically, it was it was a histogram, right?

横轴是0、1、2、3、4、5，代表符合代谢综合征标准的数量。

So on the x axis, you had zero, one, two, three, four, five, and you were looking at number of criteria met for metabolic syndrome.

给听众提醒一下，代谢综合征有这五个标准，符合的越多，就越可能胰岛素抵抗。

So for the listener, just to remind everybody, metabolic syndrome has these five criteria, and the more of them you have, the more likely you are to be insulin resistant.

所以，标准包括高血压、肥胖，也就是腰围，还有血压、空腹血糖和HDL胆固醇。

So it's there's one about having high blood pressure, obesity, so the truncal diameter, truncal girth, blood pressure, fasting glucose and HDL cholesterol.

我想就是这五个，对吧？

I think those are the five, right?

是的。

Yes.

对，包括这些。

Those include, yeah.

好的。

Okay.

所以，这个图显示的是，如果你一个都没有，那么你的LDL C和LDL P不一致的概率非常低。

So, and what this figure showed was if you had zero of them, the probability that you were discordant between your LDL C and LDL P was very low.

如果你有一个，概率会稍微上升一点。

If you had one of them, the probability went up a little bit.

有两个的话，概率就明显上升了。

Two of them considerably.

有三个的话，就很高了。

Three, a lot.

而且这是一个单调递增的关系，吉姆，也就是说当你五个代谢综合征标准全部满足时，你几乎肯定会出现不一致的情况。

And it was a monotonic increasing relationship, Jim, such that by the time you had five out of five met sin criteria, you were virtually guaranteed to be discordant.

所以我提这个是想说，你之前提到过，不一致本身并没有什么问题。

And so I bring that up to say earlier you mentioned there's nothing wrong with being discordant per se.

虽然你也可以说，不一致的程度越高，意味着你越可能有潜在的代谢性胰岛素抵抗。

Although it's, you could also argue that the more discordant you are, higher the probability that you're discordant means the higher the probability that you probably have some underlying metabolic insulin resistance.

那是个风险。

That's a risk.

所以问题就变成了，那些非常复杂的多参数风险模型之所以能消除LDL P的影响，是不是因为它们只是直接或间接地捕捉了所有的心血管代谢风险。

And so the question then becomes, is the reason that very elaborate multi parametric risk models can erase the LDL P, is that they are simply capturing all of the cardiometabolic risk indirectly and directly.

对，你基本上说出了我想说的，就是因为高密度脂蛋白胆固醇在标准风险评估模型里。

Yeah, you basically just explained what I was getting at, which is because HDL cholesterol is in the standard risk assessment models.

当你高密度脂蛋白胆固醇低的时候，你的LDL P很可能比LDL胆固醇所显示或暗示的要多。

When you have low HDL cholesterol, you're likely to have more LDL P than the LDL cholesterol indicates or suggests.

所以你的风险更高是因为LDL P高，而不是因为高密度脂蛋白胆固醇低。

And so your risk is higher because you have higher LDL P, not because HDL cholesterol is low.

但你的风险评估并没有变得更好，因为高密度脂蛋白胆固醇，虽然原因不对，如果你愿意这么说的话，不是因果关系，而是关联关系，告诉你的是一样的信息。

But you're not doing better in risk assessment because the HDL cholesterol for the wrong reason, if you will have not a causal reason, but an association reason is telling you the same thing.

这对当时的Liposcience来说非常重要，因为——这也是我至今仍在争论的一点——我和Alan Schneiderman，我们稍后会谈到apoB的问题。

So this was really important to liposcience back in the day because and this is something that I still argue with, but I Alan Schneiderman and I will get to the question of apoB.

是的，是的。

Yes, yes.

但他坚持……

But, you know, insists...

他一直想说服人们，apoB对风险评估很重要。

He keeps wanting to convince people that apoB is important for risk assessment.

而我们根据自己发现的证据转向了另一个方向，说服人们LDL P是更好的风险评估指标，也是更好的风险管理指标，因为当你风险高时，你通过降低LDL胆固醇来管理风险。

And what we pivoted to in light of the evidence that we found ourselves convinced people that LDL P was a better thing to measure for risk assessment to a better thing to measure for risk management because what you do when you have high risk is you manage it by lowering your LDL cholesterol.

这是我们工具箱里最好的工具。

This is the best tool we have in the toolbox.

实际上没有太多其他工具。

There are not actually very many others.

我们有他汀类药物，然后还有一些和他汀类药物作用相同但效果更好的药物，所以我们可以大幅降低LDL。

We have statins and then we have things that are doing the same job as statins, but better so we can lower the heck out of LDL.

那么对于心血管风险高的患者来说，问题就是：我需要把LDL降低多少？

And the question for a patient with high cardiovascular risk is how much LDL lowering do I need?

所以你真正想要的，是一个能告诉你‘我的LDL相关风险已经得到充分控制’的生物标志物。

So what you really would like is a biomarker that tells you my LDL associated risk is adequately controlled.

我的LDL已经降得够低了。

I've gotten my LDL low enough.

如果还不够，比如我已经在服用高剂量他汀，但还没达到目标，那我想再加一个PCSK9抑制剂或者其他东西，把它降得更低。

If it's not, I should add I'm on high dose statin and I'm not there, then I want to add a PCSK9 inhibitor or something else to lower it even more.

所以你想要的，是衡量LDL相关风险的最佳客观指标，不是总风险，而是LDL相关风险。

So you want the best objective measure of LDL related risk, not total risk, but LDL related risk.

在这种情况下，很明显LDL P或者apoB是更好的生物标志物，因为很多

In that case, it's very clear that LDL P or apoB is a better biomarker because a lot of

人虽然LDL胆固醇降得很低，但LDL粒子数或apoB并没有同样降得很低。

people who achieve very low LDL cholesterol have not achieved equally very low LDL particles or apoB.

如果他们能看到这一点，他们就会成为更积极降低LDL的候选者。

And they therefore with visibility to that would be candidates for more aggressive LDL lowering.

所以我们确实在临床实践中看得一清二楚，吉姆，因为我们对这些指标的管理非常积极。

And so we absolutely noticed that as clear as day in our practice, Jim, because we are very aggressive at managing these things.

这种不一致在低水平时真的发生，有没有生物学上的原因，还是说这是化学检测的问题？

Is there a biologic reason for why the discordance really happens at low levels in that way, or is it a chemical assay?

这是检测方法本身导致的吗？

Is it a property of the assays that's causing that?

不，你问的每个问题都是这样。

No, it's like everything that you ask.

这很复杂。

It's complicated.

你可以深入细节，但事实是，你的LDL水平越低，LDL颗粒中的胆固醇就越有可能部分被甘油三酯替代，因为颗粒核心中总是存在这种胆固醇酯和甘油三酯的交换。

You can get into the weeds, but what's true is that the lower your LDL level is, the more likely that the cholesterol in the LDL particle is replaced to some extent by triglyceride because there's always this interchange, this swapping of cholesterol ester and triglyceride in the core of the particle.

这取决于富含甘油三酯的颗粒和富含胆固醇的LDL颗粒的相对数量。

And it's driven by the relative amounts of the triglyceride rich particles and the LDL particles, which are cholesterol rich.

富含甘油三酯的颗粒，差距越大，就会把甘油三酯放入LDL，同时换取胆固醇酯。

The triglyceride rich particles, the bigger that gap is put triglyceride into LDL in exchange for cholesterol ester.

所以当你用他汀类药物或其他方法降低LDL时，LDL颗粒数量减少了，但LDL胆固醇降低得更多，因为不仅颗粒数量下降了，颗粒中的胆固醇也独立地减少了。

And so as you lower LDL with statins or whatever, the LDL particles are lower, but the LDL cholesterol is even lower because not only has the particle number gone down, but the cholesterol in the particles independently

这个解释真的很棒。

That's is going that's actually a great explanation.

我之前不知道。

Did not know that.

这说得通，因为我们确实看到了这一点。

And that makes sense because we see that as clear as day.

好的。

Okay.

在我们转向其他话题之前，我还想谈一件事，那就是据我所知，你基于此开发的第一个综合评分，也就是LPIR评分。

One other thing I want to talk about on this front before we pivot is, at least to my knowledge, the first composite score that you then developed out of that, which was the LPIR score.

那确实是你第一次涉足Google综合评分吗？

Was that indeed sort of your first foray into Google composite scores?

是的，而且是因为，嗯，

Yes, And it was because Still

一直用到现在。

used to this day.

所以很多听众每次做血液检查都会看到LPIR分数。

So many people again listening to us will have an LPIR score every time they get their blood test.

不，这很有趣，因为正如我所说，我们最初进入这个领域是因为我们能测量小LDL，而且区分不同大小的脂蛋白颗粒的能力看起来在临床上很有用。

No, it's interesting because as I said, we first got into this game because we could measure small LDL and And so the ability to differentiate different size lipoprotein particles seemed like it was clinically useful.

但归根结底，正如我所说，真正重要的是颗粒数量。

But at the end of the day, as I've gone through, it turns out that it's really the particle number that matters.

如果你能说服人们不要太关注LDL胆固醇，而是更关注apoB或LDL P，那会更好。

And if you can convince people to not pay so much attention to LDL cholesterol and pay more attention to apoB or LDL P, then you're better off.

但这意味着测量LDL的大小并不重要。

But that means that measuring the size of LDL doesn't matter.

哦，那太可惜了，因为我们有很好的高效方法来测量它。

Oh, that's a bummer because we have a great efficient way of doing that.

所以，接下来的问题是，脂蛋白亚类分布除了用于心血管风险评估和管理之外，是否还有其他用途？

So, then the question was, well, are the lipoprotein subclass distributions useful for something else besides cardiovascular risk assessment and management?

答案是肯定的。

And the answer is absolutely yes.

大家都知道，甘油三酯高、高密度脂蛋白胆固醇低，跟胰岛素抵抗是有密切关联的。

There is a well known association between higher triglycerides and lower HDL cholesterol and insulin resistance.

糖尿病和胰岛素抵抗会导致糖尿病风险增加，甚至直接引发糖尿病。

And diabetes and insulin resistance leading to diabetes risk or leading to diabetes.

所以，我们早就知道胰岛素抵抗有特定的血脂特征。

So, it's already known that there's a lipid signature for insulin resistance.

我们的想法是，如果能测量VLDL、LDL和HDL的不同大小，是不是比单纯用甘油三酯除以高密度脂蛋白胆固醇的比值更有效呢？

And the idea was if we could measure the different sizes of VLDL, LDL and HDL, could that do a better job than just the triglyceride over HDL cholesterol ratio?

在血脂检查中，用甘油三酯除以高密度脂蛋白胆固醇的比值，算是穷人版的胰岛素抵抗指标。

So the poor man's insulin resistance measure from a lipid panel is triglyceride over HDL cholesterol ratio.

杰瑞·里文，他真正发现并推广了胰岛素抵抗极其重要的观点，他主张用这个比值，因为人们做血脂检查时，这些信息往往没被利用起来。

And Jerry Revan, who was really discovered and promoted the idea of insulin resistance being extremely important, he advocated that it be used because people were getting lipid panels and this information was not being used for anything.

所以，这个LPIR评分，它综合了六项VLDL、LDL和HDL的大小及亚类浓度参数，把它们整合成一个从0到100的分数，分数越高，表示胰岛素抵抗越严重。

So, with this LPIR score, which brews together six VLDL, LDL and HDL size and subclass concentration parameters, it brews them into a score from zero to 100, Higher scores being more insulin resistant.

那么问题来了，这个LPIR评分在判断某人是否可能变成糖尿病患者方面，是不是做得更好？

Then the question was, does this LPIR score do a better job in assessing whether somebody is likely to become diabetic?

所以，这里得稍微讲讲病理生理学，因为这与我们今天在心血管疾病一级预防和糖尿病一级预防方面的情况有一些有趣的相似之处。

So, the pathophysiology has to be talked about a little bit here because there are some interesting parallels to where we are today with respect to primary prevention of cardiovascular disease versus primary prevention of diabetes.

在心血管疾病的情况下，大家都很清楚，最初的致病因素是胆固醇升高，或者LDL升高，或者WOB升高，但它是随着时间推移起作用的。

So, in the cardiovascular situation, as everybody pretty well understands, the initiating causal factor there is elevated cholesterol or elevated LDL or elevated WOB, but it's acting over time.

所以它需要长期暴露的累积，逐渐导致胆固醇在动脉壁上的沉积。

So it requires an integration of exposure over a long period of time and that gradually leads to cholesterol deposition in the artery wall.

这就是动脉粥样硬化。

That's atherosclerosis.

动脉粥样硬化随着时间推移，会一点点增多。

Atherosclerosis over time starts little more, more.

但这并不会引起任何临床上的担忧。

But that doesn't trigger any clinical concern.

这是胆固醇在长时间内暗中作祟的一种亚临床表现。

This is a subclinical manifestation of cholesterol doing its dirty deed over a long period of time.

然后到某个时候，你可能会发生心肌梗死或中风，这时动脉粥样硬化就转变成了临床事件。

And then at some point you might have a myocardial infarction or a stroke, and that's when the atherosclerosis has transformed into the clinical event.

从测量生物标志物的角度来看，好消息是，起始因素、因果因素是胆固醇，它很容易测量。

The good news from a measurement biomarker standpoint is that the initiator, the causal factor is cholesterol, which is easily measured.

那么糖尿病呢？

So now what about diabetes?

糖尿病非常相似。

Diabetes is very similar.

这是一个时间累积的过程，如果你胰岛素抵抗，随着时间的推移，你的β细胞不得不分泌更多胰岛素来控制你的血糖。

It's a time integrated process where if you are insulin resistant, over time your beta cells have to spit out more insulin to keep your glucose under control.

所以，如果你胰岛素抵抗而不是胰岛素敏感，你可以这样想，你让β细胞工作得更辛苦。

So, you're making the beta cells work harder, if you want to think about it that way, if if you're insulin resistant versus insulin sensitive.

因此，胰岛素抵抗乘以时间，逐渐导致高血糖，即血糖升高。

And so, insulin resistance times time leads gradually to hyperglycemia, elevated glucose.

所以，如果血糖在90或以下，你就完全没问题。

So, if it's 90 or below, you're A Okay.

但随着时间的推移，如果你要转变成糖尿病，你会经历一个血糖越来越高、直到跨过那个神奇的每分升126毫克的分界线，也就是定义糖尿病的那个线。

But over time, if you're going to convert to diabetes, you go through a transition of the glucose going higher and higher until it crosses this magic one hundred and twenty six milligram per deciliter line that defines diabetes.

为了让听众明白，我们说的是平均值。

Just for folks to know we're talking average.

没错。

Absolutely.

所以呢。

So.

因果因素是胰岛素抵抗。

The causal factor is insulin resistance.

在CBD方面，相当于动脉粥样硬化的是血糖低于126。

The thing that's sort of equivalent to atherosclerosis on the CBD side is hyperglycemia sub less than 126.

所以不是糖尿病，而是前糖尿病。

So not diabetes, but pre diabetes.

所以当血糖超过100，在100到126之间时，你就是前糖尿病。

So when glucose gets over 100 before it goes from 100 to 126, you're pre diabetic.

你猜怎么着，葡萄糖很容易测量。

Guess what's easy to measure glucose.

所以在这种情况下，原因造成的结果是可以测量的。

So in that case, the effect of the cause is measurable.

但原因本身却测不了。

The cause itself is not.

所以这意味着，从预防的角度来看，你真正要做的是防止胰岛素抵抗随着时间推移演变成高血糖，最终变成糖尿病。

And so what that means is that from a prevention standpoint, what you really want to do is to keep insulin resistance from transforming over time into hyperglycemia and ultimately diabetes.

如果你不知道自己有胰岛素抵抗，你只会等着那个容易测量的葡萄糖升高。

If you don't know that you're insulin resistant, you just you're waiting for the easily measured glucose to become elevated.

而一旦发生这种情况，你已经损失了大约50%的β细胞功能。

And now, once that happens, you've lost about 50% of your beta cell function.

所以真正有效的预防机会，无论是初级预防还是根本预防，在于对那些葡萄糖正常、还没进入这个过渡阶段的人采取行动，因为那时β细胞已经开始出现功能障碍了。

So the opportunity for real effective prevention, primary prevention, primordial prevention is to act on people whose glucose is Okay and hasn't gone to this transition yet because the beta cells have started dysfunctioning.

所以，吉姆，我想在这里打断你一下，因为你刚才的阐述非常清晰。

So, Jim, I want to pause you there because the way you've laid that out is very elegant.

而且我喜欢这个说法，我从来没像你刚才解释的那样想过。

And I like the I've never thought of it the way you just explained it.

所以我重复一遍，既是为了我自己，也是为了别人。

So I'm repeating it just as much for me as for others.

听这个播客的人都知道，我们经常用你描述CBD预防的那种方式，就是你有因果标记。

People who listen to this podcast know we constantly use the way you describe the CBD prevention thing, which is you have a causal marker.

你不需要等到疾病可测量了才去治疗。

You don't need to wait until disease is measurable to treat it.

我经常举的例子就是吸烟和肺癌。

And the example I always give is smoking and lung cancer.

我们有一个因果标记，找不到更好的词，就是吸烟。

We have a causal marker, for lack of a better word, smoking.

我们总是要说明，因果关系并不意味着一一对应。

We always have to specify causality doesn't mean one to one mapping.

有些吸烟者永远不会得肺癌。

There are some smokers that never get lung cancer.

也有一些从不吸烟的人仍然会得肺癌。

There are some never smokers who still get lung cancer.

这些事实都不能抹去烟草与肺癌之间的因果关系。

None of those facts erase the causality of tobacco and lung cancer.

我们难道要等吸烟者长出小肿瘤才让他们戒烟吗？

Do we need to wait for a smoker to develop a small cancer to tell them to stop smoking?

当然不是。

Absolutely not.

那样就是医疗事故了。

That would be malpractice.

一旦出现疾病的致病因素，就应该立刻消除。

You always eradicate causal drivers of disease the moment they appear.

所以当你LDL-C、apoB或LDL-P升高时，就要立即治疗，而不是等到他们得了病再处理。

And that's why when you have elevated LDL C or apoB or LDL P, you treat it immediately, not once they have disease.

高血压也一样，吸烟对心血管的影响也一样。现在，我们回到你刚才说的，我们知道胰岛素抵抗之于糖尿病，就像吸烟之于癌症一样。

Same with hypertension, Same with smoking as it pertains to cardiovascular Now, let's pivot to what you said, which is, look, we know that insulin resistance is the cigarette to diabetes as cancer.

对。

Yes.

我们难道要等到血糖真的升高了才行动吗？要知道，血糖升高本身就是诊断糖尿病的指标，但实际上，等到血糖升高的时候，胰腺里的β细胞可能已经受损了，基本上快撑不住了。

Do we want to wait until we actually see the glucose rise, which by the way is the biomarker that defines diabetes, when in reality, by the time that's happening, there's potentially already cellular damage at the level of the beta cell in the pancreas, and it's basically running out of steam.

那我们还能测什么呢？

And what else can we measure?

现在，我想回到刚才说的，有些方法确实有用，但操作起来非常麻烦。

Now, I want to come back to the idea of there are things that we can do, but they're very laborious.

口服葡萄糖耐量试验就是一个很好的方法，能提前很多年发现潜在的问题，就像煤矿里的金丝雀一样。

So an oral glucose tolerance test is a fantastic way to find out that canary in the coal mine years before it shows up.

但作为临床检测，它已经不太受欢迎了，因为要花两个小时。

But it's so fallen out of favor as a clinical test because it takes two hours.

实在太麻烦了，除了我们诊所和少数几家，我觉得没多少人愿意做这个检查。

It's, I mean, it's just so cumbersome that to outside of our practice and a few others, I just don't imagine many people want to do it.

然后吉姆就提出了一个想法：如果在核磁共振波谱里能找到一系列指标，能很好地反映胰岛素抵抗，在血糖升高之前就证明你走错了路，那该多好。

So Jim comes along and says, what if somewhere in this NMR spectrum is a whole series of things that turn out to be a fantastic marker for insulin resistance that we can use as causal proof that you're on the wrong path before your glucose goes up.

是的。

Yes.

而且在我们看来，这个理由非常充分，你应该针对的是根本原因，而不是结果，也不是胰岛素抵抗作用的下游效应。

And it seemed to us a very compelling case that you would want to act on the causal factor and not the effect or the downstream effect of the action of insulin resistance.

但有意思的是，

But interesting.

回到说服别人、临床转化的话题，

I mean, back to convincing people, clinical translation.

这其实是……

I mean, this is...

我用了那个词。

I use that word.

我创办这家叫 Liposcience 的公司，想推动 NMR 检测进入临床实验室时，我其实还不熟悉那个词。

I don't think I was familiar with that word when I started this company called liposcience to try to get NMR testing introduced into clinical laboratories.

但我当时觉得，LDL-P 对比 LDL-C 的论点很有说服力，人们真的应该把它作为管理 LDL 的生物标志物。

But I thought the argument of LDL P versus LDL C was quite compelling and that people really should be using it as the biomarker to determine management of LDL.

来自体制内的阻力非常大。

Tremendous resistance by the establishment.

我一直不明白为什么阻力这么大，他们为什么这么抗拒。

I could never understand why it was so why they were so resistant.

人们在医学院学到的关于胆固醇的知识。

The messaging people learn about cholesterol in medical school.

哦，我们得讲一个不同的故事，人们不会理解，还有各种在我看来相当站不住脚的理由。

Oh, we'd have to tell a different story and people wouldn't get it and all sorts of, you know, reasons that seem pretty weak to me.

所以，在糖尿病方面，情况也是一样的。

So, on the diabetes side, it's the same thing.

人们以为高血糖，也就是前糖尿病，是糖尿病的风险因素。

People imagine that hyperglycemia, prediabetes, is a risk factor for diabetes.

它不是风险因素。

It's not a risk factor.

它本身就是疾病。

It is the disease.

只是表现形式没那么明显而已。

It's just in a less manifest form.

那为什么不从根源上解决问题呢？

So, why not address the cause?

这方面阻力很大。

A lot of resistance to that.

我当时真的特别震惊。

It sort of blew my mind.

我们做了核磁共振分析。

And we did NMR analysis.

在多项研究中，我们证明了胰岛素抵抗评分与未来患糖尿病可能性之间的关联，至少是相关性。

In a number of studies to show the efficacy of or at least the relationship between insulin resistance score and likelihood of future diabetes.

顺便说一句，进入糖尿病前期并不意味着你一定会得糖尿病。

And by the way, transitioning to prediabetes by no means means that you're going get diabetes.

比如我妻子，她的血糖一直在每分升105毫克左右，处于糖尿病前期状态，已经持续25年了。

I mean, there's you really my wife has been prediabetic one hundred and five or so milligram per deciliter for twenty five years.

不会变。

Doesn't change.

所以，胰岛素抵抗评分可以告诉你，一旦你处于前糖尿病状态，你转变为糖尿病的可能性有多大。

So, the insulin resistance score can tell you whether you're more or less likely once you're prediabetic to transition.

然后到那时，即使你希望更早干预，现在做点什么也还不算晚。

And then then at that point, even though you'd like to have intervened earlier, it's not too late to still do something about it.

那么，吉姆，LPIR评分是否在纵向数据上得到验证，以预测二型糖尿病的发展？

And so, Jim, was the LPIR score validated on longitudinal data to predict the development of type two diabetes?

是的。

Yes.

或者，好的。

Or Okay.

所以从这个意义上说，我们将讨论MVX以及它在这方面有多相似。

So in that sense, we'll talk about MVX and how similar that was in that regard.

有没有做过比较，说它相对于口服葡萄糖耐受测试表现如何？

Has there ever been a comparison that says how well does it do versus an oral glucose tolerance test?

对。

Yep.

是的。

Yes.

所以，嗯，不是口服葡萄糖耐受测试，因为在现实世界中，空腹胰岛素是评估胰岛素抵抗的一种更简单的方法。

And so well, not oral glucose tolerance test because in the real world it's So you really fasting insulin is sort of an easier way to assess insulin resistance.

它有一些分析上的和实际上的问题。

It has some analytic issues and practical issues.

所以，一般来说，在临床实践中，没有人真正对使用胰岛素来达到这个目的感兴趣。

So, nobody has really been interested in using insulin for that purpose generally in clinical practice.

但是LPIR分数已经和空腹胰岛素进行了比较，并且更好。

But the LPIR score has been compared to fasting insulin and is better.

最能说明这一点的研究不幸还没有发表。

The study that shows it the best is one that unfortunately hasn't been published yet.

它非常接近完成手稿的写作。

It's it got very close to having the manuscript be written.

这是在糖尿病预防计划里，所以你找不到比这更好的研究了，因为这项研究让生活方式干预和二甲双胍在应对从血糖过高、也就是前糖尿病状态过渡到糖尿病方面，发挥了重要作用。

It's in the diabetes prevention program, so you couldn't ask for a better study because this was a study that put intervention lifestyle intervention metformin on the map in terms of being able to do something about transitioning to diabetes once you had hyperglycemia, once you were pre diabetic.

这项研究大约是二十年前做的。

So this study was done about twenty years ago.

我们有基线样本，还有治疗后一年的样本。

We have baseline samples and then one year samples post treatment.

研究中的每个人都做了核磁共振分析。

All the everybody in the study had an NMR analysis done.

LPIR以及其他通过核磁共振能测量的、能让FPIR更好的指标，被证明具有独立的预测性，比胰岛素更好。

LPIR and other things that we can measure by NMR that make FPIR better if you want it to be better were shown to be independently predictive, better than insulin.

但最重要的是，因为那是一项干预研究，生活方式的改变和体重减轻被证明能显著降低这些人患上糖尿病的几率。

But most importantly, because that was an intervention study, you know, lifestyle change and weight loss was shown to significantly reduce the incidence of diabetes in these people.

二甲双胍效果稍差，但与安慰剂相比仍然显著。

Metformin less effective, but significant compared to placebo.

所以我们能够很好地证明，LPIR分数通过生活方式干预显著降低，通过二甲双胍降低的程度稍小。

So what we're able to show really nicely is that the LPIR score was reduced significantly by lifestyle, less significantly by metformin.

支链氨基酸，我们还没聊过，但支链氨基酸水平高也和胰岛素抵抗有关，还能改善LPIR评分。

Branched chain amino acids, which we haven't talked about yet, but higher branched chain amino acids are also related to insulin resistance and can improve the LPIR score.

我们其实还开发了另一个评分，叫糖尿病风险指数，就是把支链氨基酸整合或加到LPIR里。

And we actually have developed another score called the diabetes risk index that integrates or adds branched chain amino acids to LPIR.

好的，我正想问你这个。

Okay, I was going to ask you that.

所以确认一下，DRI，也就是糖尿病风险指数，是包含了三种支链氨基酸的LPIR评分，对吧？

So just to confirm, the DRI, the diabetes risk index, is the LPIR score inclusive of the three branched chain amino acids.

那你建议什么时候用其中一个，什么时候用另一个呢？

And when do you recommend using one of those versus the other?

嗯，

Well, you know,

其实这个讨论还没发展到那个程度，DRI还没被广泛接受。

it really never has gotten to be far enough along or to have the amount of acceptance that that discussion has even occurred.

DRI在Lab Corp有商用吗？有的。

Is DRI commercially available with lab corp It is.

LabCorp 确实有这项检测。

It is at LabCorp.

好的。

Okay.

我们也得跟各位提一下，大家可能好奇，你九十年代中期创立的 Liposcience 公司，早在十多年前就被 LabCorp 收购了。

We should also point out for folks who are wondering, your company liposcience that you founded in mid nineties was acquired by LabCorp ten years ago, a little more than ten years ago.

所以像我们这种老派人士，以前还习惯性地开 Liposcience 的检测单呢。

And so for those of us like me, the dinosaurs, like we used to still order a liposcience test.

现在这一切都是通过LabCorp进行的。

Now it just all happens through LabCorp.

所以我想，这应该也推动了这项检测的采用率上升。

So that presumably that has increased, I assume, some some uptake of the of the test.

所以我之后想探讨一下，为什么这项技术还没有在临床上得到广泛应用？

So I wanted at some point to get into the question of why hasn't broad clinical translation occurred?

因为确实还没有。

Because it hasn't.

现在，你

Right now, you

只能去LabCorp获取这些信息。

can only go to LabCorp for this information.

所以，如果你不介意的话，我现在就简单讲一下。

So, I'll go there now briefly, if you don't mind.

请讲。

Please.

所以，LipoScience最初是大学的一个衍生项目，我之前提到过。

So liposcience began, as I told you, as a spinoff of the university.

我离开大学后，我们努力让人们相信，颗粒大小不重要，LDL-P才重要，我们为此努力了很长时间。

I left the university, and we tried to convince people that size didn't matter and LDL P did matter, and we did that for quite some time.

我们是一家实验室测试公司，所以样本会送到LipoScience，然后你会收到结果。

And we were a laboratory testing company, and so samples were sent to liposcience and you'd get the results back.

但你们的雄心壮志，结果很漂亮，我觉得。

But the ambition You beautiful results, I think.

还有彩色报告。

And the color report.

我非常喜欢。

I loved it so much.

为什么不用彩色打印机呢？

Why not use color printers?

不，那很漂亮。

No, it beautiful.

但商业目标从来不是让实验室变得越来越大，做更多的测试。

But the business objective was never to be a lab that got bigger and bigger and did more testing.

而是让世界上任何实验室都能进行NMR测试。

It was to make the ability to do NMR testing available to any laboratory in the world.

所以我们从现有的条件开始。

So, you know, we started by what was available.

我提到过，每个化学系都有NMR设备。

I talked about NMR machines being in every chemistry department.

这些是研究用的核磁共振设备。

These are research NMR machines.

它们是为多功能而设计的。

They're engineered for multifunctionality.

你可以做任何奇特的核磁共振实验。

You can do any weird NMR experiment.

有很多不同的变体。

There's lots of variations on the theme.

我们想让核磁共振只做一件事，而且做得非常高效、尽可能快。

We wanted NMR to do one thing very efficiently and as rapidly as possible.

所以理想情况下，三十秒或更短。

And so, you know, ideally thirty seconds or less.

自动放入一个样本。

Pop one sample in automatically.

另一个样本接着进来。

Another sample comes in.

砰砰砰。

Boom, boom, boom.

所以我们意识到，研究用的核磁共振仪没法满足这个需求。

So, we realized that we couldn't use a research NMR spectrometer for that purpose.

在脂科学公司的头几年，我们只能用这种设备，因为当时没有别的选择。

We used them for the initial years at liposcience because that's all there was.

但我们想从实验室检测公司转型为IVD公司，也就是体外诊断公司。

But we wanted to transition from a lab testing company into an IVD company, in vitro diagnostics company.

所有实验室都依赖IVD公司提供设备和试剂来做各种检测。

All laboratories rely on IVD companies to supply them the machinery and the reagents to do all these assays.

比如LabCorp要做三千种检测。

So LabCorp does 3,000 assays.

他们靠罗氏等公司提供检测所需的物资。

They rely on other people, Roche, other people to provide them with the wherewithal to do the testing.

那些就是IVD公司。

Those are IBD companies.

我们想让LipoScience成为一家体外诊断公司，制造一台NMR分析仪，让一个对NMR毫无经验、完全不懂的实验室技术员，带着200个样本走过来，放上托盘，按下绿色的开始按钮，然后就可以离开了。

We wanted to be an IBD company at liposcience, make an NMR analyzer that looked just like a regular chemistry analyzer to a med tech that had no experience, no knowledge of NMR, walk up to it with 200 samples, present the tray, push the green go button and walk away.

所以，我们真的做到了。

So, that's what we actually did.

为此投入了大量的资金、时间和精力。

And a lot of investment and a lot of time and effort was put into that.

那就是Vantera NMR分析仪。

And that is the Vantera NMR Analyzer.

它是世界上唯一一台NMR分析仪。

It's the only existing NMR Analyzer in the world.

我们去找了FDA，因为这些分析仪必须通过FDA的批准才能进入不同的实验室。

And we went to the FDA because we, you know, these analyzers have to be FDA cleared in order to go into different laboratories.

那可真是一次冒险，因为FDA对NMR光谱学了解多少呢？

That was an adventure because what did FDA know about NMR spectroscopy?

而且这是一个全新的平台，一种全新的测试方式，需要被理解。

And it was a new platform, a new or new way of testing that had to be understood.

所以，总之，

So anyway,

你是什么时候拿到批准的？

when did you get the clear?

我们拿到的不是批准，

We got the no, not clear.

我们在2011年拿到了LDL P和Vantera分析仪的FDA批准。

We got FDA clearance for LDL P and the Vantera analyzer in 2011.

哦，哇。

Oh, wow.

好的。

Okay.

对，2011年。

Yeah, 2011.

所以这些Vantera分析仪，制造了不少台。

And so these these Vantera analyzers, a number of them were manufactured.

然后大约在LipoScience被卖给LabCorp之前的一年左右。

And then about the time that just before a year or so before liposcience was sold to LabCorp.

这些分析仪开始被分发到各大实验室。

These analyzers were started to be distributed to major laboratories.

LabCorp就是这些分析仪的接收者之一，这样他们就可以在内部进行测试，而不必把样本送到LipoScience。

LabCorp was one of the recipients of these analyzers, so they could do the testing in house rather than having to send the samples to liposcience.

临床实验室讨厌送样，如果是为了某种罕见癌症之类的，当事件比较罕见时，没什么大不了的。

Clinical laboratories hate sending send out samples, And when that's for a rare cancer or something, when it's a fairly rare event, no big deal.

如果你每天要处理几百个这样的样本，你就不想有这种麻烦。

If you're doing hundreds of these a day, you don't want that hassle.

所以他们很高兴收到Vantera分析仪，这样他们就可以在内部进行测试。

So, they were very happy to receive the Vantera analyzer so they could do the testing in house.

而且每次他们这样做，都会为每次分析向LipoScience支付费用。

And every time they did, would pay liposcience for each analysis.

好的，那就是商业模式。

Okay, that was the business model.

我们还把Vantera分析仪提供给了梅奥诊所、克利夫兰诊所、斯克里普斯诊所，以及犹他州一家大型参考实验室。

We also made Vantera analyzers available to the Mayo Clinic, Cleveland Clinic, Scripps Clinic, a rough a big reference laboratory in Utah.

所以我们正在朝着广泛推广的方向前进。

So we were on the way to making it available broadly.

因为我们不想成为唯一能做NMR检测的机构，而且我们也想让人们相信这不是什么神奇的东西。

Because we didn't want to be the only people that could do NMR testing, and also we wanted to convince people that this wasn't, you know, magic.

这是真实可靠的，而且在很多方面，它在分析性能上比基于试剂的化学检测要好得多。

It was real, and it was analytically in many respects much better than reagent based chemistry testing.

不幸的是，那时Liposcience已经上市了。

Unfortunately, by that time liposcience had gone public.

我已经不在董事会了。

I was no longer on the board.

我基本上就是启动Liposcience所需的那笔投资。

I was basically the investment that we needed to start liposcience.

我们花了太长时间才让最初的投资者获得回报。

We basically took too long to get to the payout of the initial investors.

所以，投资者们没有耐心了。

So people, the investors were not patient.

他们在那之前一直很有耐心，但你几乎不能怪他们，因为他们想拿回自己的钱，尤其是风险投资。

They were very patient up until then, but you almost couldn't blame them because they wanted to get their money back, venture capital in particular.

所以，公司上市了，然后LabCorp过来说，我们想收购你们，因为如果我们每次做这个测试都不用付给liposcience那么多钱，我们能赚更多。

So, the company went public and then LabCorp came along and said, we'd like to buy you because we can make more money if we don't have to pay whatever number of dollars to liposcience every time we do this test.

所以，这纯粹是一个财务决策。

So, it was a purely financial decision.

LabCorp其实并不关心测量除了NMR血脂谱、LDL P等之外的东西。

LabCorp really didn't care about measuring things other than the NMR Lipo profile, the LDL P, etc.

这是基于财务考虑的。

It was financially based.

这对让每个实验室都有NMR分析仪的愿景来说太可惜了，因为LabCorp是一家实验室检测公司。

That was too bad for the vision of having NMR analyzers in every laboratory because LabCorp is a lab testing company.

它不是一家IVD公司。

It's not an IVD company.

所以很遗憾，IVD商业模式和IVD愿景就这样结束了。

So too bad the IVD business model, the IVD vision.

在2014年画上了句号。

Was ended in 2014.

所以是的，

So yes,

你加入了吗？

did you join?

你有没有去当科学家？

Did you go and become a scientist

所以研究团队大部分被LabCorp保留了。

So research group largely was retained by LabCorp.

所以我们当时有一系列的项目，比如LP-IR和DRI这些，都是后来会提到的。

So we had a pipeline of things like LP-IR and things DRI things that were coming down the pike that we'll talk about later.

所以其实最好的还在后面，那些能说服人们实验室里放Vantera分析仪既有商业价值又有临床价值的东西。

So really the best was yet to come in terms of the clinical value and the things that could convince people that having Vantera analyzers in their lab was a commercially useful thing, but also a clinically useful thing.

坏消息是，LabCorp 可以理解地没有分享 IVD 的愿景，而且作为一家希望 NMR 技术为自己所独有的实验室，他们收回了那些放在其他参考实验室的分析仪。

So the bad news is that LabCorp understandably not sharing the IVD vision and being a laboratory that wanted to have NMR be proprietary to themselves, took back these analyzers that had been placed in these other reference laboratories.

然后，不像 Liposcience 那样，知道在开发新测试时，需要费心去创造认知和兴趣，并进行研究来证明这些测试的临床有效性。

And then unlike liposcience that knew that when it developed a new test, it needed to go to the trouble of creating awareness and interest and doing the studies to prove the clinical efficacy of these tests.

那是一项非常重要的活动。

That's a that's a very important activity.

LabCorp 不会这样做，因为他们不是一家 IVD 公司。

LabCorp doesn't do that because they're not an IBD company.

他们是反应式的。

They are reactive.

他们不是主动式的。

They're not proactive.

他们非常擅长反应，在 COVID 期间，他们迅速增加了 COVID 测试。

They're very good at being reactive and in COVID, they ramped up the COVID testing.

而且，你知道，我并不是说 LabCorp 在他们所做的事情上做得不好。

And you know, so I'm not, you know, saying that that LabCorp doesn't do a really good job at what they do.

但他们真的不知道如何处理通过收购LipoScience在内部产生的新知识。

But they really didn't know what to do with new knowledge that they generated in house by acquisition of liposcience.

所以没有营销，没有意识培养，基本上LipoScience就消失了，而且至今仍然很大程度上不为人知。

And so there was no marketing, no awareness creation, and basically liposcience went invisible and is still largely invisible.

大部分测试仍然是由那些因为LipoScience的努力而对测试感兴趣的人完成的。

Most of the testing is still done by the people that were interested in the testing, thanks to liposcience's efforts.

所以，这些十五年前生产的X台分析仪，就是LabCorp用来生成这些信息和这些更令人兴奋的

So, these X number of analyzers that were produced fifteen years ago are what LabCorp is using to produce this information and this more exciting

这些分析仪的寿命是多久？

And what's the life of these analyzers?

问得好，因为从来没有人问过。磁体本身，这些 superconducting 磁体，能持续很长时间，不会退化，但他们用的是十年前的PC。

Good question because nobody's ever so the magnets themselves, these superconducting magnets, last a long time and don't degrade, but they're using PCs, you know, ten year old PCs.

而且，所有那些移动部件。

And anyway, they're all the moving parts.

所以它们不会持续太久了。

So they're not going to last much longer.

这也是我最担心、最希望大家了解的一点，因为要让这个临床转化在LabCorp继续下去，并且理想情况下推广到全世界，需要有人来做这件事。

And this is what maybe I'm most concerned about and most interested in people hearing about because what needs to happen for this to continue, this clinical translation to continue at LabCorp, But also ideally broaden to the rest of the world.

那就是需要一家IBD公司来收购liposcience的技术，这里面有很多相关的专利和知识产权。

Is for an IBD company to come in and basically acquire the liposcience technology and there's a lot of patents intellectual property associated with this.

还有很多专业知识，包括如何维护这些机器，让它们正常运行。

A lot of expertise that comes from in terms of service and keeping these machines functioning well.

这些不是学来的。

And you don't learn.

我们做了几百万次测试，都是通过实践积累的经验。

I mean, we've done so many millions of tests and you learn by doing.

所以大家不知道的是，在未来的某个时候，可能很快，这些第一代Vantera分析仪。

So what people don't know is that at some point in the future, maybe sooner rather than later, these Vantera analyzers first generation.

也是唯一一代，会停止工作，那将非常可惜，尤其是考虑到我们接下来要讨论的比LPIR更令人兴奋的东西，比如LDL P等等。

Only generation are going to cease to function and it would be a real shame, especially with the things that we're gonna talk about that are more exciting than LPIR, and in my mind, LDL P, etcetera.

所以这里有个问题。

So there's an issue here.

这里有个问题，希望有体外诊断公司能接手解决。

There's a problem, and hopefully it'll be addressed by an IBD company taking over.

我尝试向大型跨国体外诊断公司说明这个情况。

I've tried to make the case to big multinational IBD companies.

但他们觉得核磁共振技术太冷门了。

But NMR is too exotic.

我基本上向他们展示，这是一个完全没有风险的投资机会，因为我们已经通过了所有监管审批。

I mean, I I basically show them that this is a completely de risked population proposition because we've already gone through the regulatory hurdles.

我们已经造好了分析仪。

We've already made the analyzers.

我们也有了丰富的经验。

We already have the experience.

所以这不是从零开始，不是要面对你不熟悉的技术。

So it's not like starting from scratch with something that you're unfamiliar with, technology you're unfamiliar with.

但这些大公司往往行动迟缓，很难找到合适的负责人，或者指望他们能有创业精神。

But, you know, these big companies have a lot of inertia and talking to the right people or having these big companies be entrepreneurial.

所以，我觉得如果这事能成的话，可能会是一家较小的IVD公司，或者一家新的IVD初创公司来接替LipoScience的接力棒。

So, I think this is maybe if it happens, it'll be possibly a smaller IVD company or a new startup IVD company basically taking the torch that that liposcience has.

LipoScience有没有说过他们愿意出售这些资产？

Has liposcience said that they would be willing to sell those assets?

知识产权？

The IP?

其实是LabCorp拥有所有这些。

It's it's LabCorp that owns all

抱歉，我是说。

the Sorry, that's I mean.

LabCorp有没有说过他们愿意……

Has LabCorp said that they're

愿意出售那些？是的，他们愿意，而且我觉得他们也意识到，嗯……

willing to sell that Yes, they're and I think they realize that they well.

是的，他们对授权很感兴趣。

Yes, they're they're interested in licensing.

这些专利，大部分都是关于检测方法的。

The the patents most of the patents have to do with the assays.

就是LP-IR和MBX，我们后面会讲到。

So LP-IR and MBX that we'll talk about.

所以，绝对是的。

So absolutely.

但是，如果没有机器来产生这些信息，谁会来授权这些专利呢？

But who's going to license them if there's no machinery to produce the information?

所以，这些，这些，这些……

So so these these these

这些机器，如果要制造第二代的话，现在成本是多少？

these cost per machine now if you were going to make a Gen two?

嗯，这些机器大概要四五十万美元一台。但好处是，当然，它们能用很长时间，我们已经证明了这一点，而且检测本身不需要任何消耗品。

Well, so these these machines cost on the order of 4 or $500,000 But the beauty of it is, of course, that they last a long time, which we've shown, but they have no consumables associated with the assay.

所以，每天做10次检测和做1000次检测，成本是一样的。

So it costs just as much to do 10 assays a day as 1,000 assays a day.

所以在高流量的环境下，这些测试非常便宜。

So, in a high volume setting, these tests are very cheap.

我们之前聊过，LDL P和NMR LipoProfile报告就是给人们提供LDL P信息的。

And what we've talked about, we talked about LDL P and the NMR LipoProfile was the report that gave people the LDL P information.

但那个报告其实来自这个简单的NMR谱，我们可以从中提取出比LDL P、LPI或DRI多得多的信息。

But that comes from this simple NMR spectrum that can then use to be extract much more information than LDL P, LPI, or DRI.

这只是故事的一部分。

It's just part of the story.

后面我们还会聊到其他很多内容。

There's all these other things that we'll talk about later.

从效率和分析效率的角度来说，你找不到比这更好的了，因为你知道，如果你想用NMR来做血脂检测，而且实际上，在告诉你NMR只测量颗粒而不是胆固醇之后，基本信息都包含在这些NMR信号里。

So in terms of efficiency, analytic efficiency, you couldn't ask for anything better because you know, if you want to use NMR to produce a lipid panel and actually after telling you that NMR only measured particles and not cholesterol, the basic information is encapsulated in all these NMR signals.

所以你可以把NMR数据输入到机器学习算法或AI中，训练它来生成准确的血脂检测和apoB信息。

So you can actually feed NMR data to a machine learning algorithm AI and train it to produce accurate lipid panel and apoB information.

我们四五年前就发表过相关研究，证明可以用NMR谱来生成扩展的血脂检测，包括apoB和血脂，而且不会增加额外成本。

So we published this four or five years ago that you can actually use the NMR spectrum to produce an extended lipid panel, apoB plus lipids, no incremental cost to a lipid panel.

载脂蛋白B不会增加成本。

The apoB doesn't add cost.

如果通过化学方法检测并按照美国的常规报销标准，成本会超过血脂检测的两倍。

It more than doubles the cost of a lipid panel if you want to do it by chemistry and use regular reimbursement in The US.

所以这在分析上非常高效，也很有成本效益。

So it's extremely analytically efficient and cost effective.

人们可能没有意识到这一点，我当初作为一个天真的教授也没意识到。我当时想，如果这能降低检测成本，那肯定会有商业吸引力。

The thing that people probably don't appreciate and I didn't appreciate as a naive professor, I thought, well, surely this will be commercially attractive if it can cut the cost of doing these tests.

但这些检测的成本远低于收费价格，而且保险公司支付的费用也远高于成本，所以即使把分析成本减半，也根本没什么区别。

The cost of these tests is so much smaller than the price that is charged for these and the insurance pays for these tests that cutting the price the cost in half of doing the analysis makes no difference whatsoever.

所以，这可能是我们稍后会讨论的内容，因为事实是，一次核磁共振扫描能告诉你的远不止心血管风险、炎症水平和糖尿病风险。

So, this is, you know, my we'll maybe get into this later because what is true is that NMR, a single scan can tell you a heck of a lot more than just your cardiovascular risk, your inflammation level, your diabetes risk.

还有你的整体死亡率，也就是我们接下来要讨论的死亡风险。

Your overall mortality Your mortality risk as we're about to discuss.

这些基本上都来自同一次检测。

This all comes in the same assay, essentially.

我想不出比这更好的方式来介绍MVX检测了。

Well, I can think of no better way to introduce the MVX assay.

所以我来给你铺垫一下，然后把这个故事讲完。

So I'll tee it up for you and then take take away the story.

顺便说一下，我去做了我的第一次MVX检测。

So by the way, I went to have my first MVX drawn.

我们已经给患者做了大约四个月了，我自己却一直没抽出时间去给自己做个血液测试。

We've been doing it on our patients for about four months now, and I just haven't got around to doing a blood test on myself.

所以两周半前我去了LabCorp，因为我希望我们坐在这里的时候结果已经出来了。

So I went out to LabCorp two and a half weeks ago because I wanted to have the results back when we were sitting here.

你猜怎么着，吉姆，他们搞砸了检测。

And wouldn't you know it, Jim, they screwed up the assay.

所以我没有结果。

So I don't have it.

其他所有检测结果都拿到了。

They got everything else.

其他所有检查他们都做了，但这个他们搞砸了。

Every other test we ordered they got, but they they butchered this one.

所以我自己没有结果可以讲。

So I don't have my my own to talk about.

但MVX是一个综合评分，如果我没记错的话，它衡量六项指标。

But the MVX is a is a is a composite score that measures, if I recall, six things.

包括小HDL颗粒、甘氨酸A，这个我们还没介绍过，之后会讲，还有柠檬酸，以及三种支链氨基酸。

So small HDLP, glycA, which we haven't introduced yet and we'll talk about, citrate, and the three branched chain amino acids.

就是亮氨酸、异亮氨酸和缬氨酸。

So, leucine, isoleucine, valine.

那你来给我们讲讲你是怎么开发出这个评分的吧。

So why don't you tell us the story of how you developed this score?

我先给大家一个预告，让听众知道为什么要关注这个。

And I'll just give the punch line so the listener knows why they should be paying attention.

这个评分在归一化到0到100的数值后，似乎有非常显著的效果。

This score seems to have remarkable when it's normalized to a, you know, zero to a 100 number.

分数越高，情况越糟。

The higher the score, the worse it is.

这个分数似乎对各种我们想避免的事情都有显著的预测价值，从死亡、心血管死亡到肝脏疾病。

This score seems to have remarkable predictive value of all sorts of things we want to avoid, starting with death, cardiovascular death, liver disease.

虽然我看到的第一个研究是在一个非常高风险的导管插入患者群体中进行的，很容易被忽视，认为它只对该人群有价值，但它也在健康人群中得到了验证。

While it's first, while the first study that I saw was done in a very, very high risk group of catheterized patients, and it would be easy to dismiss that it was only valuable in that population, it's been demonstrated in healthy populations as well.

跟我们讲讲这个分数吧。

So tell us about the score.

这确实是个很有趣的故事。

So it's a really interesting story.

有人会问，你是怎么想到测量这些指标的？或者你是否有某种机制上的理由来关注这些最终构成MVX代谢脆弱性指数分数的东西？

And one question that gets asked is, well, why did you think of measuring those things, or did you have some mechanistic reason for focusing on these things that ended up contributing to this MVX metabolic vulnerability index score?

答案是没有。

And the answer is no.

事情并不是那样发生的，而且我确实想强调这一点，因为……

That's not how it happened, and I just I do want to make this point because.

MBX，尤其是MBX，目前带来的问题比答案还多。

MBX and especially MBX raises more questions than answers right now.

好的，所以你真的很想知道，如果它预测死亡率这么准，那它为什么能做到这一点？

Okay, so you really would like to understand if it predicts mortality so well, why does it do that?

这是因果关系吗？

Is it causal?

我们能干预吗？

Can we intervene?

这些才是临床上真正重要的问题。

You know, these are the things that really matter clinically.

所以一开始并不是因为觉得支链氨基酸在机制上很重要，尽管它们确实重要。

So it wasn't starting out with some idea that branched chain amino acids are really important mechanistically, even though they are.

这是因为核磁共振分析给我们提供了一个非常高效的工具，可以测量那些长期跟踪研究中的基线样本。

This was because NMR analysis has given us a very efficient tool to measure baseline samples from studies that follow people over time.

十年、二十年、三十年甚至更久。

Ten years, twenty years, thirty years longer.

去看看会发生什么，所以你真正想要的生物标志物的最终理念就是这一点。

To see what develops, and so you really would like the ultimate idea in a biomarker is that.

它能预测未来。

It predicts the future.

我们想知道的不只是它是否与心血管疾病相关，而是它是否与未来患上心血管疾病相关。

Want to know not if it's related to cardiovascular disease, but is it related to getting cardiovascular disease in the future?

所以多年来，我们利用了许多大型临床研究的基线样本。

And so we have availed ourselves of over the years of baseline samples from many very large clinical studies.

你提到了MESA，即多种族动脉粥样硬化研究。

You mentioned Mesa multiethnic study of atherosclerosis.

那是一项由美国国立卫生研究院资助的研究，大约在2000年开始。

That's an NIH funded study that started in about 2000.

到现在已经有超过二十年的随访了。

It's had more than twenty years of follow-up now.

十五、二十年前，我们被要求免费测量这些基线样本。

We were asked to measure the baseline samples fifteen, twenty years ago for free.

现在我在一家需要赚钱的公司工作，但我有足够的自由来提供那个测试。

Now I've worked for a company that has to make some money, but I had enough freedom to be able to offer that test.

起初我要求收费，但后来他们最终说，我们实在找不到资金来支付，但我们真的很想获得这些信息。

Initially I asked for money, but then they finally said, well, we just can't find the money for that, but we'd really like to have the information.

所以最后就免费测量了。

So it was measured for free.

其他大型研究也是如此。

Same thing from other very large studies.

比如女性健康研究，基线时有26000名女性，这项研究已经跟踪了很多很多年。

Women's health study, 26,000 women at baseline in a study that's been followed up for many, many years.

还有弗雷明汉后代研究，以及各种干预试验，比如Jupiter等。

Framingham Framingham offspring study, all sorts of intervention trials, Jupiter, etc.

还有糖尿病预防计划。

The diabetes prevention program.

我想快速回到这一点，就两秒钟，因为我们还没有说完糖尿病预防计划告诉我们什么，尽管它还没有发表。

I would like to quickly go back to that just for two seconds because we didn't finish the thought of what a diabetes prevention program, even though it's not published, tell us.