Sunday Sermonette: Finally some actual proverbs

Chapter three is mostly more of the same vague drivel -- listen to Daddy, fear God, yadda yadda. Verse 5 says "lean not on your own understanding," and verse 6 says "Do not be wise in your own eyes," but back in Chapter 2 -- i.e. the preceding page -- the whole point was to make yourself wise. "if you call out for insight,  and cry aloud for understanding, ⁴ and if you look for it as for silver  and search for it as for hidden treasure, ⁵ then you will understand the fear of the Lord and find the knowledge of God." Well, I did call out for insight, and cry aloud for understanding, and I didn't end up where the writer thought I would. 

Anyway, finally at the end of this we do get a few of those pithy sayings that we call proverbs in English, adjoining generosity to neighbors, which I can get behind. On the other hand, the whole thing lands on the Just World Fallacy, which I have discussed before. I'm still waiting for the profound wisdom.

Wisdom Bestows Well-Being

3 My son, do not forget my teaching,
    but keep my commands in your heart,
² for they will prolong your life many years
    and bring you peace and prosperity.

³ Let love and faithfulness never leave you;
    bind them around your neck,
    write them on the tablet of your heart.
⁴ Then you will win favor and a good name
    in the sight of God and man.

⁵ Trust in the Lord with all your heart
    and lean not on your own understanding;
⁶ in all your ways submit to him,
    and he will make your paths straight.^[a]

⁷ Do not be wise in your own eyes;
    fear the Lord and shun evil.
⁸ This will bring health to your body
    and nourishment to your bones.

⁹ Honor the Lord with your wealth,
    with the firstfruits of all your crops;
¹⁰ then your barns will be filled to overflowing,
    and your vats will brim over with new wine.

¹¹ My son, do not despise the Lord’s discipline,
    and do not resent his rebuke,
¹² because the Lord disciplines those he loves,
    as a father the son he delights in.^[b]

¹³ Blessed are those who find wisdom,
    those who gain understanding,
¹⁴ for she is more profitable than silver
    and yields better returns than gold.
¹⁵ She is more precious than rubies;
    nothing you desire can compare with her.
¹⁶ Long life is in her right hand;
    in her left hand are riches and honor.
¹⁷ Her ways are pleasant ways,
    and all her paths are peace.
¹⁸ She is a tree of life to those who take hold of her;
    those who hold her fast will be blessed.

¹⁹ By wisdom the Lord laid the earth’s foundations,
    by understanding he set the heavens in place;
²⁰ by his knowledge the watery depths were divided,
    and the clouds let drop the dew.

²¹ My son, do not let wisdom and understanding out of your sight,
    preserve sound judgment and discretion;
²² they will be life for you,
    an ornament to grace your neck.
²³ Then you will go on your way in safety,
    and your foot will not stumble.
²⁴ When you lie down, you will not be afraid;
    when you lie down, your sleep will be sweet.
²⁵ Have no fear of sudden disaster
    or of the ruin that overtakes the wicked,
²⁶ for the Lord will be at your side
    and will keep your foot from being snared.

²⁷ Do not withhold good from those to whom it is due,
    when it is in your power to act.
²⁸ Do not say to your neighbor,
    “Come back tomorrow and I’ll give it to you”—
    when you already have it with you.
²⁹ Do not plot harm against your neighbor,
    who lives trustfully near you.
³⁰ Do not accuse anyone for no reason—
    when they have done you no harm.

³¹ Do not envy the violent
    or choose any of their ways.

³² For the Lord detests the perverse
    but takes the upright into his confidence.
³³ The Lord’s curse is on the house of the wicked,
    but he blesses the home of the righteous.
³⁴ He mocks proud mockers
    but shows favor to the humble and oppressed.
³⁵ The wise inherit honor,
    but fools get only shame.

Footnotes

1. Proverbs 3:6 Or will direct your paths
2. Proverbs 3:12 Hebrew; Septuagint loves, / and he chastens everyone he accepts as his child

Cross of Gold

Like most people, I was surprised and puzzled by Joe Biden's condition on Thursday night. Maybe he had taken a cold medication, but if a shot of Vicks will do that to him he's got a problem. Of course, the conventional wisdom that being out of it is worse than spewing nonstop lies seems askew, but that's where we are. Nobody care what I think but yeah, Biden should drop out.

There are very good reasons why the clinical trials process I just described is required to get FDA approval for new drugs (or procedures, but we're sticking with drugs for now to keep it simple). I shouldn't have to tell y'all about the Thalidomide catastrophe, and even if it doesn't outright kill people or cause horrific birth defects, a pill that just doesn't work is a) going to waste a lot of money and b) stop people from taking one that does work. However . . . .

New drug development, like everything else that goes on in the medical industry, is not driven by humanitarian objectives, but by profit. Which means, ipso facto, that the drug companies are going to make their decisions about those big investments based on their best guesses about how they can make the most profit. And the profit in drugs comes in large part from patent protection and exclusive marketing rights -- if you can sell it with no competition, you can charge big bucks. This has several unfortunate consequences. e.g.:

• There's little or no money to be made in showing that a product that is already on the market and can't be patented has a previously unproven use. So there may be a lot of beneficial uses out there that we just don't know about. Same goes for products of nature.

• There's a lot more money to be made from something people have to keep taking for a long time than there is from something that you only take once, or a for a few days. That's why, for example, there's been little investment in new antibiotics, though they are sorely needed.

 

• There's little money to be made from products that treat rare diseases. There are incentives for developing these "orphan drugs," but that doesn't fully overcome the distortion that favors more common conditions.

• There's a lot of money to be made from products that treat people who are facing imminent death, for which society will countenance enormous expense. New cancer treatments typically cost $100,000 or two or three times as much, but they typically offer only very modest extension of life. Products that improve quality of life for larger numbers of people, or extend life in the long run but don't stave off imminent death, won't withstand such high prices. That's a feature of a quirk of human psychology called the Rule of Rescue, which I'll talk about more anon.

So, we really need a different way of financing new drug development, and of deciding what we're willing to pay for.

Wednesday Bible Study: Evil woman

Chapter two is mostly just more vague exhortation to listen to Daddy, heed the word of God (wherever that actually comes from is not specified), and not to listen to guys who tell you the wrong stuff, whatever that is. But then there is one specific exhortation, which is not to get involved with married women. It strikes me that this may be intended as a metaphor of some sort, but otherwise it's a bit jarring that this is the first specific advice we get. 

 

By the way, I've switched here to the New International Version, which seems cleaner. RSV has footnotes telling you the words don't actually mean what the translators have chosen, which doesn't make any sense to me. They mean, according to RSV, what the NIV actually says they do. Which is a reminder that even if you're fluent in Hebrew, you can't actually read the Tanakh as people did when it was compiled, because we just don't know exactly what a lot of it meant. That's why the Talmud exists -- centuries of effort by Jewish scholars to decide what all of this really means, and they still haven't stopped trying.

Moral Benefits of Wisdom

2 My son, if you accept my words
    and store up my commands within you,
² turning your ear to wisdom
    and applying your heart to understanding—
³ indeed, if you call out for insight
    and cry aloud for understanding,
⁴ and if you look for it as for silver
    and search for it as for hidden treasure,
⁵ then you will understand the fear of the Lord
    and find the knowledge of God.
⁶ For the Lord gives wisdom;
    from his mouth come knowledge and understanding.
⁷ He holds success in store for the upright,
    he is a shield to those whose walk is blameless,
⁸ for he guards the course of the just
    and protects the way of his faithful ones.

⁹ Then you will understand what is right and just
    and fair—every good path.
¹⁰ For wisdom will enter your heart,
    and knowledge will be pleasant to your soul.
¹¹ Discretion will protect you,
    and understanding will guard you.

¹² Wisdom will save you from the ways of wicked men,
    from men whose words are perverse,
¹³ who have left the straight paths
    to walk in dark ways,
¹⁴ who delight in doing wrong
    and rejoice in the perverseness of evil,
¹⁵ whose paths are crooked
    and who are devious in their ways.

¹⁶ Wisdom will save you also from the adulterous woman,
    from the wayward woman with her seductive words,
¹⁷ who has left the partner of her youth
    and ignored the covenant she made before God.^[a]
18 Surely her house leads down to death
    and her paths to the spirits of the dead.
¹⁹ None who go to her return
    or attain the paths of life.

²⁰ Thus you will walk in the ways of the good
    and keep to the paths of the righteous.
²¹ For the upright will live in the land,
    and the blameless will remain in it;
²² but the wicked will be cut off from the land,
    and the unfaithful will be torn from it.

Footnotes

1. Proverbs 2:17 Or covenant of her God

Clinical Trials, the downside, part two

My first bullet was basically, clinical trials are really expensive. I should add that they take a long time and there are limited resources for doing them. Ergo, there's a selection process that needs to precede a large scale, high quality trial that might convince the FDA to approve a new drug or procedure. I'll just talk about medications for now to keep it simple.

First, obviously, you need some reason to think a compound (or a more complicated biological entity such as a monoclonal antibody) will be of use for some clinical indication. Drug companies screen all sorts of candidates, often starting in vitro to see if they have an effect on cells in culture that might translate into a useful effect in a whole organism. The next step would be to try the compounds in animals. For reasons of expense and convenience, and also because people have strong reservations against experimenting on species that are closely related to us, these are usually rodents.

Your first problem is to get mice that have a condition or disease that resembles a disease of humans. If you're testing antibiotics that isn't very complicated, you can just infect them. (In case any PETA members are reading this, yes, some people think this is unethical.) Otherwise, however, diseases in mice can't really be exactly the same as diseases in people. Gene editing has now become very precise so it's possible to create mice with a mutation which is closely analogous to a human genetic defect, but since our genomes are different from those of mice to begin with this won't be a perfect analog. You can induce cancer in lab animals by various means, but again you'll never have a cancer that's identical in either it's genetic alterations or its environment to a particular cancer in humans. And so on.

Sadly, therefore, it is most often the case that treatments that appear promising in laboratory animals don't end up being useful in humans. So you've already spent some money but now you need to spend a whole lot more to see if this can work in people. The first step is called a Phase One trial. This will start with a very small number of volunteers -- maybe just one. They'll give the initial group a very small dose, to make sure it's safe; to start to understand its "pharmacokinetics," that is how it is metabolized and how long it remains in the bloodstream, or perhaps where it goes in the body; and if it has any of the desired biological effect, however measured. This doesn't mean effectively treating or curing the disease, just whether it seems to be doing whatever it is you want it to be doing in the immediate term.

Then the investigators will try gradually increasing the dose, so they can find the window in which there aren't any immediately obvious serious adverse effects but the desired biological effects are occurring. At this point it may become apparent that the trial can't proceed, because there's no therapeutic window or the stuff just doesn't work in people after all. By the way the volunteers don't necessarily even need to have the disease for this phase, though they often do because that's who's likely to volunteer. Anyway, if it still looks promising, at this point you can go to a Phase II trial.

This is a trial with more subjects, but still not enough to be confident you'll get statistically reliable results. Here you definitely do want people who have the target condition, because you want to get a preliminary idea of what the range of responses is, and of course you're also looking at more people, perhaps for a somewhat longer time, to try to catch any adverse effects. However, your length of follow-up is going to be fairly short, so unless what you have on your hands is a miracle cure the outcomes you're looking for may well be so-called "surrogate endpoints" -- not, say, longer survival or reduced risk of a heart attack or long term symptom relief. Rather, you're looking for biological markers which you believe are associated with the desired long-term outcome.

You've already spent a lot of money, but you may or may not be able to go on to Phase III. If you do get the green light and the funding, you will need to recruit hundreds of people who meet eligibility criteria. This means having the disease, likely within a certain range of severity and/or duration; maybe excluding people with certain comorbidities, children, women of childbearing age, people who can't freely give consent. (They used to experiment on prisoners and people in mental institutions, but that's severely restricted now.) That's expensive. It's probably going to require enlisting clinical practices around the country and paying them to recruit subjects and perhaps actually conduct the trial at their site.

Even at this stage, because of the expense, follow-up may be too short to really establish that the treatment is effective -- six months is typical -- so we may still be looking at surrogate endpoints. I'll get into all the other problems and limitations later, but for now we'll just stick with the fact that this is very expensive and it takes a long time. Next, I'll discuss how that very basic problem shapes and misshapes the research enterprise.

Sunday Sermonette: Something completely different

The book called Proverbs in English is attributed to Solomon, but like the attribution of the Torah to Moses and most of the Psalms to David, this is entirely fanciful. Proverbs (the Hebrew title mashal has a broader meaning, more like wisdom) is actually a compilation of at least six different works written over the course of a millennium. Actually the third section was originally an Egyptian work written in the second millennium BCE which probably came to the Hebrew scribes by way of Aramaic. I'll talk about what we know of the origins of each section as we come to them. 

The first section, chapters 1 through 9, was actually the last to be composed, probably during the Second Temple period, and it appears to have Achaemenid sources, which makes sense. The first chapter is a wordy introduction, in the persona of a father addressing his son. It doesn't manage to say much of anything except that the kid had better damn well listen to the father's advice, and if he doesn't, the father won't come to his rescue. That's it.

 

1 The proverbs of Solomon, son of David, king of Israel:

Prologue

² That men may know wisdom and instruction,
    understand words of insight,
³ receive instruction in wise dealing,
    righteousness, justice, and equity;
⁴ that prudence may be given to the simple,
    knowledge and discretion to the youth—
⁵ the wise man also may hear and increase in learning,
    and the man of understanding acquire skill,
⁶ to understand a proverb and a figure,
    the words of the wise and their riddles.

⁷ The fear of the Lord is the beginning of knowledge;
    fools despise wisdom and instruction.

Warnings against Evil Companions

⁸ Hear, my son, your father’s instruction,
    and reject not your mother’s teaching;
⁹ for they are a fair garland for your head,
    and pendants for your neck.
¹⁰ My son, if sinners entice you,
    do not consent.
¹¹ If they say, “Come with us, let us lie in wait for blood,
    let us wantonly ambush the innocent;
¹² like Sheol let us swallow them alive
    and whole, like those who go down to the Pit:
¹³ we shall find all precious goods,
    we shall fill our houses with spoil;
¹⁴ throw in your lot among us,
    we will all have one purse”—
¹⁵ my son, do not walk in the way with them,
    hold back your foot from their paths;
¹⁶ for their feet run to evil,
    and they make haste to shed blood.
¹⁷ For in vain is a net spread
    in the sight of any bird;
¹⁸ but these men lie in wait for their own blood,
    they set an ambush for their own lives.
¹⁹ Such are the ways of all who get gain by violence;
    it takes away the life of its possessors.

The Call of Wisdom

²⁰ Wisdom cries aloud in the street;
    in the markets she raises her voice;
²¹ on the top of the walls^[a] she cries out;
    at the entrance of the city gates she speaks:
²² “How long, O simple ones, will you love being simple?
How long will scoffers delight in their scoffing
    and fools hate knowledge?
²³ Give heed^[b] to my reproof;
behold, I will pour out my thoughts^[c] to you;
    I will make my words known to you.
²⁴ Because I have called and you refused to listen,
    have stretched out my hand and no one has heeded,
²⁵ and you have ignored all my counsel
    and would have none of my reproof,
²⁶ I also will laugh at your calamity;
    I will mock when panic strikes you,
²⁷ when panic strikes you like a storm,
    and your calamity comes like a whirlwind,
    when distress and anguish come upon you.
²⁸ Then they will call upon me, but I will not answer;
    they will seek me diligently but will not find me.
²⁹ Because they hated knowledge
    and did not choose the fear of the Lord,
³⁰ would have none of my counsel,
    and despised all my reproof,
³¹ therefore they shall eat the fruit of their way
    and be sated with their own devices.
³² For the simple are killed by their turning away,
    and the complacence of fools destroys them;
³³ but he who listens to me will dwell secure
    and will be at ease, without dread of evil.”

Footnotes

1. Proverbs 1:21 Heb uncertain
2. Proverbs 1:23 Heb Turn
3. Proverbs 1:23 Heb spirit

 

Back on Track: Cross of Gold

Randomized controlled trials (RCTs) are said to be the "gold standard" of evidence.  (Which is a misapplication of the term, BTW, a gold standard means a monetary system in which the unit of account is based on a quantity of gold. Doesn't really make sense. But I digress.) However, if we were dependent on them for our biomedical knowledge we wouldn't actually know very much. In fact, that we depend on them so much constrains our knowledge. Let me first give a bullet list of problems and limitations. Then I'll unpack it.

1. They're very expensive. This is a really big problem because pharmaceutical companies won't do them unless there's a bit pot of gold at the end of the rainbow. That means, for example, that they are much less interested in drugs that cure quickly than they are in drugs you have to take for the rest of your life. And lots of other reasons why the cheapest and best drugs don't even make it to market.
2. The strictly defined and controlled conditions of RCTs are not the conditions in the real world in which interventions will actually be used. What works in an RCT might not work as well, or at all, in the wild.
3. To provide for cleaner inference, the people who are eligible for RCTs are usually not typical. For example, people with certain comorbidities may be excluded, or women of childbearing age, or children. Also, for various reasons, some categories of people may be underrepresented.
4. RCT results are confounded by "heterogeneity of treatment effect." Some people may respond well to a treatment, others not at all, or they have severe side effects, or the original problem can even get worse. When this averages out or dilutes the effect, we may not be able to see that the treatment really does work for some people. Post-hoc analyses are statistically invalid, so if it looks as though a subgroup may benefit, you have to go back and do a new trial just to confirm that. Again, that's expensive, and if the number of people who may benefit is small, the drug companies won't invest the money.
5. In many situations, it's literally impossible to do a RCT. It may be impossible to blind subjects or assessors, it may be unethical to have an adequate comparison,  it may not be possible to assign people at random, and there are other problems.

I'll start with the basic question of money in the next post.

Wednesday Bible Study: Let's get this over with

The last four psalms are just over-the-top songs of praise to God. He makes everything happen, basically. Like most of the psalms, these don't really add anything. They just say the same things over and over. I won't say much about these except that, again, Yahweh is not a universal God, He is exclusive to Israel; and one reason he gets praise is because he humiliates and murders other people. 

Anyway, here goes. Next we're on to Proverbs.

147 Praise the Lord!
For it is good to sing praises to our God;
    for he is gracious, and a song of praise is seemly.
² The Lord builds up Jerusalem;
    he gathers the outcasts of Israel.
³ He heals the brokenhearted,
    and binds up their wounds.
⁴ He determines the number of the stars,
    he gives to all of them their names.
⁵ Great is our Lord, and abundant in power;
    his understanding is beyond measure.
⁶ The Lord lifts up the downtrodden,
    he casts the wicked to the ground.

⁷ Sing to the Lord with thanksgiving;
    make melody to our God upon the lyre!
⁸ He covers the heavens with clouds,
    he prepares rain for the earth,
    he makes grass grow upon the hills.
⁹ He gives to the beasts their food,
    and to the young ravens which cry.
¹⁰ His delight is not in the strength of the horse,
    nor his pleasure in the legs of a man;
¹¹ but the Lord takes pleasure in those who fear him,
    in those who hope in his steadfast love.

¹² Praise the Lord, O Jerusalem!
    Praise your God, O Zion!
¹³ For he strengthens the bars of your gates;
    he blesses your sons within you.
¹⁴ He makes peace in your borders;
    he fills you with the finest of the wheat.
¹⁵ He sends forth his command to the earth;
    his word runs swiftly.
¹⁶ He gives snow like wool;
    he scatters hoarfrost like ashes.
¹⁷ He casts forth his ice like morsels;
    who can stand before his cold?
¹⁸ He sends forth his word, and melts them;
    he makes his wind blow, and the waters flow.
¹⁹ He declares his word to Jacob,
    his statutes and ordinances to Israel.
²⁰ He has not dealt thus with any other nation;
    they do not know his ordinances.
Praise the Lord!

 

Praise the Lord!
Praise the Lord from the heavens,
    praise him in the heights!
² Praise him, all his angels,
    praise him, all his host!

³ Praise him, sun and moon,
    praise him, all you shining stars!
⁴ Praise him, you highest heavens,
    and you waters above the heavens!

⁵ Let them praise the name of the Lord!
    For he commanded and they were created.
⁶ And he established them for ever and ever;
    he fixed their bounds which cannot be passed.^[a]

⁷ Praise the Lord from the earth,
    you sea monsters and all deeps,
⁸ fire and hail, snow and frost,
    stormy wind fulfilling his command!

⁹ Mountains and all hills,
    fruit trees and all cedars!
¹⁰ Beasts and all cattle,
    creeping things and flying birds!

¹¹ Kings of the earth and all peoples,
    princes and all rulers of the earth!
¹² Young men and maidens together,
    old men and children!

¹³ Let them praise the name of the Lord,
    for his name alone is exalted;
    his glory is above earth and heaven.
¹⁴ He has raised up a horn for his people,
    praise for all his saints,
    for the people of Israel who are near to him.
Praise the Lord!

Footnotes

1. Psalm 148:6 Or he set a law which cannot pass away

149 Praise the Lord!
Sing to the Lord a new song,
    his praise in the assembly of the faithful!
² Let Israel be glad in his Maker,
    let the sons of Zion rejoice in their King!
³ Let them praise his name with dancing,
    making melody to him with timbrel and lyre!
⁴ For the Lord takes pleasure in his people;
    he adorns the humble with victory.
⁵ Let the faithful exult in glory;
    let them sing for joy on their couches.
⁶ Let the high praises of God be in their throats
    and two-edged swords in their hands,
⁷ to wreak vengeance on the nations
    and chastisement on the peoples,
⁸ to bind their kings with chains
    and their nobles with fetters of iron,
⁹ to execute on them the judgment written!
    This is glory for all his faithful ones.50 Praise the Lord!
Praise God in his sanctuary;
    praise him in his mighty firmament!
² Praise him for his mighty deeds;
    praise him according to his exceeding greatness!

³ Praise him with trumpet sound;
    praise him with lute and harp!
⁴ Praise him with timbrel and dance;
    praise him with strings and pipe!
⁵ Praise him with sounding cymbals;
    praise him with loud clashing cymbals!
⁶ Let everything that breathes praise the Lord!
Praise the Lord!

 

THE END

Praise the Lord!

 

 

 

 

A digression

I'm going to interrupt the series on clinical trials to discuss a specific clinical issue, dementia. For those of you who are expecting a debate between the presidential candidates next week, I will bet you a substantial sum that it will not happen. That is because one of the candidates is currently experiencing a rapidly progressing condition of at least moderate dementia that is close to tipping over into the severe category. It is difficult to explain, however, why the corporate media not only resolutely ignores this fact, but works actively to cover it up. Here is your Dear Leader, in what is purported to be on of his relatively lucid moments:  

"It must because of MIT, my relationship to MIT, very smart, he goes, I say, what would happen if the boat sank from its weight, and you’re in the boat, and you have this tremendously powerful battery, and the battery’s now under water, and there’s a shark that’s approximately 10 yards over there — by the way, a lot of shark attacks lately, do you notice that? lotta shark attacks — I watched some guys justifying it today, ‘well they weren’t really that angry, they bit off the young lady’s leg because of the fact that they were, they were … not hungry but they misunderstood who she was.’ these people are crazy. he said, ‘there’s no problem with sharks, they just didn’t really understand a young woman swimming,’ no, really got decimated and other people too, a lot of shark attacks. so I said, ‘there’s a shark 10 yards away from the boat, 10 yards, or here. do I get electrocuted if the boat is sinking, water goes over the battery, the boat is sinking? do I stay on top of the boat and get electrocuted or do I jump over by the shark and not get electrocuted, because I will tell you, he didn’t know the answer. he said, ‘you know, nobody’s ever asked me that question.’ I said, ‘I think it’s a good question. I think there’s a lot of electric current coming through that water.’ but you know what I’d do if there was a shark or you get electrocuted? I’ll take electrocution every single time. I’m not getting near the shark. so we’re going to end that, we’re going to end it for boats, we’re going to end it for trucks.”

 

You want to give the nuclear codes to this person.

Sunday Sermonette: We're almost done with this . . .

The next post will be the last on the Book of Psalms, which ought to be good news but unfortunately Proverbs comes next. The three psalms we'll read today are attributed to David, although they were in fact written long after he was dead, assuming he ever existed. They are all songs of praise to the Big Guy in the Sky, but they praise him for some weird stuff.

 

Psalm 144 is one of those martial anthems that praises God for making Israel militarily strong. It repeats the common trope in these of calling Israel's enemies liars, although it isn't stated what they are lying about. Psalm 145 makes the bizarre assertion that God "satisfies the desires of every living thing" and "fulfills the desire of all who fear him," which is, obviously, not true. Psalm 146 asserts that the world is just -- 

"⁷  who executes justice for the oppressed;
    who gives food to the hungry.The Lord sets the prisoners free;
⁸     the Lord opens the eyes of the blind.
The Lord lifts up those who are bowed down;
    the Lord loves the righteous.
⁹ The Lord watches over the sojourners,
    he upholds the widow and the fatherless;
    but the way of the wicked he brings to ruin.

 

This "just world" delusion is a common affliction of the religious. Obviously none of these assertions are true. In fact, in the society in which this was written the widow and the fatherless were generally destitute, and there was plenty of hunger. But you know, you can just say it.

 

A Psalm of David.

144 Blessed be the Lord, my rock,
who trains my hands for war,
    and my fingers for battle;
² my rock^[a] and my fortress,
    my stronghold and my deliverer,
my shield and he in whom I take refuge,
    who subdues the peoples under him.^[b]

³ O Lord, what is man that thou dost regard him,
    or the son of man that thou dost think of him?
⁴ Man is like a breath,
    his days are like a passing shadow.

⁵ Bow thy heavens, O Lord, and come down!
    Touch the mountains that they smoke!
⁶ Flash forth the lightning and scatter them,
    send out thy arrows and rout them!
⁷ Stretch forth thy hand from on high,
    rescue me and deliver me from the many waters,
    from the hand of aliens,
⁸ whose mouths speak lies,
    and whose right hand is a right hand of falsehood.

⁹ I will sing a new song to thee, O God;
    upon a ten-stringed harp I will play to thee,
¹⁰ who givest victory to kings,
    who rescuest David thy^[c] servant.
¹¹ Rescue me from the cruel sword,
    and deliver me from the hand of aliens,
whose mouths speak lies,
    and whose right hand is a right hand of falsehood.

¹² May our sons in their youth
    be like plants full grown,
our daughters like corner pillars
    cut for the structure of a palace;
¹³ may our garners be full,
    providing all manner of store;
may our sheep bring forth thousands
    and ten thousands in our fields;
¹⁴ may our cattle be heavy with young,
    suffering no mischance or failure in bearing;
may there be no cry of distress in our streets!
¹⁵ Happy the people to whom such blessings fall!
    Happy the people whose God is the Lord!

Footnotes

1. Psalm 144:2 With Ps 18.2, 2 Sam 22.2: Heb my steadfast love
2. Psalm 144:2 Another reading is my people under me
3. Psalm 144:10 Heb his

A Song of Praise. Of David.

145 I will extol thee, my God and King,
    and bless thy name for ever and ever.
² Every day I will bless thee,
    and praise thy name for ever and ever.
³ Great is the Lord, and greatly to be praised,
    and his greatness is unsearchable.

⁴ One generation shall laud thy works to another,
    and shall declare thy mighty acts.
⁵ On the glorious splendor of thy majesty,
    and on thy wondrous works, I will meditate.
⁶ Men shall proclaim the might of thy terrible acts,
    and I will declare thy greatness.
⁷ They shall pour forth the fame of thy abundant goodness,
    and shall sing aloud of thy righteousness.

⁸ The Lord is gracious and merciful,
    slow to anger and abounding in steadfast love.
⁹ The Lord is good to all,
    and his compassion is over all that he has made.

¹⁰ All thy works shall give thanks to thee, O Lord,
    and all thy saints shall bless thee!
¹¹ They shall speak of the glory of thy kingdom,
    and tell of thy power,
¹² to make known to the sons of men thy^[a] mighty deeds,
    and the glorious splendor of thy^[b] kingdom.
¹³ Thy kingdom is an everlasting kingdom,
    and thy dominion endures throughout all generations.

The Lord is faithful in all his words,
    and gracious in all his deeds.^[c]
14 The Lord upholds all who are falling,
    and raises up all who are bowed down.
¹⁵ The eyes of all look to thee,
    and thou givest them their food in due season.
¹⁶ Thou openest thy hand,
    thou satisfiest the desire of every living thing.
¹⁷ The Lord is just in all his ways,
    and kind in all his doings.
¹⁸ The Lord is near to all who call upon him,
    to all who call upon him in truth.
¹⁹ He fulfils the desire of all who fear him,
    he also hears their cry, and saves them.
²⁰ The Lord preserves all who love him;
    but all the wicked he will destroy.

²¹ My mouth will speak the praise of the Lord,
    and let all flesh bless his holy name for ever and ever.

Footnotes

1. Psalm 145:12 Heb his
2. Psalm 145:12 Heb his
3. Psalm 145:13 These two lines are supplied by one Hebrew Ms, Gk and Syr

Praise for God’s Help

146 Praise the Lord!
Praise the Lord, O my soul!
² I will praise the Lord as long as I live;
    I will sing praises to my God while I have being.

³ Put not your trust in princes,
    in a son of man, in whom there is no help.
⁴ When his breath departs he returns to his earth;
    on that very day his plans perish.

⁵ Happy is he whose help is the God of Jacob,
    whose hope is in the Lord his God,
⁶ who made heaven and earth,
    the sea, and all that is in them;
who keeps faith for ever;
⁷     who executes justice for the oppressed;
    who gives food to the hungry.

The Lord sets the prisoners free;
⁸     the Lord opens the eyes of the blind.
The Lord lifts up those who are bowed down;
    the Lord loves the righteous.
⁹ The Lord watches over the sojourners,
    he upholds the widow and the fatherless;
    but the way of the wicked he brings to ruin.

¹⁰ The Lord will reign for ever,
    thy God, O Zion, to all generations.
Praise the Lord!

 

 

 

 

 

 

Clinical Trials Part Three: Assessment

As I have said, to do experiments rigorously you need to specify in advance the outcomes you will be measuring, and how you will measure them. (A fancy word for that is operationalizing your variables.) For example, if you want to know if your magic pill is effective at treating Covid-19, you need to be precise about the outcomes you will be comparing between the intervention and comparison groups. You also need to be precise about the starting condition of the population you will be studying. Are we talking about people with mild to moderate disease, who would not normally be hospitalized? People who are already in the hospital? How do you define and measure disease severity?

Let's say we're going with an outpatient population. You need to test them so you know they actually all have Covid-19, and you need some reasonably objective measure of disease severity. Oxygen saturation, viral load, a structured questionnaire assessing symptoms, that sort of thing. You need to specify how long you will follow the people, and how you will define your outcomes. For example, proportion who end up being hospitalized, days to recovery as defined by a pre-specified response to your questionnaire. Oh yeah, this is very important: the person who does the assessment, such as administering the questionnaire, must not be an investigator and must be blinded to the trial arm. The reason is that someone who knows who is in the intervention vs. control group, and has a stake in the outcome, can easily skew the result, even if unconsciously. 

Usually, preliminary studies are put together quickly, have little or no funding, and so have small sample sizes and less than rigorous design. That is why typically early, quick and dirty studies report positive results that don't hold up when people try to replicate them more rigorously. And that is what happened with ivermectin and hydroxychloroquine. Some ambitious docs did poorly conducted trials and announced that the drugs were effective. Actually, some of these weren't even controlled at all, it was just "I give this to my patients and they recover." Well yeah, most people do. 

 

And that is why somebody thought they had a gotcha when they sent a link to a study that found hydroxychloroquine to be effective against Covid-19. No, it isn't. And the people who made that claim ended up wasting millions of dollars and urgently needed investigator time and resources because NIH felt compelled to fund rigorous studies of what were essentially folk remedies, that as it turns out absolutely, incontrovertibly, do not work. It is also highly irresponsible for elected officials to promote unproven treatments. 

Now that I've given an idea of what constitutes a well designed and well conducted trial, I'll go on to the limitations of this kind of study, what it doesn't tell us, and when it's actually impossible. What else can we do?

Clinical Trials continued: Under Control

In standard parlance a clinical trial (and other experiments with similar structure) has at least two "arms," the intervention and the control arm. "Control" is perhaps a strange word choice in this context, and I'm not sure how it originated, but it's whatever the intervention is being compared to. If we're doing experiments with chemicals or cell cultures we could compare the intervention to doing nothing, or more precisely to keeping all conditions the same except for the intervention. 

When we're doing clinical trials, however, we're experimenting on humans, who have some properties that make the proposition of "keeping all conditions the same" complicated; and we're also inevitably doing more than just the intervention we're testing. Testing whether a pill is effective against depression or pain or high blood pressure or cancer -- whatever it may be -- means doing more than just getting the chemical into the person's body. It requires quite an elaborate interaction with the research subjects (or participants, there's debate about the right word for them). 

People who will be assigned to either arm need to go through the informed consent process, so that's the same for everybody. Ideally, assignment to the intervention or control arm happens after that. But you can't just tell the people in the control arm to go home, we'll see you in a few weeks to give you the assessment. The people in the intervention arm are going to have an interaction with a clinician, including a discussion of possible side effects and what to do if you think you're experiencing them; the importance of taking the pills on schedule; and then whatever else the person brings up and since they're talking to a doctor or a nurse that could be anything and it might require a referral. Then, ideally, you need to monitor the people in some way to make sure they really are taking the pills as prescribed. (Half of the time people don't, even in a real world context.) 

All of this attention is likely to change people's expectations, and it may even change them in other ways. If you're trying to treat depression or anxiety, it might even be effective without the pill. If you're assessment will depend even in part on self-reports, it can change those even without any biological effect. And of course, ethically, if some other problem comes up in the interaction you do have to make a referral, which means the people may be more likely to get other treatments during the course of the trial. Ergo, you need to go through the identical rigamarole with the people in the control group. Also, the people who perform the rigamarole have to be "blinded" to which condition the person is in, or they might behave differently in some subtle way. 

So that's where the whole  placebo control concept comes from. Typically, people in both arms of a trial will be found to improve over the course of the study, so we need to ask whether the improvement in the intervention arm is greater than the improvement in the control arm. But what is this "placebo effect," exactly?

There is a widespread belief that it is some mysterious "mind over body" phenomenon in which just expecting to get better heals your body. However, as far as we can tell that is rare to nonexistent, at least when we're talking about measurable biological effects. There's a bit of a philosophical problem if we're talking about effects that are only measurable by self-report, such as pain or depression. If people say they feel better then presumably they do, badabing badaboom, but if we measure, say, the actual range of motion of someone with arthritis, or the size of a tumor, or the viral load, we won't see any effect. So what is the placebo effect, really?

First of all, as I said before, most conditions get better on their own; or, in the case of chronic conditions, people are most likely to enter the trial at a time when they are experiencing an exacerbation. Either way, you're going to see improvement just with the passing of time. And often, even when we are using objective biological measures, outcome measure will also include participant self-reports so it's important to separate those out and not just put them together in an index. Finally, it's possible that the placebo affects people's behavior. If they're more optimistic about their condition, they might be more likely to take other steps to improve their health, such as eating better. They might sleep better or be more physically active. They might socialize more. 

 

So that's why you need a double blind placebo control. Now, there are situations in which that might be impossible or unethical. I'll talk about those next.