<?xml version="1.0" encoding="UTF-8"?>
<opml version="2.0">
  <head>
    <title>092-02 Human variation, penetrance, complex traits, population genetics, and association</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Human variation, population genetics, and association">
      <outline text="Variant classes and frequency">
        <outline text="Millions of variants, mostly neutral or small effect"/>
        <outline text="Separate ancestry from race, probability from destiny"/>
        <outline text="Single nucleotides, indels, copy number, structure"/>
        <outline text="Short tandem repeats may expand unstably"/>
        <outline text="Frequency counted among chromosomes, not people"/>
        <outline text="Rare is not pathogenic, common not harmless">
          <outline text="Recessive, late-onset alleles can become frequent"/>
        </outline>
      </outline>
      <outline text="Mutation, drift, selection">
        <outline text="Mutation rates vary by context and parental age">
          <outline text="CpG cytosines mutate after deamination"/>
          <outline text="Recurrent mutation in unrelated families"/>
        </outline>
        <outline text="Drift strongest in small populations">
          <outline text="Founder effect and bottleneck raise rare alleles"/>
          <outline text="Founder testing must not replace broad analysis"/>
        </outline>
        <outline text="Negative selection removes harmful alleles"/>
        <outline text="Balancing selection maintains variation">
          <outline text="Sickle heterozygotes: less severe malaria"/>
        </outline>
      </outline>
      <outline text="Ancestry, race, gene flow">
        <outline text="Migration moves alleles between populations"/>
        <outline text="Variation shared, no discrete biological races"/>
        <outline text="Genetic ancestry is statistical similarity"/>
        <outline text="Race reflects exposures, not genotype"/>
      </outline>
      <outline text="Hardy–Weinberg equilibrium">
        <outline text="Random mating, large population, no disturbing forces"/>
        <outline text="p squared, 2pq, q squared"/>
        <outline text="A null model, not a claim about populations"/>
        <outline text="Departure: structure, inbreeding, selection, error"/>
        <outline text="Carrier frequency about twice allele frequency">
          <outline text="Fails with founders, assortative mating"/>
          <outline text="Use measured population data"/>
        </outline>
      </outline>
      <outline text="Linkage and linkage disequilibrium">
        <outline text="Nearby loci transmitted together"/>
        <outline text="Recombination fraction at most one-half"/>
        <outline text="Centimorgans differ from base pairs">
          <outline text="Vary by sex and region"/>
        </outline>
        <outline text="Hotspots shape haplotype blocks"/>
        <outline text="Linkage disequilibrium: nonrandom allele association">
          <outline text="Marker tags an unmeasured causal variant"/>
          <outline text="Strength and direction differ by ancestry"/>
          <outline text="Fine mapping seeks the causal set"/>
        </outline>
      </outline>
      <outline text="Heritability and complex traits">
        <outline text="Heritability: variance share in a context">
          <outline text="Not an individual&#x27;s genetic share"/>
          <outline text="High heritability yet diet treats phenylketonuria"/>
        </outline>
        <outline text="Broad includes all, narrow is additive"/>
        <outline text="Twin studies rest on assumptions"/>
        <outline text="Common variants small, rare variants larger effects"/>
        <outline text="Liability threshold for binary disease"/>
        <outline text="Familial clustering need not be Mendelian"/>
        <outline text="Interaction depends on statistical scale"/>
        <outline text="Gene–environment correlation mimics interaction"/>
      </outline>
      <outline text="Genome-wide association">
        <outline text="Quality control of samples and genotypes"/>
        <outline text="Stringent significance for multiple testing"/>
        <outline text="Association alone does not establish mechanism"/>
        <outline text="Stratification confounds association">
          <outline text="Principal components reduce, not eliminate"/>
          <outline text="Diverse recruitment improves transferability"/>
        </outline>
        <outline text="Odds ratio is not absolute risk">
          <outline text="Overstates risk ratio when outcome common"/>
        </outline>
        <outline text="Winner&#x27;s curse inflates discovery effects"/>
      </outline>
      <outline text="Scores, instruments, rare variants">
        <outline text="Polygenic score sums weighted risk alleles">
          <outline text="Stratifies relative risk within populations"/>
          <outline text="High is not diagnosis, low is not exclusion"/>
        </outline>
        <outline text="Mendelian randomisation: variants as instruments">
          <outline text="Pleiotropy and structure violate assumptions"/>
        </outline>
        <outline text="Rare variants aggregated by gene or region">
          <outline text="Burden assumes same direction, kernel mixed"/>
        </outline>
      </outline>
      <outline text="Bias and interpretation limits">
        <outline text="Family penetrance inflated by ascertainment"/>
        <outline text="Biobanks underrepresent severe childhood disease"/>
        <outline text="Collider bias from selective participation"/>
        <outline text="Records misclassify missing diagnoses as absence"/>
        <outline text="Large samples cannot repair systematic bias"/>
        <outline text="Database absence supports rarity only"/>
        <outline text="Three levels: molecule, probability, population"/>
      </outline>
    </outline>
  </body>
</opml>
