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  <head>
    <title>102-03 Experimental design, uncertainty, reproducibility, ethics, and laboratory safety</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Design, reproducibility, ethics, and safety">
      <outline text="Defining the comparison">
        <outline text="Link causal question to answerable comparison"/>
        <outline text="Define intervention, control, unit, outcome first"/>
        <outline text="Experimental unit: smallest independent assignment">
          <outline text="Cells in one treated dish are subsamples"/>
          <outline text="Wrong unit: pseudoreplication, false precision"/>
        </outline>
      </outline>
      <outline text="Randomisation and blinding">
        <outline text="Chance assignment balances baseline on average"/>
        <outline text="Blocking balances batch, sex, site"/>
        <outline text="Randomise processing order against drift"/>
        <outline text="Implement and record, not merely state">
          <outline text="Alternation and cage position are predictable"/>
        </outline>
        <outline text="Blinding separates assignment from handling">
          <outline text="Outcomes, labels, images, code can be blinded"/>
          <outline text="Phenotypes or adverse effects break blinding"/>
          <outline text="Automation inherits human thresholds"/>
        </outline>
      </outline>
      <outline text="Controls">
        <outline text="Negative control estimates background"/>
        <outline text="Positive control shows response is detectable">
          <outline text="Failure makes negative results uninterpretable"/>
        </outline>
        <outline text="Vehicle, sham, isotype, rescue answer different questions"/>
        <outline text="Active negative control can hide or create effects"/>
      </outline>
      <outline text="Designs and biological variation">
        <outline text="Factorial designs estimate interactions efficiently"/>
        <outline text="Dose-response shows shape and threshold"/>
        <outline text="Time course separates cause from consequence"/>
        <outline text="Crossover reduces between-subject variation">
          <outline text="Needs stable disease and adequate washout"/>
          <outline text="Carryover or irreversible effects violate it"/>
        </outline>
        <outline text="Design biological variation in from the start">
          <outline text="Intended inference sets relevant diversity"/>
          <outline text="Standardisation for precision, heterogeneity for reach"/>
        </outline>
      </outline>
      <outline text="Sample size and protocol">
        <outline text="Needs outcome, variance, effect, error rates"/>
        <outline text="Pilot effect sizes too imprecise for power"/>
        <outline text="Sequential designs stop by prespecified rules"/>
        <outline text="More cells cannot replace too few donors"/>
        <outline text="Protocols make tacit choices visible"/>
        <outline text="Preregistration time-stamps hypotheses and analyses">
          <outline text="Makes selective change detectable"/>
          <outline text="Report deviations with reasons"/>
        </outline>
      </outline>
      <outline text="Records and quality">
        <outline text="Provenance: identifiers, lots, calibration, versions"/>
        <outline text="Electronic notebooks need access control and export"/>
        <outline text="Keep raw data; clean through traceable scripts"/>
        <outline text="Quality assurance prevents error"/>
        <outline text="Quality control monitors each run">
          <outline text="Passing a narrow control does not validate method"/>
        </outline>
        <outline text="Set acceptance criteria before seeing groups">
          <outline text="Re-running one group&#x27;s failures biases results"/>
        </outline>
      </outline>
      <outline text="Reproducibility and integrity">
        <outline text="Methods, materials, data, code, independent tests"/>
        <outline text="Unexplained direction reversal needs investigation"/>
        <outline text="Direct repeats conditions; conceptual tests the claim"/>
        <outline text="Fabrication, falsification, plagiarism"/>
        <outline text="Omission, duplicate publication, gift authorship"/>
        <outline text="Disclose and manage conflicts of interest"/>
        <outline text="Uniform adjustment acceptable if original kept">
          <outline text="Selective alteration misrepresents evidence"/>
        </outline>
        <outline text="Quantify raw data, not presentation images"/>
      </outline>
      <outline text="Human and animal research ethics">
        <outline text="Respect, benefit over harm, fair selection"/>
        <outline text="Uninformative studies are themselves unethical"/>
        <outline text="Consent: purpose, risks, alternatives, voluntariness"/>
        <outline text="Extra safeguards for vulnerability"/>
        <outline text="Unjust exclusion denies groups evidence"/>
        <outline text="Coding does not anonymise genomic data">
          <outline text="Re-identification grows with linkage and technology"/>
        </outline>
        <outline text="Replacement, reduction, refinement">
          <outline text="Reduce without underpowered waste"/>
          <outline text="Humane endpoints before death"/>
          <outline text="Justify species and model validity"/>
        </outline>
      </outline>
      <outline text="Laboratory safety">
        <outline text="Match containment to agent and procedure"/>
        <outline text="Aerosols, sharps, centrifugation, spills, waste"/>
        <outline text="Biological safety cabinets are not fume hoods"/>
        <outline text="Chemical controls follow hazard and exposure">
          <outline text="Substitution and enclosure beat PPE alone"/>
        </outline>
        <outline text="Incidents arise from interacting system weaknesses">
          <outline text="Near misses are signals if reporting is safe"/>
        </outline>
        <outline text="Practise emergency plans for use under stress"/>
      </outline>
      <outline text="Complete reporting">
        <outline text="Link question, design, conduct, analysis, limits"/>
        <outline text="Separate planned from exploratory work"/>
        <outline text="Report null and adverse findings"/>
        <outline text="Give effect sizes, uncertainty, exclusions"/>
        <outline text="Avoid causal language beyond the design"/>
        <outline text="Guidelines are checklists, not judgment"/>
        <outline text="Aim: an auditable chain"/>
      </outline>
    </outline>
  </body>
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