rwe 0.0.8

Real World Evidence utilities and reporting

Real world evidence of siRNA targets

The current pipeline generates a real world genetic evidence document of an siRNA target by providing phenotypic details of individuals carrying predicted loss of function mutations in that target from multiple biobanks. The report can be used for the following three broader utilities:

• Discover new target-indication pairs
• Safety evaluation of potential target
• Repurposing opportunity of existing target

Description of the report

The report currently has the following sections:

• Variant information and demographics
• Clinical records
• Labs and measurements
• Survey information
• Homozygous loss of function carriers
• Indication specific report

Future updates might have the following additional sections:

• OpenTargets
• Plasma protein effect: https://azphewas.com/geneView/6319c068-fd59-46d8-85ee-82d82482eb14/APOC3/glr/continuous
• Knowledge portal networks: https://hugeamp.org/research.html?pageid=kpn_portals
• Genomics England information: https://www.genomicsengland.co.uk/
• Genes and Health information: https://www.genesandhealth.org/

Variant information and demographics

Variant information

Provides number of pLoF carriers across four variant categories in the All of Us cohort:

• stop gained
• frameshift
• splice acceptor
• splice donor

Demographics

Includes age, sex, ancestry and ethnicity information of pLoF carriers in comparison with non-carriers.

Clinical records

Provides phenomewide association study results of pLoF carriers in All of Us and UK Biobank cohorts. The All of Us association results are generated in-house. The UK Biobank results are collected from genebass and astrazeneca open-source portal.

Labs and measurements

Provides lab results of pLoF carriers in All of Us cohort in comparison to the non-carriers. The following labs and measurements are currently being collected:

Name of measurement	Concept ID (All of Us)	Category	Lower than baseline (clinical meaning)	Higher than baseline (clinical meaning)
Body mass index (BMI) [Ratio]	3038553	Vitals / anthropometrics	Often indicates underweight or low body fat; may reflect malnutrition, chronic illness, or frailty.	Often indicates overweight/obesity; associated with insulin resistance and higher cardiometabolic risk.
Body height	3036277	Vitals / anthropometrics	If decreased vs prior: possible measurement error or age-related height loss (vertebral compression/kyphosis). Persistently low stature may reflect childhood growth disorders.	Tall stature can be constitutional; if extreme may suggest connective-tissue disorders (e.g., Marfan) or growth hormone excess (gigantism).
Body weight	3025315	Vitals / anthropometrics	Weight loss or low weight can reflect malnutrition, cachexia, dehydration, or endocrine/GI disease.	Weight gain/high weight may reflect obesity or fluid retention (edema, heart/renal failure).
Systolic blood pressure	3004249	Vitals / anthropometrics	Hypotension: possible dehydration, blood loss, sepsis, cardiogenic shock, or antihypertensive effects; may cause dizziness/syncope.	Hypertension: increased risk of stroke, MI, HF, CKD; may reflect primary or secondary hypertension.
Diastolic blood pressure	3012888	Vitals / anthropometrics	Low DBP may reflect hypotension or widened pulse pressure (e.g., arterial stiffness, aortic regurgitation); can reduce coronary perfusion in some patients.	High DBP suggests hypertension and increased cardiovascular risk, especially in younger adults.
Heart rate	3027018	Vitals / anthropometrics	Bradycardia: can be physiologic (athletes, sleep) or due to drugs (beta-blockers), conduction disease, or hypothyroidism.	Tachycardia: may reflect fever, pain, anxiety, hypovolemia, anemia, hyperthyroidism, or arrhythmia.
Hemoglobin [Mass/volume] in Blood	3000963	Hematology	Anemia: blood loss, iron/B12/folate deficiency, chronic disease, hemolysis, marrow suppression.	Polycythemia/hemoconcentration: dehydration, chronic hypoxia/smoking, or myeloproliferative disease.
Hematocrit [Volume Fraction] of Blood by Automated count	3023314	Hematology	Low hematocrit supports anemia or hemodilution.	High hematocrit suggests hemoconcentration or polycythemia; increases viscosity/thrombosis risk.
Erythrocytes [#/volume] in Blood by Automated count	3020416	Hematology	Low RBC count supports anemia (production loss, bleeding, hemolysis).	High RBC count suggests polycythemia or chronic hypoxia; may also reflect dehydration.
Erythrocyte distribution width [Entitic volume]	3002888	Hematology	Low RDW-SD is usually not clinically meaningful (uniform RBC size).	High RDW-SD indicates anisocytosis; seen with iron deficiency, B12/folate deficiency, mixed anemias, or recent transfusion.
MCV [Entitic volume] by Automated count	3023599	Hematology	Microcytosis: commonly iron deficiency or thalassemia; can occur in chronic inflammation/lead exposure.	Macrocytosis: B12/folate deficiency, alcohol use, liver disease, hypothyroidism, certain drugs, or reticulocytosis.
Platelets [#/volume] in Blood by Automated count	3024929	Hematology	Thrombocytopenia: bleeding risk; causes include marrow suppression, immune destruction (ITP), infection, liver disease, or consumption (DIC).	Thrombocytosis: reactive (inflammation, iron deficiency, postsplenectomy) or myeloproliferative; may raise thrombosis risk.
Monocytes [#/volume] in Blood by Automated count	3033575	Hematology	Low monocytes are often not clinically significant; can be seen with marrow suppression or steroid effect.	Monocytosis: chronic infection/inflammation, recovery phase of neutropenia, autoimmune disease, or myeloid neoplasm.
Eosinophils [#/volume] in Blood by Automated count	3028615	Hematology	Low eosinophils are usually not clinically significant; may be seen with stress or corticosteroids.	Eosinophilia: allergy/asthma, parasitic infection, drug reaction, adrenal insufficiency, or eosinophilic disorders.
Basophils [#/volume] in Blood by Automated count	3013429	Hematology	Low basophils are usually not clinically significant.	Basophilia: can occur in allergy/inflammation; classically associated with myeloproliferative neoplasms (e.g., CML).
Basophils [#/volume] in Blood	3006315	Hematology	Low basophils are usually not clinically significant.	Basophilia: allergy/inflammation or myeloproliferative neoplasm.
Basophils/100 leukocytes in Blood by Automated count	3013869	Hematology	Low percent basophils is usually not clinically significant.	High percent basophils (relative basophilia) may reflect allergy/inflammation or myeloproliferative disease.
Basophils/100 leukocytes in Blood by Manual count	3009797	Hematology	Low percent basophils is usually not clinically significant.	High percent basophils (relative basophilia) may reflect allergy/inflammation or myeloproliferative disease.
Basophils/100 leukocytes in Blood	3013580	Hematology	Low percent basophils is usually not clinically significant.	High percent basophils (relative basophilia) may reflect allergy/inflammation or myeloproliferative disease.
Immature granulocytes [#/volume] in Blood by Automated count	3013209	Hematology	Low/absent immature granulocytes is expected in healthy individuals.	Elevated immature granulocytes (left shift): acute infection/inflammation, physiologic stress, or marrow stimulation.
Immature granulocytes [#/volume] in Blood	3033400	Hematology	Low/absent immature granulocytes is expected in healthy individuals.	Elevated immature granulocytes (left shift): acute infection/inflammation, physiologic stress, or marrow stimulation.
Immature granulocytes/100 leukocytes in Blood by Automated count	42869452	Hematology	Low/near-zero percentage is typical in health.	High percentage suggests left shift from infection/inflammation, stress response, or marrow stimulation.
Immature granulocytes/100 leukocytes in Blood	3025784	Hematology	Low/near-zero percentage is typical in health.	High percentage suggests left shift from infection/inflammation, stress response, or marrow stimulation.
Nucleated erythrocytes [#/volume] in Blood by Automated count	3023049	Hematology	Absent/very low NRBCs is normal in adults.	Presence/elevation suggests marrow stress (severe hypoxia, hemolysis, hemorrhage), severe infection, or marrow infiltration; also normal in neonates.
Nucleated erythrocytes/100 leukocytes [Ratio] in Blood by Automated count	40761514	Hematology	Absent/very low ratio is normal in adults.	Elevated ratio indicates circulating NRBCs from marrow stress or severe illness (hypoxia, hemolysis, hemorrhage, sepsis).
Nucleated erythrocytes/100 leukocytes [Ratio] in Blood	3007993	Hematology	Absent/very low ratio is normal in adults.	Elevated ratio indicates circulating NRBCs from marrow stress or severe illness.
Leukocytes [#/volume] in Blood by Automated count	3010813	Hematology	Leukopenia: viral infection, marrow suppression, autoimmune disease, or chemotherapy; increases infection risk if severe.	Leukocytosis: infection/inflammation, stress/steroids, smoking, or hematologic malignancy.
Neutrophils [#/volume] in Blood by Automated count	3000909	Hematology	Neutropenia: increased risk for bacterial/fungal infection; causes include chemo, drugs, viral infection, autoimmune disease, marrow failure.	Neutrophilia: bacterial infection, inflammation, stress response, corticosteroids, or myeloproliferative disease.
Lymphocytes [#/volume] in Blood by Automated count	3018974	Hematology	Lymphopenia: immunosuppression (steroids), severe illness, HIV, autoimmune disease, or malnutrition.	Lymphocytosis: often viral infection; can indicate chronic lymphocytic leukemia or other lymphoproliferative disorders.
MCH [Entitic mass] by Automated count	3000809	Hematology	Low MCH suggests hypochromic microcytic anemia (often iron deficiency or thalassemia).	High MCH often accompanies macrocytosis (B12/folate deficiency, liver disease, alcohol).
MCHC [Mass/volume] by Automated count	3008526	Hematology	Low MCHC indicates hypochromia, commonly iron deficiency.	High MCHC may be seen with hereditary spherocytosis or some hemolytic states; can also be analytic artifact (e.g., cold agglutinins).
Erythrocyte distribution width [Ratio] by Automated count	3008499	Hematology	Low RDW% is usually not clinically meaningful.	High RDW% indicates anisocytosis; associated with iron/B12/folate deficiency, mixed anemia, or recent transfusion.
Platelet mean volume [Entitic volume] in Blood by Automated count	3028132	Hematology	Low MPV can suggest reduced platelet production (marrow suppression) in context of thrombocytopenia.	High MPV suggests larger/younger platelets (increased turnover, e.g., ITP) or inherited macrothrombocytopenias.
Creatinine [Mass/volume] in Serum or Plasma	3016723	Renal / electrolytes	Low creatinine often reflects low muscle mass, frailty, or pregnancy; less commonly severe liver disease.	High creatinine suggests reduced kidney function or acute kidney injury; can also rise with dehydration, high muscle mass, or rhabdomyolysis.
Urea nitrogen [Mass/volume] in Serum or Plasma	3028287	Renal / electrolytes	Low BUN can reflect low protein intake, malnutrition, liver dysfunction, or overhydration.	High BUN suggests reduced kidney function, dehydration, high protein catabolism, or GI bleeding.
Glomerular filtration rate/1.73 sq M.predicted [Volume Rate/Area] in Serum, Plasma or Blood by Creatinine-based formula (MDRD)	46236952	Renal / electrolytes	Lower eGFR indicates reduced kidney function/CKD (or AKI if acute).	Higher eGFR can reflect hyperfiltration (early diabetes), pregnancy, or low creatinine from low muscle mass.
Sodium [Moles/volume] in Serum or Plasma	3019550	Renal / electrolytes	Hyponatremia: excess free water (SIADH), heart/liver failure, diuretics, adrenal insufficiency; can cause confusion/seizures if severe.	Hypernatremia: water deficit/dehydration or diabetes insipidus; can cause neurologic symptoms.
Potassium [Moles/volume] in Serum or Plasma	3023103	Renal / electrolytes	Hypokalemia: GI loss, diuretics, alkalosis; can cause weakness and arrhythmias.	Hyperkalemia: renal failure, acidosis, tissue breakdown, RAAS-inhibiting drugs; can cause life-threatening arrhythmias.
Bicarbonate [Moles/volume] in Serum or Plasma	3014576	Renal / electrolytes	Low bicarbonate suggests metabolic acidosis (e.g., DKA, lactic acidosis, renal failure, diarrhea).	High bicarbonate suggests metabolic alkalosis (vomiting, diuretics) or compensation for chronic respiratory acidosis.
Chloride [Moles/volume] in Serum or Plasma	3010156	Renal / electrolytes	Hypochloremia: often with vomiting/NG suction or metabolic alkalosis; can also reflect dilutional states.	Hyperchloremia: metabolic acidosis (non–anion gap), dehydration, renal tubular acidosis, or large-volume normal saline.
Calcium [Mass/volume] in Serum or Plasma	3006906	Renal / electrolytes	Hypocalcemia: vitamin D deficiency, hypoparathyroidism, CKD; can cause paresthesias/tetany/seizures.	Hypercalcemia: primary hyperparathyroidism, malignancy, granulomatous disease, vitamin D excess; can cause stones, constipation, confusion.
Magnesium [Mass/volume] in Serum or Plasma	3024328	Renal / electrolytes	Hypomagnesemia: GI loss, diuretics, alcoholism; can cause arrhythmias and refractory hypokalemia/hypocalcemia.	Hypermagnesemia: usually renal failure or excess supplementation; can cause hypotension, bradycardia, respiratory depression.
Phosphate [Mass/volume] in Serum or Plasma	3018920	Renal / electrolytes	Hypophosphatemia: refeeding syndrome, hyperparathyroidism, insulin therapy; can cause muscle weakness/respiratory failure if severe.	Hyperphosphatemia: CKD, tumor lysis/rhabdomyolysis, hypoparathyroidism; contributes to vascular calcification.
Anion gap 3 in Serum or Plasma	3003708	Renal / electrolytes	Low anion gap most often reflects hypoalbuminemia; can also be lab artifact or paraproteinemia (e.g., multiple myeloma).	High anion gap indicates anion-gap metabolic acidosis (lactate, ketoacids, toxins, renal failure).
Albumin [Mass/volume] in Serum or Plasma	3002752	Liver / protein balance	Hypoalbuminemia: chronic liver disease, nephrotic syndrome, protein-losing enteropathy, malnutrition, or inflammation.	High albumin is uncommon and usually reflects dehydration/hemoconcentration.
Protein [Mass/volume] in Serum or Plasma	3018302	Liver / protein balance	Low total protein: malnutrition, liver disease, nephrotic syndrome, protein-losing enteropathy.	High total protein: dehydration or increased immunoglobulins (chronic inflammation or monoclonal gammopathy).
Alanine aminotransferase [Enzymatic activity/volume] in Serum or Plasma	3005755	Liver / protein balance	Low ALT is usually not clinically significant.	High ALT suggests hepatocellular injury (viral hepatitis, NAFLD, ischemia, toxins/drugs).
Aspartate aminotransferase [Enzymatic activity/volume] in Serum or Plasma	3013721	Liver / protein balance	Low AST is usually not clinically significant.	High AST suggests hepatocellular injury and can also reflect muscle injury or hemolysis; interpret with ALT/CK.
Alkaline phosphatase [Enzymatic activity/volume] in Serum or Plasma	3012902	Liver / protein balance	Low ALP is uncommon; can be seen with malnutrition, hypothyroidism, zinc deficiency, or hypophosphatasia.	High ALP suggests cholestasis/biliary obstruction or bone turnover (e.g., Paget, healing fracture); also rises in pregnancy.
Bilirubin.total [Mass/volume] in Serum or Plasma	3024128	Liver / protein balance	Low bilirubin is typically not clinically significant.	High bilirubin: jaundice; can be due to hemolysis, impaired conjugation (e.g., Gilbert), hepatocellular disease, or cholestasis/obstruction.
Glucose [Mass/volume] in Serum or Plasma	3004501	Metabolic	Hypoglycemia: excess insulin/sulfonylureas, adrenal insufficiency, severe liver disease, sepsis; can cause neuroglycopenic symptoms.	Hyperglycemia: diabetes, stress response, steroids; severe elevations risk DKA/HHS.
Hemoglobin A1c/Hemoglobin.total in Blood	3004410	Metabolic	Lower A1c usually reflects lower average glucose; if unexpectedly low, consider shortened RBC lifespan (hemolysis), recent blood loss, or transfusion.	Higher A1c indicates higher average glucose over ~2–3 months; supports diabetes/poor glycemic control.
Cholesterol [Mass/volume] in Serum or Plasma	3007070	Metabolic	Low total cholesterol can reflect malnutrition, hyperthyroidism, chronic illness, or liver disease.	High total cholesterol increases atherosclerotic cardiovascular risk depending on LDL/HDL fractions.
Cholesterol in LDL [Mass/volume] in Serum or Plasma by calculation	3048961	Metabolic	Low LDL is generally associated with lower ASCVD risk; very low levels can be seen with malabsorption, hyperthyroidism, or genetic hypolipidemias.	High LDL is strongly associated with increased ASCVD risk (familial hypercholesterolemia, diet, metabolic disease).
Cholesterol in HDL [Mass/volume] in Serum or Plasma	3007215	Metabolic	Low HDL is associated with higher cardiometabolic/ASCVD risk and often accompanies metabolic syndrome.	Higher HDL is often associated with lower ASCVD risk, though extremely high levels can be genetic and not always protective.
Triglyceride [Mass/volume] in Serum or Plasma	3022192	Metabolic	Low triglycerides are usually benign; can reflect low fat intake or malnutrition.	High triglycerides: insulin resistance, alcohol use, hypothyroidism, genetic causes; very high levels increase pancreatitis risk.
Thyroxine (T4) free [Mass/volume] in Serum or Plasma	3018617	Metabolic	Low free T4 suggests hypothyroidism (primary or central) depending on TSH context.	High free T4 suggests hyperthyroidism or excess thyroid hormone; interpret with TSH and clinical context.
25-Hydroxyvitamin D3+25-Hydroxyvitamin D2 [Mass/volume] in Serum or Plasma	40765040	Metabolic	Low 25(OH)D suggests vitamin D deficiency/insufficiency (risk for osteomalacia, fractures).	High 25(OH)D suggests excessive supplementation; can cause hypercalcemia and toxicity.
Protein [Mass/volume] in Urine by Test strip	3033235	Urine / kidney damage	Negative/low protein is generally normal.	Higher protein on dipstick suggests proteinuria (glomerular disease, diabetic nephropathy) or transient causes (UTI, fever, exercise).
Leukocytes [#/area] in Urine sediment by Microscopy high power field	3013483	Urine / kidney damage	Low/none is normal.	High urine WBCs (pyuria) suggests UTI, interstitial nephritis, or urinary tract inflammation.
Erythrocytes [#/area] in Urine sediment by Microscopy high power field	3013984	Urine / kidney damage	Low/none is normal.	High urine RBCs (hematuria) suggests stones, infection, glomerulonephritis, trauma, or urologic malignancy.
Epithelial cells.squamous [#/area] in Urine sediment by Microscopy high power field	3035405	Urine / kidney damage	Low squamous cells suggests a cleaner (less contaminated) specimen.	High squamous cells often indicates sample contamination (poor clean-catch technique).
Albumin/Creatinine [Mass Ratio] in Urine	3034485	Urine / kidney damage	Low ACR is normal (minimal albumin excretion).	High ACR indicates albuminuria—kidney damage often from diabetes or hypertension; higher levels predict CKD/CV risk.
C reactive protein [Mass/volume] in Serum or Plasma	3000968	Inflammation	Low CRP is expected and suggests absence of significant systemic inflammation.	High CRP indicates acute-phase inflammation (infection, autoimmune flare, tissue injury); persistent elevation can reflect chronic inflammation.
Erythrocyte sedimentation rate by Westergren method	3007529	Inflammation	Low ESR is usually not clinically significant; can be seen with polycythemia or some RBC abnormalities.	High ESR is nonspecific for inflammation/infection, autoimmune disease, malignancy, or anemia.
Natriuretic peptide B [Mass/volume] in Serum or Plasma	3034939	Cardiac biomarkers	Low BNP is generally reassuring against significant heart failure in the right clinical context.	High BNP suggests myocardial wall stress/heart failure; can also rise with renal dysfunction, older age, and pulmonary hypertension.
Natriuretic peptide.B prohormone N-Terminal [Mass/volume] in Serum or Plasma	3034840	Cardiac biomarkers	Low NT-proBNP is generally reassuring against significant heart failure in the right clinical context.	High NT-proBNP suggests heart failure/wall stress; also increases with age and reduced kidney function.
Troponin I.cardiac [Mass/volume] in Serum or Plasma	3021337	Cardiac biomarkers	Undetectable/low troponin is expected (no evidence of myocardial injury at that time).	Elevated troponin indicates myocardial injury (MI, myocarditis, demand ischemia); can be chronically elevated in CKD.
Creatine kinase [Enzymatic activity/volume] in Serum or Plasma	3000959	Cardiac biomarkers	Low CK is usually not clinically significant; can reflect low muscle mass.	High CK indicates muscle injury (exercise, myositis, rhabdomyolysis) and can rise with MI; interpret with symptoms and troponin.

Survey information

Includes self-reported survey information about general, mental, physical and overall health of pLoF carriers in comparison with non-carriers in the All of Us cohort.

Homozygous loss of function carriers

Provides demographics and survey information of the biallelic lof variant carriers in All of Us.

Indication specific report

Provides association results for user specified indications from All of Us and UK Biobank cohorts.

Resources used to generate the report

Controlled Datasets

All of Us

The All of Us cohort currently consists of 420k participants with whole genome sequencing and phenotypic data.

Open Source Databases

Here we describe the open source databases used for gathering evidence about the targets:

GeneBass

GeneBass reports phenomewide associations for LoF carriers among 380k participants from the UK Biobank cohort.

AstraZeneca PheWAS portal

AstraZeneca reports phenomewide associations for LoF carriers among 500k participants from the UK Biobank cohort.

Updates and Installation

v0.0.6

Provides biallelic loss of function carrier information as a new section: Homozygous loss of function carriers to the report.

v0.0.5

First working version. Generates a report in docx format that includes variant information, demographics, clinical records, and survey information. All individual level data is obtained from All of Us where as summary statistics are obtained from All of Us and UK Biobank cohorts.

python -m pip install -U pip build
python -m build
python -m venv .venv
source .venv/bin/activate
pip install -U pip
pip install dist/rwe-0.0.1-py3-none-any.whl
python -c "import rwe; print('import ok')"

pip install twine
twine upload dist/*


conda install -c conda-forge python=3.12
pip install -r requirements.txt
playwright install
python -m playwright install-deps

# New version
rm -rf dist build *.egg-info src/*.egg-info
python -m build
pip install dist/rwe-0.0.8-py3-none-any.whl
python -c "from rwe.generate_report import generate_rwe_report; print('import ok')"
twine upload dist/*

Resources

1. ICD to Phecode mappings: https://www.vumc.org/wei-lab/sites/default/files/public_files/ICD_to_Phecode_mapping.csv