MILTON is an automated framework for learning phenotype contributing factors from UK Biobank (UKB) structured data. The tool can also be used to define case-control cohorts based on continuous or binary traits contained in UKB or by prediction from the fitted machine learning models.
Original Hypothesis & MILTON outcomes:
Standard PheWAS analyses rely on ICD10 codes annotations for patient diagnosis. However, these may result to misdiagnosed patients or even undiagnosed ones (i.e. cryptic cases). We, thus, wanted to explore first whether we could identify those cryptic cases based on common biomarker signatures shared with already diagnosed patients. This would allow us to create predictive models to detect disease (prior or after onset) across 3,000 phenotypes, using blood and urine based biomarkers as well as plasma protein expression levels. A follow-up outcome of this analysis was to construct augmented case cohorts and perform enhanced PheWAS analyses, allowing us to detect novel genetic signals.
MILTON is not currently available via PyPi but it will install with pip in debug mode. For complete installation procedure that creates a conda env and installs everything with pip, run:
scripts/init.sh
If you already have a conda env that you want to use, activate it and from within the MILTON folder run:
pip install -r requirements.txt
pip install -e .
MILTON uses dask for parallel reading of partitioned datasets, hence it
needs to start a session beforehand.
from milton import *
sess = Session('local') # use multiprocessing - most recommended
The session object offers a high-level interface for running MILTON pipelines
based on pipeline configurations. The configurations are special objects that
have two-level hierarchy of settings and which define all aspects of a MILTON
run. The Settings objects pretty-print their full contents in Jupyter
notebooks so you can use that to learn the available options:
>> conf = Settings()
>> conf
Milton Settings
---------------
analysis:
data_location : /home/.../dummy_ukb_data
default_model : xgb
disease_prevalence : None
gene_significance_thresh : 0.05
cohort:
collapsing_controls : None
icd10_codes : None
training_controls : None
features:
biomarkers : False
derived_biomarkers : None
environmental : False
lifestyle : False
medical_history : False
mental_health : False
olink : False
olink_covariates : False
overall_health : False
pulse_wave : False
respiratory : False
social : False
processing:
correlation_thresh : 0.5
drop_features : None
drop_patients_with_missing_frac : 1.0
feature_scaling : standard
na_imputation : median
report:
effect_sizes : True
embedding : False
feature_embeddings : None
feature_importance : True
location : .
model_performance : True
title : Milton Report
To view the full list of settings (lower-level) run:
conf()
By default, MILTON will run on the dummy UKB data included in the distribution. The following example sets up a dummy config to make it run on the dummy data:
conf().analysis.min_cases = 10
conf().analysis.min_prediction_thresh = .5 # accept low quality predictions
conf().features.biomarkers = True # default 67 biomarkers
conf().patients.spec = pd.Series(1, index=range(1, 51)) # dummy subject IDs for cases
# fit models, estimates feature importance
result = sess.evaluate(conf)
# collapsing analysis and rest of pipeline
result.save_report('/path/to/folder')
MILTON features a dedicated data access layer that requires data to be stored in
the parquet binary format. It uses pandas and pyarrow for data reading and
processing. Check out the contents of the dummy_ukb_data folder to see how
MILTON expects its datasets to be stored under a single root. The folder
contains also companion files such as ancestry-specific sample ID files, ID
lists for subjects that opted out from UKB and should not be included in
analyses and collapsed variant matrices (UKB-derived data, see description
below). Make sure you check the contents of the data_info.py file which
defines the datasets expected to be found as well as the MILTON data root folder
under the UKB_DATA_LOCATION global constant.
UKB data comes by default as a collection of large CSV files which are quite costly to work with directly, especially if you need to read them multiple times. MILTON includes tools to convert the standard UKB data files into parquet. There are two routines, one converts the main UKB dataset which, due to the large number of columns, requires dedicated treatment and a more generic function for conversion of remaining companion datasets.
You will need a Dask cluster of several nodes, each with about 64 GB of RAM.
The conversion if fully automatic and it sets up a small cluster with slurm:
from pathlib import Path
from milton.ukb_csv_to_parquet import *
convert_ukb_csv_to_parquet(
Path('/path/to/ukb/release/main-ukb-file.csv'),
n_chunks=8,
output_path=Path(f'/path/to/output/folder/ukb.parquet'))
The following example converts the gp_clinical.txt dataset to parquet and
splits it into a number of chunks for quicker reads. No dask cluster is used
but the full file is read to memory so make such you have enough of it:
from pathlib import Path
from pyarrow import csv
from milton.ukb_csv_to_parquet import *
ehr_csv_to_parquet(
Path('/path/to/file/gp_clinical.txt'),
Path('/path/to/output/gp_clinical.parquet'),
read_options=csv.ReadOptions(
block_size=2**30,
encoding='cp1252',
use_threads=True),
parse_options=csv.ParseOptions(delimiter='\t'),
convert_options=csv.ConvertOptions(
include_columns=[
'eid', 'data_provider', 'event_dt', 'read_2', 'read_3',
],
strings_can_be_null=True,
auto_dict_encode=True,
column_types={
'value1': pa.string(),
'value2': pa.string(),
},
timestamp_parsers=['%d/%m/%Y']),
use_dictionary=['read_2', 'read_3'],
write_statistics=False)
MILTON runs collapsing analysis on its extended cohorts and uses sparse matrices
(csr_matrix from scipy) to represent genotypes of all UKB subjects. Dummy
examples are included in qv_models sub-folder of the dummy data folder and
they comprise pickled triplets: subject IDs (matrix rows), gene names (matrix
columns), the csr_matrix object containing binary data that indicates presence/absence
of a variant in a gene for a subject.
The collapsed variant matrices were derived from UKB WES data by AZ Centre for
Genomics Research and more information can be found in the following two publications:
Please note that when specifying your own case/control ids, MILTON doesn't know which ICD10 to use for time-lag calculation. Therefore, only time-agnostic model is implemented in this case. Please perform the sub-setting yourself while deriving case and control ids.
To specify multiple ICD10 codes
from milton import *
desired_codes=['N18', 'C50', 'C61', 'F30']
all_codes_list=[]
for code in desired_codes:
all_codes_list.append(list(ICD10.find_by_code(code)))
settings().patients.spec = list(itertools.chain(*all_codes_list))
To specify your own list of cases and controls:
- using case ids only
settings().patients.spec = pd.Series(1, index=case_ids)
- using case and control ids
settings().patients.spec = pd.concat([pd.Series(1, index=case_ids), pd.Series(0, index=control_ids)])
To set minimum number of training cases to 0, default 100
settings().analysis.min_cases = 0
To specify control subset for training XGBoost
settings().patients.training_controls = <list of control ids>
To specify control subset for performing collapsing analysis
settings().patients.collapsing_controls = <list of control ids>
To remove certain subjects from analysis.
settings().patients.used_subjects = list(set(settings().patients.used_subjects).difference(<list of subject ids to exclude>)
To perform low power collapsing analysis (only on subjects with Olink or NMR metabolomics data, for example, and not the entire UKB cohort)
settings().analysis.collapsing_on_data_index = True
To run MILTON on a subset of proteins:
settings().features.olink = <list of olink protein names such as ['C2', 'TNF']>
To add extra features from UKB based on their field ids:
settings().features.ukb_custom = [21025, 21027] #UKB field IDs for additional 7 features
settings().preproc.na_imputation_extra = {
'Testosterone': GenderSpecNAStrategy(males='median', females='median'),
Col.RHEUMATOID_FACTOR: ('constant', 0.0),
Col.OESTRADIOL: GenderSpecNAStrategy(males=36.71, females=110.13),
'Had menopause': CategoricalNAStrategy(),
'Smoking status': CategoricalNAStrategy(),
'Age when periods started (menarche)': ('constant', -5),
'Age at first live birth': ('constant', -5),
}
MILTON ships with version 0.4 of boruta_py
package since it cannot as of July 2024 be installed with pip. The implementation
is included verbatim.