transfer/code/scDFM/src/data_process/_datamanager.py

from collections.abc import Sequence
from typing import Any

import anndata
import jax
import jax.numpy as jnp
import numpy as np
import pandas as pd
import scipy.sparse as sp
import sklearn.preprocessing as preprocessing
from pandas.api.types import is_numeric_dtype
from tqdm import tqdm

from src.utils._logging import logger
from src.utils._types import ArrayLike
from src.data_process._data import ConditionData, PredictionData, ReturnData, TrainingData, ValidationData
import pdb
from src.utils._utils import _flatten_list, _to_list

__all__ = ["DataManager"]


class DataManager:
    """Data manager for handling perturbation data.

    Parameters
    ----------
    adata
        An :class:`~anndata.AnnData` object.
    covariate_encoder
        Encoder for the primary covariate.
    categorical
        Whether the primary covariate is categorical.
    max_combination_length
        Maximum number of combinations of primary ``perturbation_covariates``.
    sample_rep
        Key in :attr:`~anndata.AnnData.obsm` where the sample representation is stored or ``'X'``
        to use :attr:`~anndata.AnnData.X`.
    covariate_data
        Dataframe with covariates. If :obj:`None`, :attr:`~anndata.AnnData.obs` is used.
    condition_id_key
        Key in :attr:`~anndata.AnnData.obs` that defines the condition id.
    perturbation_covariates
        A dictionary where the keys indicate the name of the covariate group
        and the values are keys in :attr:`~anndata.AnnData.uns`. The corresponding
        columns should be either boolean (presence/abscence of the perturbation) or
        numeric (concentration or magnitude of the perturbation). If multiple groups
        are provided, the first is interpreted as the primary perturbation and the
        others as covariates corresponding to these perturbations, e.g.
        ``{"drug":("drugA", "drugB"), "time":("drugA_time", "drugB_time")}``.
    perturbation_covariate_reps
        A dictionary where the keys indicate the name of the covariate group and the
        values are keys in :attr:`~anndata.AnnData.uns` storing a dictionary with
        the representation of the covariates. E.g. ``{"drug":"drug_embeddings"}``
        with ``adata.uns["drug_embeddings"] = {"drugA": np.array, "drugB": np.array}``.
    sample_covariates
        Keys in :attr:`~anndata.AnnData.obs` indicating sample covatiates to be taken
        into account for training and prediction, e.g. ``["age", "cell_type"]``.
    sample_covariate_reps
        A dictionary where the keys indicate the name of the covariate group and the
        values are keys in :attr:`~anndata.AnnData.uns` storing a dictionary with the
        representation of the covariates. E.g. ``{"cell_type": "cell_type_embeddings"}`` with
        ``adata.uns["cell_type_embeddings"] = {"cell_typeA": np.array, "cell_typeB": np.array}``.
    split_covariates
        Covariates in :attr:`~anndata.AnnData.obs` to split all control cells into
        different control populations. The perturbed cells are also split according to these
        columns, but if these covariates should also be encoded in the model, the corresponding
        column should also be used in ``perturbation_covariates`` or ``sample_covariates``.
    null_value
        Value to use for padding to ``max_combination_length``.
    """

    def __init__(
        self,
        adata: anndata.AnnData,
        sample_rep: str | dict[str, str],
        control_key: str,
        perturbation_covariates: dict[str, Sequence[str]] | None = None,
        perturbation_covariate_reps: dict[str, str] | None = None,
        sample_covariates: Sequence[str] | None = None,
        sample_covariate_reps: dict[str, str] | None = None,
        split_covariates: Sequence[str] | None = None,
        max_combination_length: int | None = None,
        null_value: float = 0.0,
    ):
        self._adata = adata
        self._sample_rep = self._verify_sample_rep(sample_rep)
        self._control_key = control_key
        self._perturbation_covariates = self._verify_perturbation_covariates(perturbation_covariates)
        self._perturbation_covariate_reps = self._verify_perturbation_covariate_reps(
            adata,
            perturbation_covariate_reps,
            self._perturbation_covariates,
        )
        self._sample_covariates = self._verify_sample_covariates(sample_covariates)
        self._sample_covariate_reps = self._verify_sample_covariate_reps(
            adata, sample_covariate_reps, self._sample_covariates
        )
        self._split_covariates = self._verify_split_covariates(adata, split_covariates, control_key)
        self._max_combination_length = self._get_max_combination_length(
            self._perturbation_covariates, max_combination_length
        )
        self._null_value = null_value
        self._primary_one_hot_encoder, self._is_categorical = self._get_primary_covar_encoder(
            self._adata,
            self._perturbation_covariates,
            self._perturbation_covariate_reps,
        )
        self._linked_perturb_covars = self._get_linked_perturbation_covariates(self._perturbation_covariates)
        sample_cov_groups = {covar: _to_list(covar) for covar in self._sample_covariates}
        covariate_groups = self._perturbation_covariates | sample_cov_groups
        self._covariate_reps = (self._perturbation_covariate_reps or {}) | (self._sample_covariate_reps or {})

        self._covar_to_idx = self._get_covar_to_idx(covariate_groups)  # type: ignore[arg-type]
        perturb_covar_keys = _flatten_list(self._perturbation_covariates.values()) + list(self._sample_covariates)
        perturb_covar_keys += [col for col in self._split_covariates if col not in perturb_covar_keys]
        self._perturb_covar_keys = [k for k in perturb_covar_keys if k is not None]

        # get the unique values of the split covariates
        condition = np.unique(list(self.adata.obs['condition']))
        unique_drug = []
        np.array([unique_drug.extend(perturbation.split('+')) for perturbation in condition])
        unique_drug = np.unique(unique_drug)
        unique_drug.sort()
        self.unique_drug = unique_drug
        self.drug_dict = {drug: i for i, drug in enumerate(unique_drug)}

    def get_train_data(self, adata: anndata.AnnData, one_hot: bool = False) -> Any:
        """Get training data for the model.

        Parameters
        ----------
        adata
            An :class:`~anndata.AnnData` object.

        Returns
        -------
        Training data for the model.
        """
        # create a
        split_cov_combs = self._get_split_cov_combs(adata.obs)
        cond_data = self._get_condition_data(split_cov_combs=split_cov_combs, adata=adata, one_hot=one_hot)
        cell_data = self._get_cell_data(adata)
        return TrainingData(
            cell_data=cell_data,
            split_covariates_mask=cond_data.split_covariates_mask,
            split_idx_to_covariates=cond_data.split_idx_to_covariates,
            perturbation_covariates_mask=cond_data.perturbation_covariates_mask,
            perturbation_idx_to_covariates=cond_data.perturbation_idx_to_covariates,
            perturbation_idx_to_id=cond_data.perturbation_idx_to_id,
            condition_data=cond_data.condition_data,
            control_to_perturbation=cond_data.control_to_perturbation,
            max_combination_length=cond_data.max_combination_length,
            null_value=self._null_value,
            data_manager=self,
            condition_data_id=cond_data.condition_data_id,
            cell_data_id=adata.obs.index,
        )

    def get_validation_data(
        self,
        adata: anndata.AnnData,
        n_conditions_on_log_iteration: int | None = None,
        n_conditions_on_train_end: int | None = None,
        one_hot: bool = False,
    ) -> ValidationData:
        """Get validation data for the model.

        Parameters
        ----------
        adata
            An :class:`~anndata.AnnData` object.
        n_conditions_on_log_iteration
            Number of conditions to validate on during logging.
        n_conditions_on_train_end
            Number of conditions to validate on at the end of training.

        Returns
        -------
        Validation data for the model.
        """
        split_cov_combs = self._get_split_cov_combs(adata.obs)
        cond_data = self._get_condition_data(split_cov_combs=split_cov_combs, adata=adata, one_hot=one_hot)
        cell_data = self._get_cell_data(adata)
        return ValidationData(
            cell_data=cell_data,
            split_covariates_mask=cond_data.split_covariates_mask,
            split_idx_to_covariates=cond_data.split_idx_to_covariates,
            perturbation_covariates_mask=cond_data.perturbation_covariates_mask,
            perturbation_idx_to_covariates=cond_data.perturbation_idx_to_covariates,
            perturbation_idx_to_id=cond_data.perturbation_idx_to_id,
            condition_data=cond_data.condition_data,
            control_to_perturbation=cond_data.control_to_perturbation,
            max_combination_length=cond_data.max_combination_length,
            null_value=self._null_value,
            data_manager=self,
            condition_data_id=cond_data.condition_data_id,
            n_conditions_on_log_iteration=n_conditions_on_log_iteration,
            n_conditions_on_train_end=n_conditions_on_train_end,
        )

    def get_prediction_data(
        self,
        adata: anndata.AnnData,
        sample_rep: str,
        covariate_data: pd.DataFrame,
        rep_dict: dict[str, Any] | None = None,
        condition_id_key: str | None = None,
        one_hot: bool = False,
    ) -> Any:
        """Get predictions for control cells.

        Extracts source distributions from  ``'adata'`` and simulates cells perturbed
        with covariates defined in ``'covariate_data'``.

        Parameters
        ----------
        adata
            An :class:`~anndata.AnnData` object to extract control cells from.
        sample_rep
            Key in :attr:`~anndata.AnnData.obsm` where the sample representation of the control
            is stored or ``'X'`` to use :attr:`~anndata.AnnData.X`.
        covariate_data
            A :class:`~pandas.DataFrame` with columns defining the covariates as
            in :meth:`cellflow.model.CellFlow.prepare_data` and stored in
            :attr:`cellflow.model.CellFlow.data_manager`.
        rep_dict
            Dictionary with representations of the covariates.
            If not provided, :attr:`~anndata.AnnData.uns` is used.
        condition_id_key
            Key in :class:`~pandas.DataFrame` that defines the condition names.

        Returns
        -------
        Training data for the model.
        """
        self._verify_prediction_data(adata)
        split_cov_combs = self._get_split_cov_combs(covariate_data=covariate_data)

        # adata is None since we don't extract cell masks for predicted covariates
        cond_data = self._get_condition_data(
            split_cov_combs=split_cov_combs,
            adata=None,
            covariate_data=covariate_data,
            rep_dict=adata.uns if rep_dict is None else rep_dict,
            condition_id_key=condition_id_key,
            one_hot=one_hot,
        )

        cell_data = self._get_cell_data(adata, sample_rep)
        split_covariates_mask, split_idx_to_covariates = self._get_split_covariates_mask(
            adata=adata, split_cov_combs=split_cov_combs
        )

        return PredictionData(
            cell_data=cell_data,
            split_covariates_mask=split_covariates_mask,
            split_idx_to_covariates=split_idx_to_covariates,
            condition_data=cond_data.condition_data,
            control_to_perturbation=cond_data.control_to_perturbation,
            perturbation_idx_to_covariates=cond_data.perturbation_idx_to_covariates,
            perturbation_idx_to_id=cond_data.perturbation_idx_to_id,
            max_combination_length=cond_data.max_combination_length,
            null_value=self._null_value,
            data_manager=self,
            condition_data_id=cond_data.condition_data_id,
        )

    def get_condition_data(
        self,
        covariate_data: pd.DataFrame,
        rep_dict: dict[str, Any] | None = None,
        condition_id_key: str | None = None,
        one_hot: bool = False,
    ) -> ConditionData:
        """Get condition data for the model.

        Parameters
        ----------
        covariate_data
            Dataframe with covariates.
        condition_id_key
            Key in ``covariate_data`` that defines the condition id.
        rep_dict

        Returns
        -------
        Condition data for the model.
        """
        self._verify_covariate_data(covariate_data, self._perturb_covar_keys)
        split_cov_combs = self._get_split_cov_combs(covariate_data)
        cond_data = self._get_condition_data(
            split_cov_combs=split_cov_combs,
            adata=None,
            covariate_data=covariate_data,
            rep_dict=rep_dict,
            condition_id_key=condition_id_key,
            one_hot=one_hot,
        )
        return ConditionData(
            condition_data=cond_data.condition_data,
            max_combination_length=cond_data.max_combination_length,
            perturbation_idx_to_covariates=cond_data.perturbation_idx_to_covariates,
            perturbation_idx_to_id=cond_data.perturbation_idx_to_id,
            null_value=self._null_value,
            data_manager=self,
            condition_data_id=cond_data.condition_data_id,
        )

    def _get_split_cov_combs(self, covariate_data: pd.DataFrame) -> np.ndarray | list[list[Any]]:  # type: ignore[type-arg]
        if len(self._split_covariates) > 0:
            return covariate_data[self._split_covariates].drop_duplicates().values
        else:
            return [[]]

    def _get_condition_data(
        self,
        split_cov_combs: np.ndarray | list[list[Any]],  # type: ignore[type-arg]
        adata: anndata.AnnData | None,
        covariate_data: pd.DataFrame | None = None,
        rep_dict: dict[str, Any] | None = None,
        condition_id_key: str | None = None,
        one_hot: bool = False,
    ) -> ReturnData:
        # for prediction: adata is None, covariate_data is provided
        # for training/validation: adata is provided and used to get cell masks, covariate_data is None
        if adata is None and covariate_data is None:
            raise ValueError("Either `adata` or `covariate_data` must be provided.")
        covariate_data = covariate_data if covariate_data is not None else adata.obs  # type: ignore[union-attr]
        if rep_dict is None:
            rep_dict = adata.uns if adata is not None else {}
        # check if all perturbation/split covariates and control cells are present in the input
        self._verify_covariate_data(
            covariate_data,
            {covar: _to_list(covar) for covar in self._sample_covariates},
        )
        self._verify_control_data(adata)
        self._verify_covariate_data(covariate_data, _to_list(self._split_covariates))

        # extract unique combinations of perturbation covariates
        if condition_id_key is not None:
            self._verify_condition_id_key(covariate_data, condition_id_key)
            select_keys = self._perturb_covar_keys + [condition_id_key]
        else:
            select_keys = self._perturb_covar_keys
        perturb_covar_df = covariate_data[select_keys].drop_duplicates()
        if condition_id_key is not None:
            perturb_covar_df = perturb_covar_df.set_index(condition_id_key)
        else:
            perturb_covar_df = perturb_covar_df.reset_index()

        # get indices of cells belonging to each unique condition
        _perturb_covar_df, _covariate_data = (
            perturb_covar_df[self._perturb_covar_keys],
            covariate_data[self._perturb_covar_keys],
        )
        _perturb_covar_df["row_id"] = range(len(perturb_covar_df))
        _covariate_data["cell_index"] = _covariate_data.index
        _perturb_covar_merged = _perturb_covar_df.merge(_covariate_data, on=self._perturb_covar_keys, how="inner")
        perturb_covar_to_cells = _perturb_covar_merged.groupby("row_id")["cell_index"].apply(list).to_list()

        # intialize data containers
        if adata is not None:
            split_covariates_mask = np.full((len(adata),), -1, dtype=jnp.int32)
            perturbation_covariates_mask = np.full((len(adata),), -1, dtype=jnp.int32)
            control_mask = covariate_data[self._control_key]
        else:
            split_covariates_mask = None
            perturbation_covariates_mask = None
            control_mask = jnp.ones((len(covariate_data),))

        condition_data: dict[str, list[jnp.ndarray]] = {i: [] for i in self._covar_to_idx.keys()}

        control_to_perturbation: dict[int, ArrayLike] = {}
        split_idx_to_covariates: dict[int, tuple[Any]] = {}
        perturbation_idx_to_covariates: dict[int, tuple[Any]] = {}
        perturbation_idx_to_id: dict[int, Any] = {}
        condition_data_id_list: list[jnp.ndarray] = []

        src_counter = 0
        tgt_counter = 0
        
        # iterate over unique split covariate combinations
        for split_combination in split_cov_combs:
            # get masks for split covariates; for prediction, it's done outside this method
            if adata is not None:
                split_covariates_mask, split_idx_to_covariates, split_cov_mask = self._get_split_combination_mask(
                    covariate_data=adata.obs,
                    split_covariates_mask=split_covariates_mask,  # type: ignore[arg-type]
                    split_combination=split_combination,  # type: ignore[arg-type]
                    split_idx_to_covariates=split_idx_to_covariates,
                    control_mask=control_mask,
                    src_counter=src_counter,
                )
            conditional_distributions = []

            # iterate over target conditions
            filter_dict = dict(zip(self.split_covariates, split_combination, strict=False))
            pc_df = perturb_covar_df[
                (perturb_covar_df[list(filter_dict.keys())] == list(filter_dict.values())).all(axis=1)
            ]
            pbar = tqdm(pc_df.iterrows(), total=pc_df.shape[0])
            
            for i, tgt_cond in pbar:
                tgt_cond = tgt_cond[self._perturb_covar_keys]
                # for train/validation, only extract covariate combinations that are present in adata
                if adata is not None:
                    mask = covariate_data.index.isin(perturb_covar_to_cells[i])
                    mask *= (1 - control_mask) * split_cov_mask
                    mask = np.array(mask == 1)
                    if mask.sum() == 0:
                        continue
                    # map unique condition id to target id
                    perturbation_covariates_mask[mask] = tgt_counter  # type: ignore[index]

                # map target id to unique conditions and their ids
                conditional_distributions.append(tgt_counter)
                perturbation_idx_to_covariates[tgt_counter] = tgt_cond.values
                if condition_id_key is not None:
                    perturbation_idx_to_id[tgt_counter] = i

                # get embeddings for conditions
                embedding = self._get_perturbation_covariates(
                    condition_data=tgt_cond,
                    rep_dict=rep_dict,
                    perturb_covariates={k: _to_list(v) for k, v in self._perturbation_covariates.items()},
                )
                for pert_cov, emb in embedding.items():
                    condition_data[pert_cov].append(emb)

                condition_name, condition_id_emb = self._generate_condition_name_and_embedding(tgt_cond, tgt_counter, embedding, one_hot=one_hot)
                condition_data_id_list.append(condition_id_emb)
                tgt_counter += 1

            # map source (control) to target condition ids
            control_to_perturbation[src_counter] = np.array(conditional_distributions)
            src_counter += 1
        # convert outputs to jax arrays
        for pert_cov, emb in condition_data.items():
            condition_data[pert_cov] = jnp.array(emb)
        condition_data_id = jnp.stack(condition_data_id_list, axis=0)  # shape: (N, D)
        split_covariates_mask = jnp.asarray(split_covariates_mask) if split_covariates_mask is not None else None
        perturbation_covariates_mask = (
            jnp.asarray(perturbation_covariates_mask) if perturbation_covariates_mask is not None else None
        )
        return ReturnData(
            split_covariates_mask=split_covariates_mask,
            split_idx_to_covariates=split_idx_to_covariates,
            perturbation_covariates_mask=perturbation_covariates_mask,
            perturbation_idx_to_covariates=perturbation_idx_to_covariates,
            perturbation_idx_to_id=perturbation_idx_to_id,
            condition_data=condition_data,  # type: ignore[arg-type]
            control_to_perturbation=control_to_perturbation,
            max_combination_length=self._max_combination_length,
            condition_data_id=condition_data_id,
        )

    def _generate_condition_name_and_embedding(
        self,
        tgt_cond: pd.Series,
        tgt_counter: int,
        embedding: dict[str, jnp.ndarray],
        one_hot: bool = False,
    ) -> tuple[str, jnp.ndarray]:
        """
        基于 self.drug_dict 映射 tgt_cond 中的药物组合，生成唯一名称和 embedding。
        """
        # 展开所有 perturbation covariates（如 Drug1, Drug2）
        drug_names = []
        for covar_group in self._perturbation_covariates.values():
            for col in covar_group:
                val = tgt_cond[col]
                if isinstance(val, str):
                    drug_names.extend(val.split('+'))
                else:
                    drug_names.append(str(val))
        drug_names = sorted(set(drug_names))  # 去重 + 排序
        drug_ids = [self.drug_dict[name] for name in drug_names]

        condition_name = 'drug_' + '_'.join(str(i) for i in drug_ids)
        if one_hot:
            one_hots = []
            for idx in drug_ids:
                vec = jnp.zeros((num_drugs,), dtype=jnp.float32).at[idx].set(1.0)
                one_hots.append(vec)
            condition_id_emb = jnp.concatenate(one_hots, axis=-1)
        else:
            condition_id_emb = jnp.array(drug_ids, dtype=jnp.int32)
        return condition_name, condition_id_emb

    @staticmethod
    def _verify_condition_id_key(covariate_data: pd.DataFrame, condition_id_key: str | None) -> None:
        if condition_id_key is not None and condition_id_key not in covariate_data.columns:
            raise ValueError(f"The `condition_id_key` column ('{condition_id_key}') was not found in `adata.obs`.")
        if not len(covariate_data[condition_id_key].unique()) == len(covariate_data):
            raise ValueError(f"The `condition_id_key` column ('{condition_id_key}') must contain unique values.")

    @staticmethod
    def _verify_sample_rep(sample_rep: str | dict[str, str]) -> str | dict[str, str]:
        if not (isinstance(sample_rep, str) or isinstance(sample_rep, dict)):
            raise ValueError(
                f"`sample_rep` should be of type `str` or `dict`, found {sample_rep} to be of type {type(sample_rep)}."
            )
        return sample_rep

    def _get_cell_data(
        self,
        adata: anndata.AnnData,
        sample_rep: str | None = None,
    ) -> jax.Array:
        sample_rep = self._sample_rep if sample_rep is None else sample_rep
        if sample_rep == "X":
            sample_rep = adata.X
            if isinstance(sample_rep, sp.csr_matrix):
                return jnp.asarray(sample_rep.toarray())
            else:
                return jnp.asarray(sample_rep)
        if isinstance(self._sample_rep, str):
            if self._sample_rep not in adata.obsm:
                raise KeyError(f"Sample representation '{self._sample_rep}' not found in `adata.obsm`.")
            return jnp.asarray(adata.obsm[self._sample_rep])
        attr, key = next(iter(sample_rep.items()))  # type: ignore[union-attr]
        return jnp.asarray(getattr(adata, attr)[key])

    def _verify_control_data(self, adata: anndata.AnnData | None) -> None:
        if adata is None:
            return None
        if self._control_key not in adata.obs:
            raise ValueError(f"Control column '{self._control_key}' not found in adata.obs.")
        if not isinstance(adata.obs[self._control_key].dtype, pd.BooleanDtype):
            try:
                adata.obs[self._control_key] = adata.obs[self._control_key].astype("boolean")
            except TypeError as e:
                raise ValueError(f"Control column '{self._control_key}' could not be converted to boolean.") from e
        if adata.obs[self._control_key].sum() == 0:
            raise ValueError("No control cells found in adata.")

    def _verify_prediction_data(self, adata: anndata.AnnData) -> None:
        if self._control_key not in adata.obs:
            raise ValueError(f"Control column '{self._control_key}' not found in adata.obs.")
        if not isinstance(adata.obs[self._control_key].dtype, pd.BooleanDtype):
            try:
                adata.obs[self._control_key] = adata.obs[self._control_key].astype("boolean")
            except ValueError as e:
                raise ValueError(f"Control column '{self._control_key}' could not be converted to boolean.") from e
        if not adata.obs[self._control_key].all():
            raise ValueError(
                f"For prediction, all cells in `adata` should be from control condition. Ensure that '{self._control_key}' is `True` for all cells, even if you're setting `.obs` to predicted condition."
            )

    def _get_split_combination_mask(
        self,
        covariate_data: pd.DataFrame,
        split_covariates_mask: ArrayLike,
        split_combination: ArrayLike,
        split_idx_to_covariates: dict[int, tuple[Any]],
        control_mask: ArrayLike,
        src_counter: int,
    ) -> tuple[ArrayLike, dict[int, tuple[Any]], ArrayLike]:
        filter_dict = dict(zip(self.split_covariates, split_combination, strict=False))
        split_cov_mask = (covariate_data[list(filter_dict.keys())] == list(filter_dict.values())).all(axis=1)
        mask = jnp.array(control_mask * split_cov_mask).astype(bool)
        split_covariates_mask[mask] = src_counter
        split_idx_to_covariates[src_counter] = tuple(split_combination)
        return split_covariates_mask, split_idx_to_covariates, split_cov_mask

    def _get_split_covariates_mask(
        self,
        adata: anndata.AnnData,
        split_cov_combs: np.ndarray | list[list[Any]],  # type: ignore[type-arg]
    ) -> tuple[ArrayLike, dict[int, tuple[Any]]]:
        # here we assume that adata only contains source cells
        if len(self.split_covariates) == 0:
            return jnp.full((len(adata),), 0, dtype=jnp.int32), {}
        split_covariates_mask = np.full((len(adata),), -1, dtype=jnp.int32)
        split_idx_to_covariates: dict[int, Any] = {}
        src_counter = 0
        for split_combination in split_cov_combs:
            split_covariates_mask_previous = split_covariates_mask.copy()
            split_covariates_mask, split_idx_to_covariates, _ = self._get_split_combination_mask(
                covariate_data=adata.obs,
                split_covariates_mask=split_covariates_mask,
                split_combination=split_combination,  # type: ignore[arg-type]
                split_idx_to_covariates=split_idx_to_covariates,
                control_mask=jnp.ones((adata.n_obs,)),
                src_counter=src_counter,
            )
            if (split_covariates_mask == split_covariates_mask_previous).all():
                raise ValueError(f"No cells found in `adata` for split covariates {split_combination}.")
            src_counter += 1
        return jnp.asarray(split_covariates_mask), split_idx_to_covariates

    @staticmethod
    def _verify_perturbation_covariates(data: dict[str, Sequence[str]] | None) -> dict[str, list[str]]:
        if data is None:
            return {}
        if not isinstance(data, dict):
            raise ValueError(
                f"`perturbation_covariates` should be a dictionary, found {data} to be of type {type(data)}."
            )
        if len(data) == 0:
            raise ValueError("No perturbation covariates provided.")
        for key, covars in data.items():
            if not isinstance(key, str):
                raise ValueError(f"Key should be a string, found {key} to be of type {type(key)}.")
            if not isinstance(covars, tuple | list):
                raise ValueError(f"Value should be a tuple, found {covars} to be of type {type(covars)}.")
            if len(covars) == 0:
                raise ValueError(f"No covariates provided for perturbation group {key}.")
        lengths = [len(covs) for covs in data.values()]
        if len(set(lengths)) != 1:
            raise ValueError(f"Length of perturbation covariate groups must match, found lengths {lengths}.")
        return {k: list(el) for k, el in data.items()}

    @staticmethod
    def _verify_sample_covariates(
        sample_covariates: Sequence[str] | None,
    ) -> list[str]:
        if sample_covariates is None:
            return []
        if not isinstance(sample_covariates, tuple | list):
            raise ValueError(
                f"`sample_covariates` should be a tuple or list, found {sample_covariates} to be of type {type(sample_covariates)}."
            )
        for covar in sample_covariates:
            if not isinstance(covar, str):
                raise ValueError(f"Key should be a string, found {covar} to be of type {type(covar)}.")
        return list(sample_covariates)

    @staticmethod
    def _verify_split_covariates(
        adata: anndata.AnnData,
        data: Sequence[str] | None,
        control_key: str,
    ) -> Sequence[str]:
        if data is None:
            return []
        if not isinstance(data, tuple | list):
            raise ValueError(f"`split_covariates` should be a tuple or list, found {data} to be of type {type(data)}.")
        for covar in data:
            if not isinstance(covar, str):
                raise ValueError(f"Key should be a string, found {covar} to be of type {type(covar)}.")
        source_splits = adata.obs[adata.obs[control_key]][data].drop_duplicates()
        source_splits = map(tuple, source_splits.values)
        target_splits = adata.obs[~adata.obs[control_key]][data].drop_duplicates()
        target_splits = map(tuple, target_splits.values)
        source_without_targets = set(source_splits) - set(target_splits)
        if len(source_without_targets) > 0:
            raise ValueError(
                f"Source distribution with split covariate values {source_without_targets} do not have a corresponding target distribution."
            )
        return data

    @staticmethod
    def _verify_covariate_data(covariate_data: pd.DataFrame, covars) -> None:
        for covariate in covars:
            if covariate is not None and covariate not in covariate_data:
                raise ValueError(f"Covariate {covariate} not found in adata.obs or covariate_data.")

    @staticmethod
    def _get_linked_perturbation_covariates(perturb_covariates: dict[str, list[str]]) -> dict[str, dict[Any, Any]]:
        primary_group, primary_covars = next(iter(perturb_covariates.items()))
        linked_perturb_covars: dict[str, dict[Any, Any]] = {k: {} for k in primary_covars}
        for cov_group, covars in list(perturb_covariates.items())[1:]:
            for primary_cov, linked_cov in zip(primary_covars, covars, strict=False):
                linked_perturb_covars[primary_cov][cov_group] = linked_cov

        return linked_perturb_covars

    @staticmethod
    def _verify_perturbation_covariate_reps(
        adata: anndata.AnnData,
        perturbation_covariate_reps: dict[str, str] | None,
        perturbation_covariates: dict[str, list[str]],
    ) -> dict[str, str]:
        if perturbation_covariate_reps is None:
            return {}
        for key, value in perturbation_covariate_reps.items():
            if key not in perturbation_covariates:
                raise ValueError(f"Key '{key}' not found in covariates.")
            if value not in adata.uns:
                raise ValueError(f"Perturbation covariate representation '{value}' not found in `adata.uns`.")
            if not isinstance(adata.uns[value], dict):
                raise ValueError(
                    f"Perturbation covariate representation '{value}' in `adata.uns` should be of type `dict`, found {type(adata.uns[value])}."
                )
        return perturbation_covariate_reps

    @staticmethod
    def _verify_sample_covariate_reps(
        adata: anndata.AnnData,
        sample_covariate_reps: dict[str, str] | None,
        covariates: list[str],
    ) -> dict[str, str]:
        if sample_covariate_reps is None:
            return {}
        for key, value in sample_covariate_reps.items():
            if key not in covariates:
                raise ValueError(f"Key '{key}' not found in covariates.")
            if value not in adata.uns:
                raise ValueError(f"Sample covariate representation '{value}' not found in `adata.uns`.")
            if not isinstance(adata.uns[value], dict):
                raise ValueError(
                    f"Sample covariate representation '{value}' in `adata.uns` should be of type `dict`, found {type(adata.uns[value])}."
                )
        return sample_covariate_reps

    @staticmethod
    def _get_max_combination_length(
        perturbation_covariates: dict[str, list[str]],
        max_combination_length: int | None,
    ) -> int:
        obs_max_combination_length = max(len(comb) for comb in perturbation_covariates.values())
        if max_combination_length is None:
            return obs_max_combination_length
        elif max_combination_length < obs_max_combination_length:
            logger.warning(
                f"Provided `max_combination_length` is smaller than the observed maximum combination length of the perturbation covariates. Setting maximum combination length to {obs_max_combination_length}.",
                stacklevel=2,
            )
            return obs_max_combination_length
        else:
            return max_combination_length

    def _get_primary_covar_encoder(
        self,
        adata: anndata.AnnData,
        perturbation_covariates: dict[str, list[str]],
        perturbation_covariate_reps: dict[str, str],
    ) -> tuple[preprocessing.OneHotEncoder | None, bool]:
        primary_group, primary_covars = next(iter(perturbation_covariates.items()))
        is_categorical = self._check_covariate_type(adata, primary_covars)
        if perturbation_covariate_reps and primary_group in perturbation_covariate_reps:
            return None, is_categorical
        if is_categorical:
            encoder = preprocessing.OneHotEncoder(sparse_output=False)
            all_values = np.unique(adata.obs[primary_covars].values.flatten())
            encoder.fit(all_values.reshape(-1, 1))
            return encoder, is_categorical
        encoder = preprocessing.OneHotEncoder(sparse_output=False)
        encoder.fit(np.array(primary_covars).reshape(-1, 1))
        return encoder, is_categorical

    @staticmethod
    def _check_covariate_type(adata: anndata.AnnData, covars: Sequence[str]) -> bool:
        col_is_cat = []
        for covariate in covars:
            if is_numeric_dtype(adata.obs[covariate]):
                col_is_cat.append(False)
                continue
            if adata.obs[covariate].isin(["True", "False", True, False]).all():
                adata.obs[covariate] = adata.obs[covariate].astype(int)
                col_is_cat.append(False)
                continue
            try:
                adata.obs[covariate] = adata.obs[covariate].astype("category")
                col_is_cat.append(True)
            except ValueError as e:
                raise ValueError(
                    f"Perturbation covariates `{covariate}` should be either numeric/boolean or categorical."
                ) from e

        if max(col_is_cat) != min(col_is_cat):
            raise ValueError(
                f"Groups of perturbation covariates `{covariate}` should be either all numeric/boolean or all categorical."
            )

        return max(col_is_cat)

    @staticmethod
    def _verify_covariate_type(covariate_data: pd.DataFrame, covars: Sequence[str], categorical: bool) -> None:
        for covariate in covars:
            if is_numeric_dtype(covariate_data[covariate]):
                if categorical:
                    raise ValueError(f"Perturbation covariates `{covariate}` should be categorical, found numeric.")
                continue
            if covariate_data[covariate].isin(["True", "False", True, False]).all():
                if categorical:
                    raise ValueError(f"Perturbation covariates `{covariate}` should be categorical, found boolean.")
                continue
            try:
                covariate_data[covariate] = covariate_data[covariate].astype("category")
            except ValueError as e:
                raise ValueError(
                    f"Perturbation covariates `{covariate}` should be either numeric/boolean or categorical."
                ) from e
            else:
                if not categorical:
                    raise ValueError(
                        f"Perturbation covariates `{covariate}` should be numeric/boolean, found categorical."
                    )

    @staticmethod
    def _check_shape(arr: float | ArrayLike) -> ArrayLike:
        if not hasattr(arr, "shape") or len(arr.shape) == 0:
            return jnp.ones((1, 1)) * arr
        if arr.ndim == 1:  # type: ignore[union-attr]
            return jnp.expand_dims(arr, 0)
        elif arr.ndim == 2:  # type: ignore[union-attr]
            if arr.shape[0] == 1:
                return arr  # type: ignore[return-value]
            if arr.shape[1] == 1:
                return jnp.transpose(arr)
            raise ValueError(
                "Condition representation has an unexpected shape. Should be (1, n_features) or (n_features, )."
            )
        elif arr.ndim > 2:  # type: ignore[union-attr]
            raise ValueError("Condition representation has too many dimensions. Should be 1 or 2.")

        raise ValueError(
            "Condition representation as an unexpected format. Expected an array of shape (1, n_features) or (n_features, )."
        )

    @staticmethod
    def _get_covar_to_idx(covariate_groups: dict[str, Sequence[str]]) -> dict[str, int]:
        idx_to_covar = {}
        for idx, cov_group in enumerate(covariate_groups):
            idx_to_covar[idx] = cov_group
        covar_to_idx = {v: k for k, v in idx_to_covar.items()}
        return covar_to_idx

    @staticmethod
    def _pad_to_max_length(arr: jax.Array, max_combination_length: int, null_value: Any) -> jax.Array:
        if arr.shape[0] < max_combination_length:
            null_arr = jnp.full((max_combination_length - arr.shape[0], arr.shape[1]), null_value)
            arr = jnp.concatenate([arr, null_arr], axis=0)
        return arr

    def _get_perturbation_covariates(
        self,
        condition_data: pd.DataFrame,
        rep_dict: dict[str, dict[str, ArrayLike]],
        perturb_covariates: Any,  # TODO: check if we can save as attribtue
    ) -> dict[str, jax.Array]:
        primary_group, primary_covars = next(iter(perturb_covariates.items()))

        perturb_covar_emb: dict[str, list[jax.Array]] = {group: [] for group in perturb_covariates}
        for primary_cov in primary_covars:
            value = condition_data[primary_cov]
            cov_name = value if self.is_categorical else primary_cov
            if primary_group in self._covariate_reps:
                rep_key = self._covariate_reps[primary_group]
                try:
                    prim_arr = rep_dict[rep_key][cov_name]
                except KeyError as err:
                    raise ValueError(
                        f"Representation for '{cov_name}' not found in `adata.uns['{rep_key}']` or `rep_dict`."
                    ) from err
                prim_arr = jnp.asarray(prim_arr)
            else:
                prim_arr = jnp.asarray(
                    self.primary_one_hot_encoder.transform(  # type: ignore[union-attr]
                        np.array(cov_name).reshape(-1, 1)
                    )
                )

            if not self.is_categorical:
                prim_arr *= value

            prim_arr = self._check_shape(prim_arr)
            perturb_covar_emb[primary_group].append(prim_arr)

            for linked_covar in self._linked_perturb_covars[primary_cov].items():
                linked_group, linked_cov = list(linked_covar)

                if linked_cov is None:
                    linked_arr = jnp.full((1, 1), self._null_value)
                    linked_arr = self._check_shape(linked_arr)
                    perturb_covar_emb[linked_group].append(linked_arr)
                    continue

                cov_name = condition_data[linked_cov]

                if linked_group in self._covariate_reps:
                    rep_key = self._covariate_reps[linked_group]
                    if cov_name not in rep_dict[rep_key]:
                        raise ValueError(f"Representation for '{cov_name}' not found in `adata.uns['{rep_key}']`.")
                    linked_arr = jnp.asarray(rep_dict[rep_key][cov_name])
                else:
                    linked_arr = jnp.asarray(condition_data[linked_cov])

                linked_arr = self._check_shape(linked_arr)
                perturb_covar_emb[linked_group].append(linked_arr)

        perturb_covar_emb = {
            k: self._pad_to_max_length(
                jnp.concatenate(v, axis=0),
                self._max_combination_length,
                self._null_value,
            )
            for k, v in perturb_covar_emb.items()
        }

        sample_covar_emb: dict[str, jax.Array] = {}
        for sample_cov in self._sample_covariates:
            value = condition_data[sample_cov]
            if sample_cov in self._covariate_reps:
                rep_key = self._covariate_reps[sample_cov]
                if value not in rep_dict[rep_key]:
                    raise ValueError(f"Representation for '{value}' not found in `adata.uns['{sample_cov}']`.")
                cov_arr = jnp.asarray(rep_dict[rep_key][value])
            else:
                cov_arr = jnp.asarray(value)

            cov_arr = self._check_shape(cov_arr)
            sample_covar_emb[sample_cov] = jnp.tile(cov_arr, (self._max_combination_length, 1))

        return perturb_covar_emb | sample_covar_emb

    @property
    def is_categorical(self) -> bool:
        """Whether the primary covariate is categorical."""
        return self._is_categorical

    @property
    def adata(self) -> anndata.AnnData:
        """An :class:`~anndata.AnnData` object used for instantiating the DataManager."""
        return self._adata

    @property
    def control_key(self) -> str:
        """Boolean key in :attr:`~anndata.AnnData.obs` indicating whether belongs to control group."""
        return self._control_key

    @property
    def perturbation_covariates(self) -> dict[str, list[str]]:
        """Dictionary with keys indicating the name of the covariate group and values are keys in :attr:`~anndata.AnnData.obs` which together define the covariates."""
        return self._perturbation_covariates

    @property
    def perturbation_covariate_reps(self) -> dict[str, str]:
        """Dictionary with keys indicating the name of the covariate group and values are keys in :attr:`~anndata.AnnData.uns` storing a dictionary with the representation of the covariates."""
        return self._perturbation_covariate_reps

    @property
    def sample_covariates(self) -> Sequence[str]:
        """Keys in :attr:`~anndata.AnnData.obs` indicating which sample the cell belongs to (e.g. cell line)."""
        return self._sample_covariates

    @property
    def sample_covariate_reps(self) -> dict[str, str]:
        """Dictionary with keys indicating the name of the sample covariate group and values are keys in :attr:`~anndata.AnnData.uns` storing a dictionary with the representation of the sample covariates."""
        return self._sample_covariate_reps

    @property
    def split_covariates(self) -> Sequence[str]:
        """Covariates in :attr:`~anndata.AnnData.obs` to split all control cells into different control populations."""
        return self._split_covariates

    @property
    def max_combination_length(self) -> int:
        """Maximum combination length of perturbation covariates."""
        return self._max_combination_length

    @property
    def null_value(self) -> float:
        """Value to use for padding to :attr:`~max_combination_length`."""
        return self._null_value

    @property
    def primary_one_hot_encoder(self) -> preprocessing.OneHotEncoder | None:
        """One-hot encoder for the primary covariate."""
        return self._primary_one_hot_encoder

    @property
    def linked_perturb_covars(self) -> dict[str, dict[Any, Any]]:
        """Dictionary with keys indicating the name of the primary covariate and values are dictionaries with keys indicating the name of the linked covariate group and values are the linked covariates."""
        return self._linked_perturb_covars

    @property
    def covariate_reps(self) -> dict[str, str]:
        """Dictionary which stores representation of covariates, i.e. the union of ``sample_covariate_reps`` and ``perturbation_covariate_reps``."""
        return self._covariate_reps

    @property
    def covar_to_idx(self) -> dict[str, int]:
        """TODO: add description"""
        return self._covar_to_idx

    @property
    def perturb_covar_keys(self) -> list[str]:
        """List of all perturbation covariates."""
        return self._perturb_covar_keys

    @property
    def sample_rep(self) -> str | dict[str, str]:
        """Key of the sample representation."""
        return self._sample_rep