geneformer/in_silico_perturber.py

"""
Geneformer in silico perturber.

Usage:
  from geneformer import InSilicoPerturber
  isp = InSilicoPerturber(perturb_type="delete",
                          perturb_rank_shift=None,
                          genes_to_perturb="all",
                          combos=0,
                          anchor_gene=None,
                          model_type="CellClassifier",
                          num_classes=0,
                          emb_mode="cell",
                          cell_emb_style="mean_pool",
                          filter_data={"cell_type":["cardiomyocyte"]},
                          cell_states_to_model={"state_key": "disease", "start_state": "dcm", "goal_state": "nf", "alt_states": ["hcm", "other1", "other2"]},
                          state_embs_dict ={"nf": emb_nf, "hcm": emb_hcm, "dcm": emb_dcm, "other1": emb_other1, "other2": emb_other2},
                          max_ncells=None,
                          emb_layer=0,
                          forward_batch_size=100,
                          nproc=16)
  isp.perturb_data("path/to/model",
                   "path/to/input_data",
                   "path/to/output_directory",
                   "output_prefix")
"""

import logging

# imports
import os
import pickle
from collections import defaultdict

import seaborn as sns
import torch
from datasets import Dataset
from tqdm.auto import trange

from . import perturber_utils as pu
from .emb_extractor import get_embs
from .tokenizer import TOKEN_DICTIONARY_FILE

sns.set()


logger = logging.getLogger(__name__)


class InSilicoPerturber:
    valid_option_dict = {
        "perturb_type": {"delete", "overexpress", "inhibit", "activate"},
        "perturb_rank_shift": {None, 1, 2, 3},
        "genes_to_perturb": {"all", list},
        "combos": {0, 1},
        "anchor_gene": {None, str},
        "model_type": {"Pretrained", "GeneClassifier", "CellClassifier"},
        "num_classes": {int},
        "emb_mode": {"cell", "cell_and_gene"},
        "cell_emb_style": {"mean_pool"},
        "filter_data": {None, dict},
        "cell_states_to_model": {None, dict},
        "state_embs_dict": {None, dict},
        "max_ncells": {None, int},
        "cell_inds_to_perturb": {"all", dict},
        "emb_layer": {-1, 0},
        "forward_batch_size": {int},
        "nproc": {int},
    }

    def __init__(
        self,
        perturb_type="delete",
        perturb_rank_shift=None,
        genes_to_perturb="all",
        combos=0,
        anchor_gene=None,
        model_type="Pretrained",
        num_classes=0,
        emb_mode="cell",
        cell_emb_style="mean_pool",
        filter_data=None,
        cell_states_to_model=None,
        state_embs_dict=None,
        max_ncells=None,
        cell_inds_to_perturb="all",
        emb_layer=-1,
        forward_batch_size=100,
        nproc=4,
        token_dictionary_file=TOKEN_DICTIONARY_FILE,
    ):
        """
        Initialize in silico perturber.

        Parameters
        ----------
        perturb_type : {"delete","overexpress","inhibit","activate"}
            Type of perturbation.
            "delete": delete gene from rank value encoding
            "overexpress": move gene to front of rank value encoding
            "inhibit": move gene to lower quartile of rank value encoding
            "activate": move gene to higher quartile of rank value encoding
        perturb_rank_shift : None, {1,2,3}
            Number of quartiles by which to shift rank of gene.
            For example, if perturb_type="activate" and perturb_rank_shift=1:
                genes in 4th quartile will move to middle of 3rd quartile.
                genes in 3rd quartile will move to middle of 2nd quartile.
                genes in 2nd quartile will move to middle of 1st quartile.
                genes in 1st quartile will move to front of rank value encoding.
            For example, if perturb_type="inhibit" and perturb_rank_shift=2:
                genes in 1st quartile will move to middle of 3rd quartile.
                genes in 2nd quartile will move to middle of 4th quartile.
                genes in 3rd or 4th quartile will move to bottom of rank value encoding.
        genes_to_perturb : "all", list
            Default is perturbing each gene detected in each cell in the dataset.
            Otherwise, may provide a list of ENSEMBL IDs of genes to perturb.
            If gene list is provided, then perturber will only test perturbing them all together
            (rather than testing each possible combination of the provided genes).
        combos : {0,1}
            Whether to perturb genes individually (0) or in pairs (1).
        anchor_gene : None, str
            ENSEMBL ID of gene to use as anchor in combination perturbations.
            For example, if combos=1 and anchor_gene="ENSG00000148400":
                anchor gene will be perturbed in combination with each other gene.
        model_type : {"Pretrained","GeneClassifier","CellClassifier"}
            Whether model is the pretrained Geneformer or a fine-tuned gene or cell classifier.
        num_classes : int
            If model is a gene or cell classifier, specify number of classes it was trained to classify.
            For the pretrained Geneformer model, number of classes is 0 as it is not a classifier.
        emb_mode : {"cell","cell_and_gene"}
            Whether to output impact of perturbation on cell and/or gene embeddings.
            Gene embedding shifts only available as compared to original cell, not comparing to goal state.
        cell_emb_style : "mean_pool"
            Method for summarizing cell embeddings.
            Currently only option is mean pooling of gene embeddings for given cell.
        filter_data : None, dict
            Default is to use all input data for in silico perturbation study.
            Otherwise, dictionary specifying .dataset column name and list of values to filter by.
        cell_states_to_model : None, dict
            Cell states to model if testing perturbations that achieve goal state change.
            Four-item dictionary with keys: state_key, start_state, goal_state, and alt_states
            state_key: key specifying name of column in .dataset that defines the start/goal states
            start_state: value in the state_key column that specifies the start state
            goal_state: value in the state_key column taht specifies the goal end state
            alt_states: list of values in the state_key column that specify the alternate end states
            For example: {"state_key": "disease",
                          "start_state": "dcm",
                          "goal_state": "nf",
                          "alt_states": ["hcm", "other1", "other2"]}
        state_embs_dict : None, dict
            Embedding positions of each cell state to model shifts from/towards (e.g. mean or median).
            Dictionary with keys specifying each possible cell state to model.
            Values are target embedding positions as torch.tensor.
            For example: {"nf": emb_nf,
                          "hcm": emb_hcm,
                          "dcm": emb_dcm,
                          "other1": emb_other1,
                          "other2": emb_other2}
        max_ncells : None, int
            Maximum number of cells to test.
            If None, will test all cells.
        cell_inds_to_perturb : "all", list
            Default is perturbing each cell in the dataset.
            Otherwise, may provide a dict of indices of cells to perturb with keys start_ind and end_ind.
            start_ind: the first index to perturb.
            end_ind: the last index to perturb (exclusive).
            Indices will be selected *after* the filter_data criteria and sorting.
            Useful for splitting extremely large datasets across separate GPUs.
        emb_layer : {-1, 0}
            Embedding layer to use for quantification.
            0: last layer (recommended for questions closely tied to model's training objective)
            -1: 2nd to last layer (recommended for questions requiring more general representations)
        forward_batch_size : int
            Batch size for forward pass.
        nproc : int
            Number of CPU processes to use.
        token_dictionary_file : Path
            Path to pickle file containing token dictionary (Ensembl ID:token).
        """

        self.perturb_type = perturb_type
        self.perturb_rank_shift = perturb_rank_shift
        self.genes_to_perturb = genes_to_perturb
        self.combos = combos
        self.anchor_gene = anchor_gene
        if self.genes_to_perturb == "all":
            self.perturb_group = False
        else:
            self.perturb_group = True
            if (self.anchor_gene is not None) or (self.combos != 0):
                self.anchor_gene = None
                self.combos = 0
                logger.warning(
                    "anchor_gene set to None and combos set to 0. "
                    "If providing list of genes to perturb, "
                    "list of genes_to_perturb will be perturbed together, "
                    "without anchor gene or combinations."
                )
        self.model_type = model_type
        self.num_classes = num_classes
        self.emb_mode = emb_mode
        self.cell_emb_style = cell_emb_style
        self.filter_data = filter_data
        self.cell_states_to_model = cell_states_to_model
        self.state_embs_dict = state_embs_dict
        self.max_ncells = max_ncells
        self.cell_inds_to_perturb = cell_inds_to_perturb
        self.emb_layer = emb_layer
        self.forward_batch_size = forward_batch_size
        self.nproc = nproc

        self.validate_options()

        # load token dictionary (Ensembl IDs:token)
        with open(token_dictionary_file, "rb") as f:
            self.gene_token_dict = pickle.load(f)

        self.pad_token_id = self.gene_token_dict.get("<pad>")

        if self.anchor_gene is None:
            self.anchor_token = None
        else:
            try:
                self.anchor_token = [self.gene_token_dict[self.anchor_gene]]
            except KeyError:
                logger.error(f"Anchor gene {self.anchor_gene} not in token dictionary.")
                raise

        if self.genes_to_perturb == "all":
            self.tokens_to_perturb = "all"
        else:
            missing_genes = [
                gene
                for gene in self.genes_to_perturb
                if gene not in self.gene_token_dict.keys()
            ]
            if len(missing_genes) == len(self.genes_to_perturb):
                logger.error(
                    "None of the provided genes to perturb are in token dictionary."
                )
                raise
            elif len(missing_genes) > 0:
                logger.warning(
                    f"Genes to perturb {missing_genes} are not in token dictionary."
                )
            self.tokens_to_perturb = [
                self.gene_token_dict.get(gene) for gene in self.genes_to_perturb
            ]

    def validate_options(self):
        # first disallow options under development
        if self.perturb_type in ["inhibit", "activate"]:
            logger.error(
                "In silico inhibition and activation currently under development. "
                "Current valid options for 'perturb_type': 'delete' or 'overexpress'"
            )
            raise
        if (self.combos > 0) and (self.anchor_token is None):
            logger.error(
                "Combination perturbation without anchor gene is currently under development. "
                "Currently, must provide anchor gene for combination perturbation."
            )
            raise

        # confirm arguments are within valid options and compatible with each other
        for attr_name, valid_options in self.valid_option_dict.items():
            attr_value = self.__dict__[attr_name]
            if type(attr_value) not in {list, dict}:
                if attr_value in valid_options:
                    continue
                if attr_name in ["anchor_gene"]:
                    if type(attr_name) in {str}:
                        continue
            valid_type = False
            for option in valid_options:
                if (option in [bool, int, list, dict]) and isinstance(
                    attr_value, option
                ):
                    valid_type = True
                    break
            if valid_type:
                continue
            logger.error(
                f"Invalid option for {attr_name}. "
                f"Valid options for {attr_name}: {valid_options}"
            )
            raise

        if self.perturb_type in ["delete", "overexpress"]:
            if self.perturb_rank_shift is not None:
                if self.perturb_type == "delete":
                    logger.warning(
                        "perturb_rank_shift set to None. "
                        "If perturb type is delete then gene is deleted entirely "
                        "rather than shifted by quartile"
                    )
                elif self.perturb_type == "overexpress":
                    logger.warning(
                        "perturb_rank_shift set to None. "
                        "If perturb type is overexpress then gene is moved to front "
                        "of rank value encoding rather than shifted by quartile"
                    )
            self.perturb_rank_shift = None

        if (self.anchor_gene is not None) and (self.emb_mode == "cell_and_gene"):
            self.emb_mode = "cell"
            logger.warning(
                "emb_mode set to 'cell'. "
                "Currently, analysis with anchor gene "
                "only outputs effect on cell embeddings."
            )

        if self.cell_states_to_model is not None:
            pu.validate_cell_states_to_model(self.cell_states_to_model)

            if self.anchor_gene is not None:
                self.anchor_gene = None
                logger.warning(
                    "anchor_gene set to None. "
                    "Currently, anchor gene not available "
                    "when modeling multiple cell states."
                )

            if self.state_embs_dict is None:
                logger.error(
                    "state_embs_dict must be provided for mode with cell_states_to_model. "
                    "Format is dictionary with keys specifying each possible cell state to model. "
                    "Values are target embedding positions as torch.tensor."
                )
                raise

            for state_emb in self.state_embs_dict.values():
                if not torch.is_tensor(state_emb):
                    logger.error(
                        "state_embs_dict must be dictionary with values being torch.tensor."
                    )
                    raise

            keys_absent = []
            for k, v in self.cell_states_to_model.items():
                if (k == "start_state") or (k == "goal_state"):
                    if v not in self.state_embs_dict.keys():
                        keys_absent.append(v)
                if k == "alt_states":
                    for state in v:
                        if state not in self.state_embs_dict.keys():
                            keys_absent.append(state)
            if len(keys_absent) > 0:
                logger.error(
                    "Each start_state, goal_state, and alt_states in cell_states_to_model "
                    "must be a key in state_embs_dict with the value being "
                    "the state's embedding position as torch.tensor. "
                    f"Missing keys: {keys_absent}"
                )
                raise

        if self.perturb_type in ["inhibit", "activate"]:
            if self.perturb_rank_shift is None:
                logger.error(
                    "If perturb_type is inhibit or activate then "
                    "quartile to shift by must be specified."
                )
                raise

        if self.filter_data is not None:
            for key, value in self.filter_data.items():
                if not isinstance(value, list):
                    self.filter_data[key] = [value]
                    logger.warning(
                        "Values in filter_data dict must be lists. "
                        f"Changing {key} value to list ([{value}])."
                    )

        if self.cell_inds_to_perturb != "all":
            if set(self.cell_inds_to_perturb.keys()) != {"start", "end"}:
                logger.error(
                    "If cell_inds_to_perturb is a dictionary, keys must be 'start' and 'end'."
                )
                raise
            if (
                self.cell_inds_to_perturb["start"] < 0
                or self.cell_inds_to_perturb["end"] < 0
            ):
                logger.error("cell_inds_to_perturb must be positive.")
                raise

    def perturb_data(
        self, model_directory, input_data_file, output_directory, output_prefix
    ):
        """
        Perturb genes in input data and save as results in output_directory.

        Parameters
        ----------
        model_directory : Path
            Path to directory containing model
        input_data_file : Path
            Path to directory containing .dataset inputs
        output_directory : Path
            Path to directory where perturbation data will be saved as batched pickle files
        output_prefix : str
            Prefix for output files
        """

        ### format output path ###
        output_path_prefix = os.path.join(
            output_directory, f"in_silico_{self.perturb_type}_{output_prefix}"
        )

        ### load model and define parameters ###
        model = pu.load_model(self.model_type, self.num_classes, model_directory)
        self.max_len = pu.get_model_input_size(model)
        layer_to_quant = pu.quant_layers(model) + self.emb_layer

        ### filter input data ###
        # general filtering of input data based on filter_data argument
        filtered_input_data = pu.load_and_filter(
            self.filter_data, self.nproc, input_data_file
        )
        filtered_input_data = self.apply_additional_filters(filtered_input_data)

        if self.perturb_group is True:
            self.isp_perturb_set(
                model, filtered_input_data, layer_to_quant, output_path_prefix
            )
        else:
            self.isp_perturb_all(
                model, filtered_input_data, layer_to_quant, output_path_prefix
            )

    def apply_additional_filters(self, filtered_input_data):
        # additional filtering of input data dependent on isp mode
        if self.cell_states_to_model is not None:
            # filter for cells with start_state and log result
            filtered_input_data = pu.filter_data_by_start_state(
                filtered_input_data, self.cell_states_to_model, self.nproc
            )

        if (self.tokens_to_perturb != "all") and (self.perturb_type != "overexpress"):
            # filter for cells with tokens_to_perturb and log result
            filtered_input_data = pu.filter_data_by_tokens_and_log(
                filtered_input_data,
                self.tokens_to_perturb,
                self.nproc,
                "genes_to_perturb",
            )

        if self.anchor_token is not None:
            # filter for cells with anchor gene and log result
            filtered_input_data = pu.filter_data_by_tokens_and_log(
                filtered_input_data, self.anchor_token, self.nproc, "anchor_gene"
            )

        # downsample and sort largest to smallest to encounter memory constraints earlier
        filtered_input_data = pu.downsample_and_sort(
            filtered_input_data, self.max_ncells
        )

        # slice dataset if cells_inds_to_perturb is not "all"
        if self.cell_inds_to_perturb != "all":
            filtered_input_data = pu.slice_by_inds_to_perturb(
                filtered_input_data, self.cell_inds_to_perturb
            )

        return filtered_input_data

    def isp_perturb_set(
        self,
        model,
        filtered_input_data: Dataset,
        layer_to_quant: int,
        output_path_prefix: str,
    ):
        def make_group_perturbation_batch(example):
            example_input_ids = example["input_ids"]
            example["tokens_to_perturb"] = self.tokens_to_perturb
            indices_to_perturb = [
                example_input_ids.index(token) if token in example_input_ids else None
                for token in self.tokens_to_perturb
            ]
            indices_to_perturb = [
                item for item in indices_to_perturb if item is not None
            ]
            if len(indices_to_perturb) > 0:
                example["perturb_index"] = indices_to_perturb
            else:
                # -100 indicates tokens to overexpress are not present in rank value encoding
                example["perturb_index"] = [-100]
            if self.perturb_type == "delete":
                example = pu.delete_indices(example)
            elif self.perturb_type == "overexpress":
                example = pu.overexpress_tokens(example, self.max_len)
                example["n_overflow"] = pu.calc_n_overflow(
                    self.max_len,
                    example["length"],
                    self.tokens_to_perturb,
                    indices_to_perturb,
                )
            return example

        total_batch_length = len(filtered_input_data)
        if self.cell_states_to_model is None:
            cos_sims_dict = defaultdict(list)
        else:
            cos_sims_dict = {
                state: defaultdict(list)
                for state in pu.get_possible_states(self.cell_states_to_model)
            }

        perturbed_data = filtered_input_data.map(
            make_group_perturbation_batch, num_proc=self.nproc
        )
        if self.perturb_type == "overexpress":
            filtered_input_data = filtered_input_data.add_column(
                "n_overflow", perturbed_data["n_overflow"]
            )
            # remove overflow genes from original data so that embeddings are comparable
            # i.e. if original cell has genes 0:2047 and you want to overexpress new gene 2048,
            # then the perturbed cell will be 2048+0:2046 so we compare it to an original cell 0:2046.
            # (otherwise we will be modeling the effect of both deleting 2047 and adding 2048,
            # rather than only adding 2048)
            filtered_input_data = filtered_input_data.map(
                pu.truncate_by_n_overflow, num_proc=self.nproc
            )

        if self.emb_mode == "cell_and_gene":
            stored_gene_embs_dict = defaultdict(list)

        # iterate through batches
        for i in trange(0, total_batch_length, self.forward_batch_size):
            max_range = min(i + self.forward_batch_size, total_batch_length)
            inds_select = [i for i in range(i, max_range)]

            minibatch = filtered_input_data.select(inds_select)
            perturbation_batch = perturbed_data.select(inds_select)

            if self.cell_emb_style == "mean_pool":
                full_original_emb = get_embs(
                    model,
                    minibatch,
                    "gene",
                    layer_to_quant,
                    self.pad_token_id,
                    self.forward_batch_size,
                    summary_stat=None,
                    silent=True,
                )
                indices_to_perturb = perturbation_batch["perturb_index"]
                # remove indices that were perturbed
                original_emb = pu.remove_perturbed_indices_set(
                    full_original_emb,
                    self.perturb_type,
                    indices_to_perturb,
                    self.tokens_to_perturb,
                    minibatch["length"],
                )
                full_perturbation_emb = get_embs(
                    model,
                    perturbation_batch,
                    "gene",
                    layer_to_quant,
                    self.pad_token_id,
                    self.forward_batch_size,
                    summary_stat=None,
                    silent=True,
                )

                # remove overexpressed genes
                if self.perturb_type == "overexpress":
                    perturbation_emb = full_perturbation_emb[
                        :, len(self.tokens_to_perturb) :, :
                    ]

                elif self.perturb_type == "delete":
                    perturbation_emb = full_perturbation_emb[
                        :, : max(perturbation_batch["length"]), :
                    ]

                n_perturbation_genes = perturbation_emb.size()[1]

                # if no goal states, the cosine similarties are the mean of gene cosine similarities
                if (
                    self.cell_states_to_model is None
                    or self.emb_mode == "cell_and_gene"
                ):
                    gene_cos_sims = pu.quant_cos_sims(
                        perturbation_emb,
                        original_emb,
                        self.cell_states_to_model,
                        self.state_embs_dict,
                        emb_mode="gene",
                    )

                # if there are goal states, the cosine similarities are the cell cosine similarities
                if self.cell_states_to_model is not None:
                    original_cell_emb = pu.mean_nonpadding_embs(
                        full_original_emb,
                        torch.tensor(minibatch["length"], device="cuda"),
                        dim=1,
                    )
                    perturbation_cell_emb = pu.mean_nonpadding_embs(
                        full_perturbation_emb,
                        torch.tensor(perturbation_batch["length"], device="cuda"),
                        dim=1,
                    )
                    cell_cos_sims = pu.quant_cos_sims(
                        perturbation_cell_emb,
                        original_cell_emb,
                        self.cell_states_to_model,
                        self.state_embs_dict,
                        emb_mode="cell",
                    )

                # get cosine similarities in gene embeddings
                # if getting gene embeddings, need gene names
                if self.emb_mode == "cell_and_gene":
                    gene_list = minibatch["input_ids"]
                    # need to truncate gene_list
                    gene_list = [
                        [g for g in genes if g not in self.tokens_to_perturb][
                            :n_perturbation_genes
                        ]
                        for genes in gene_list
                    ]

                    for cell_i, genes in enumerate(gene_list):
                        for gene_j, affected_gene in enumerate(genes):
                            if len(self.genes_to_perturb) > 1:
                                tokens_to_perturb = tuple(self.tokens_to_perturb)
                            else:
                                tokens_to_perturb = self.tokens_to_perturb

                            # fill in the gene cosine similarities
                            try:
                                stored_gene_embs_dict[
                                    (tokens_to_perturb, affected_gene)
                                ].append(gene_cos_sims[cell_i, gene_j].item())
                            except KeyError:
                                stored_gene_embs_dict[
                                    (tokens_to_perturb, affected_gene)
                                ] = gene_cos_sims[cell_i, gene_j].item()
                else:
                    gene_list = None

            if self.cell_states_to_model is None:
                # calculate the mean of the gene cosine similarities for cell shift
                # tensor of nonpadding lengths for each cell
                if self.perturb_type == "overexpress":
                    # subtract number of genes that were overexpressed
                    # since they are removed before getting cos sims
                    n_overexpressed = len(self.tokens_to_perturb)
                    nonpadding_lens = [
                        x - n_overexpressed for x in perturbation_batch["length"]
                    ]
                else:
                    nonpadding_lens = perturbation_batch["length"]
                cos_sims_data = pu.mean_nonpadding_embs(
                    gene_cos_sims, torch.tensor(nonpadding_lens, device="cuda")
                )
                cos_sims_dict = self.update_perturbation_dictionary(
                    cos_sims_dict,
                    cos_sims_data,
                    filtered_input_data,
                    indices_to_perturb,
                    gene_list,
                )
            else:
                cos_sims_data = cell_cos_sims
                for state in cos_sims_dict.keys():
                    cos_sims_dict[state] = self.update_perturbation_dictionary(
                        cos_sims_dict[state],
                        cos_sims_data[state],
                        filtered_input_data,
                        indices_to_perturb,
                        gene_list,
                    )
            del minibatch
            del perturbation_batch
            del original_emb
            del perturbation_emb
            del cos_sims_data

            torch.cuda.empty_cache()

        pu.write_perturbation_dictionary(
            cos_sims_dict,
            f"{output_path_prefix}_cell_embs_dict_{self.tokens_to_perturb}",
        )

        if self.emb_mode == "cell_and_gene":
            pu.write_perturbation_dictionary(
                stored_gene_embs_dict,
                f"{output_path_prefix}_gene_embs_dict_{self.tokens_to_perturb}",
            )

    def isp_perturb_all(
        self,
        model,
        filtered_input_data: Dataset,
        layer_to_quant: int,
        output_path_prefix: str,
    ):
        pickle_batch = -1
        if self.cell_states_to_model is None:
            cos_sims_dict = defaultdict(list)
        else:
            cos_sims_dict = {
                state: defaultdict(list)
                for state in pu.get_possible_states(self.cell_states_to_model)
            }

        if self.emb_mode == "cell_and_gene":
            stored_gene_embs_dict = defaultdict(list)
        for i in trange(len(filtered_input_data)):
            example_cell = filtered_input_data.select([i])
            full_original_emb = get_embs(
                model,
                example_cell,
                "gene",
                layer_to_quant,
                self.pad_token_id,
                self.forward_batch_size,
                summary_stat=None,
                silent=True,
            )

            # gene_list is used to assign cos sims back to genes
            # need to remove the anchor gene
            gene_list = example_cell["input_ids"][0][:]
            if self.anchor_token is not None:
                for token in self.anchor_token:
                    gene_list.remove(token)

            perturbation_batch, indices_to_perturb = pu.make_perturbation_batch(
                example_cell,
                self.perturb_type,
                self.tokens_to_perturb,
                self.anchor_token,
                self.combos,
                self.nproc,
            )

            full_perturbation_emb = get_embs(
                model,
                perturbation_batch,
                "gene",
                layer_to_quant,
                self.pad_token_id,
                self.forward_batch_size,
                summary_stat=None,
                silent=True,
            )

            num_inds_perturbed = 1 + self.combos
            # need to remove overexpressed gene to quantify cosine shifts
            if self.perturb_type == "overexpress":
                perturbation_emb = full_perturbation_emb[:, num_inds_perturbed:, :]
                gene_list = gene_list[
                    num_inds_perturbed:
                ]  # index 0 is not overexpressed

            elif self.perturb_type == "delete":
                perturbation_emb = full_perturbation_emb

            original_batch = pu.make_comparison_batch(
                full_original_emb, indices_to_perturb, perturb_group=False
            )

            if self.cell_states_to_model is None or self.emb_mode == "cell_and_gene":
                gene_cos_sims = pu.quant_cos_sims(
                    perturbation_emb,
                    original_batch,
                    self.cell_states_to_model,
                    self.state_embs_dict,
                    emb_mode="gene",
                )
            if self.cell_states_to_model is not None:
                original_cell_emb = pu.compute_nonpadded_cell_embedding(
                    full_original_emb, "mean_pool"
                )
                perturbation_cell_emb = pu.compute_nonpadded_cell_embedding(
                    full_perturbation_emb, "mean_pool"
                )

                cell_cos_sims = pu.quant_cos_sims(
                    perturbation_cell_emb,
                    original_cell_emb,
                    self.cell_states_to_model,
                    self.state_embs_dict,
                    emb_mode="cell",
                )

            if self.emb_mode == "cell_and_gene":
                # remove perturbed index for gene list
                perturbed_gene_dict = {
                    gene: gene_list[:i] + gene_list[i + 1 :]
                    for i, gene in enumerate(gene_list)
                }

                for perturbation_i, perturbed_gene in enumerate(gene_list):
                    for gene_j, affected_gene in enumerate(
                        perturbed_gene_dict[perturbed_gene]
                    ):
                        try:
                            stored_gene_embs_dict[
                                (perturbed_gene, affected_gene)
                            ].append(gene_cos_sims[perturbation_i, gene_j].item())
                        except KeyError:
                            stored_gene_embs_dict[
                                (perturbed_gene, affected_gene)
                            ] = gene_cos_sims[perturbation_i, gene_j].item()

            if self.cell_states_to_model is None:
                cos_sims_data = torch.mean(gene_cos_sims, dim=1)
                cos_sims_dict = self.update_perturbation_dictionary(
                    cos_sims_dict,
                    cos_sims_data,
                    filtered_input_data,
                    indices_to_perturb,
                    gene_list,
                )
            else:
                cos_sims_data = cell_cos_sims
                for state in cos_sims_dict.keys():
                    cos_sims_dict[state] = self.update_perturbation_dictionary(
                        cos_sims_dict[state],
                        cos_sims_data[state],
                        filtered_input_data,
                        indices_to_perturb,
                        gene_list,
                    )

            # save dict to disk every 100 cells
            if i % 100 == 0:
                pu.write_perturbation_dictionary(
                    cos_sims_dict,
                    f"{output_path_prefix}_dict_cell_embs_1Kbatch{pickle_batch}",
                )
                if self.emb_mode == "cell_and_gene":
                    pu.write_perturbation_dictionary(
                        stored_gene_embs_dict,
                        f"{output_path_prefix}_dict_gene_embs_1Kbatch{pickle_batch}",
                    )

            # reset and clear memory every 1000 cells
            if i % 1000 == 0:
                pickle_batch += 1
                if self.cell_states_to_model is None:
                    cos_sims_dict = defaultdict(list)
                else:
                    cos_sims_dict = {
                        state: defaultdict(list)
                        for state in pu.get_possible_states(self.cell_states_to_model)
                    }

                if self.emb_mode == "cell_and_gene":
                    stored_gene_embs_dict = defaultdict(list)

                torch.cuda.empty_cache()

        pu.write_perturbation_dictionary(
            cos_sims_dict, f"{output_path_prefix}_dict_cell_embs_1Kbatch{pickle_batch}"
        )

        if self.emb_mode == "cell_and_gene":
            pu.write_perturbation_dictionary(
                stored_gene_embs_dict,
                f"{output_path_prefix}_dict_gene_embs_1Kbatch{pickle_batch}",
            )

    def update_perturbation_dictionary(
        self,
        cos_sims_dict: defaultdict,
        cos_sims_data: torch.Tensor,
        filtered_input_data: Dataset,
        indices_to_perturb: list[list[int]],
        gene_list=None,
    ):
        if gene_list is not None and cos_sims_data.shape[0] != len(gene_list):
            logger.error(
                f"len(cos_sims_data.shape[0]) != len(gene_list). \n \
                            cos_sims_data.shape[0] = {cos_sims_data.shape[0]}.\n \
                            len(gene_list) = {len(gene_list)}."
            )
            raise

        if self.perturb_group is True:
            if len(self.tokens_to_perturb) > 1:
                perturbed_genes = tuple(self.tokens_to_perturb)
            else:
                perturbed_genes = self.tokens_to_perturb[0]

            # if cell embeddings, can just append
            # shape will be (batch size, 1)
            cos_sims_data = torch.squeeze(cos_sims_data).tolist()

            # handle case of single cell left
            if not isinstance(cos_sims_data, list):
                cos_sims_data = [cos_sims_data]

            cos_sims_dict[(perturbed_genes, "cell_emb")] += cos_sims_data

        else:
            for i, cos in enumerate(cos_sims_data.tolist()):
                cos_sims_dict[(gene_list[i], "cell_emb")].append(cos)

        return cos_sims_dict