import pandas as pd
import numpy as np
import matplotlib.pyplot as plt


def analyze_tf_dynamics(patient_data):
    '''
    Analyze tumor fraction dynamics over treatment.

    Args:
        patient_data: DataFrame with columns [sample_id, timepoint, tumor_fraction, treatment_phase]
    '''
    # Sort by timepoint
    patient_data = patient_data.sort_values('timepoint')

    # Calculate log2 fold changes
    baseline_tf = patient_data.iloc[0]['tumor_fraction']
    patient_data['log2_fc'] = np.log2(patient_data['tumor_fraction'] / baseline_tf)

    # Calculate response metrics
    min_tf = patient_data['tumor_fraction'].min()
    min_timepoint = patient_data.loc[patient_data['tumor_fraction'].idxmin(), 'timepoint']

    metrics = {
        'baseline_tf': baseline_tf,
        'nadir_tf': min_tf,
        'nadir_timepoint': min_timepoint,
        'max_reduction': baseline_tf - min_tf,
        'log2_max_reduction': np.log2(baseline_tf / min_tf) if min_tf > 0 else np.inf
    }

    return patient_data, metrics


def define_response(tf_series, baseline, criteria='2log'):
    '''
    Define molecular response based on tumor fraction changes.

    Args:
        tf_series: Series of tumor fractions
        baseline: Baseline tumor fraction
        criteria: Response criteria (e.g., '2log' for 2-log reduction)
    '''
    if criteria == '2log':
        # 2-log (100-fold) reduction
        threshold = baseline / 100
    elif criteria == '1log':
        threshold = baseline / 10
    elif criteria == 'undetectable':
        threshold = 0.001  # Assay-dependent LOD

    response = tf_series < threshold
    return response

def track_mutations(mutation_data):
    '''
    Track specific mutations across timepoints.

    Args:
        mutation_data: DataFrame with [timepoint, mutation, vaf]
    '''
    # Pivot to get VAF per mutation per timepoint
    pivot = mutation_data.pivot_table(
        index='timepoint',
        columns='mutation',
        values='vaf',
        aggfunc='first'
    )

    # Calculate mean VAF trend
    pivot['mean_vaf'] = pivot.mean(axis=1)

    # Identify cleared mutations
    last_timepoint = pivot.index.max()
    cleared = []
    for mut in pivot.columns:
        if mut == 'mean_vaf':
            continue
        if pivot.loc[last_timepoint, mut] < 0.001 or pd.isna(pivot.loc[last_timepoint, mut]):
            cleared.append(mut)

    return pivot, cleared


def calculate_clearance_kinetics(mutation_data, mutation):
    '''
    Calculate mutation clearance half-life.
    '''
    mut_data = mutation_data[mutation_data['mutation'] == mutation].sort_values('timepoint')

    if len(mut_data) < 3:
        return None

    # Log-linear regression for exponential decay
    from scipy import stats

    x = mut_data['timepoint'].values
    y = np.log(mut_data['vaf'].values + 1e-6)  # Add small value to avoid log(0)

    slope, intercept, r_value, p_value, std_err = stats.linregress(x, y)

    # Half-life = ln(2) / |slope|
    half_life = np.log(2) / abs(slope) if slope < 0 else np.inf

    return {
        'mutation': mutation,
        'half_life': half_life,
        'slope': slope,
        'r_squared': r_value**2
    }

def detect_molecular_relapse(tf_series, baseline, threshold_increase=2):
    '''
    Detect molecular relapse from tumor fraction series.

    Args:
        tf_series: DataFrame with [timepoint, tumor_fraction]
        baseline: Post-treatment nadir
        threshold_increase: Fold-increase to call relapse
    '''
    tf_series = tf_series.sort_values('timepoint')

    # Find nadir
    nadir_idx = tf_series['tumor_fraction'].idxmin()
    nadir_tf = tf_series.loc[nadir_idx, 'tumor_fraction']
    nadir_time = tf_series.loc[nadir_idx, 'timepoint']

    # Check for increase after nadir
    post_nadir = tf_series[tf_series['timepoint'] > nadir_time]

    relapse_detected = False
    relapse_timepoint = None

    for idx, row in post_nadir.iterrows():
        if row['tumor_fraction'] > nadir_tf * threshold_increase:
            relapse_detected = True
            relapse_timepoint = row['timepoint']
            break

    return {
        'nadir_tf': nadir_tf,
        'nadir_timepoint': nadir_time,
        'relapse_detected': relapse_detected,
        'relapse_timepoint': relapse_timepoint
    }

def plot_ctdna_dynamics(patient_data, treatment_lines=None, output_file=None):
    '''
    Plot ctDNA dynamics over treatment.
    '''
    fig, ax = plt.subplots(figsize=(10, 6))

    # Plot tumor fraction on log scale
    ax.semilogy(patient_data['timepoint'], patient_data['tumor_fraction'],
                'o-', linewidth=2, markersize=8)

    # Add treatment lines
    if treatment_lines:
        for time, label in treatment_lines:
            ax.axvline(x=time, color='gray', linestyle='--', alpha=0.5)
            ax.text(time, ax.get_ylim()[1], label, rotation=90, va='top')

    ax.set_xlabel('Time (days)')
    ax.set_ylabel('Tumor Fraction')
    ax.set_title('ctDNA Dynamics During Treatment')

    # Add LOD line
    ax.axhline(y=0.01, color='red', linestyle=':', alpha=0.5, label='LOD')

    ax.legend()

    if output_file:
        plt.savefig(output_file, dpi=150, bbox_inches='tight')

    return fig, ax

def generate_monitoring_report(patient_id, tf_data, mutation_data, imaging_data=None):
    '''
    Generate clinical monitoring report.
    '''
    report = {
        'patient_id': patient_id,
        'analysis_date': pd.Timestamp.now()
    }

    # Tumor fraction analysis
    tf_data, tf_metrics = analyze_tf_dynamics(tf_data)
    report['tumor_fraction'] = tf_metrics

    # Mutation analysis
    mutation_pivot, cleared = track_mutations(mutation_data)
    report['mutations_tracked'] = len(mutation_pivot.columns) - 1
    report['mutations_cleared'] = len(cleared)

    # Response assessment
    current_tf = tf_data.iloc[-1]['tumor_fraction']
    baseline_tf = tf_data.iloc[0]['tumor_fraction']

    if current_tf < 0.001:
        report['response'] = 'Complete molecular response'
    elif current_tf < baseline_tf * 0.01:
        report['response'] = 'Major molecular response (>2 log)'
    elif current_tf < baseline_tf * 0.5:
        report['response'] = 'Partial molecular response'
    else:
        report['response'] = 'Stable/Progressive'

    return report